Triquilar 28 Product Monograph

Recent Major Label Changes

Not applicable

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Table of Contents .............................................................................................................. 2

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

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

4.4 Administration .................................................................................................................... 5

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

5 Overdose ........................................................................................................................ 8

6 Dosage, Strengths, Composition, and Packaging .............................................................. 8

7 Warnings and Precautions .............................................................................................. 9

General .................................................................................................................................... 9

Carcinogenesis and Genotoxicity ........................................................................................... 10

Cardiovascular ........................................................................................................................ 11

Driving and Operating Machinery .......................................................................................... 11

Endocrine and Metabolism .................................................................................................... 11

Gastrointestinal ...................................................................................................................... 11

Genitourinary ......................................................................................................................... 11

Hematologic ............................................................................................................................ 12

Hepatic/Biliary/Pancreatic...................................................................................................... 13

Immune .................................................................................................................................. 14

Monitoring and Laboratory Tests ........................................................................................... 14

Neurologic .............................................................................................................................. 14

Ophthalmologic ...................................................................................................................... 14

Perioperative Considerations ................................................................................................. 15

Psychiatric ............................................................................................................................... 15

Renal ....................................................................................................................................... 15

Reproductive Health ............................................................................................................... 15

Skin ......................................................................................................................................... 16

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

7.1.1 Pregnancy .................................................................................................................... 16

7.1.2 Breastfeeding .............................................................................................................. 16

7.1.3 Pediatrics ..................................................................................................................... 16

7.1.4 Geriatrics ..................................................................................................................... 16

8 Adverse Reactions ........................................................................................................ 16

8.1 Adverse Reaction Overview.............................................................................................. 16

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

8.3 Less Common Clinical Trial Adverse Reactions ................................................................ 19

9 Drug Interactions .......................................................................................................... 20

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

9.3 Drug-Behaviour Interactions ............................................................................................ 20

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

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

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

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

10 Clinical Pharmacology ................................................................................................. 25

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

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

10.3 Pharmacokinetics ........................................................................................................... 26

11 Storage, Stability, and Disposal ................................................................................... 28

Part 2: Scientific Information ........................................................................................... 29

13 Pharmaceutical Information ........................................................................................ 29

14 Clinical Trials ............................................................................................................... 31

14.1 Clinical Trials by Indication ............................................................................................. 31

16 Non-Clinical Toxicology ............................................................................................... 34

Patient Medication Information ...................................................................................... 38

Part 1: Health Professional Information

1 Indications

TRIQUILAR (levonorgestrel and ethinyl estradiol) is indicated for:

• Conception control

1.1 Pediatrics

Pediatrics (˂16 years of age): Based on the data submitted and reviewed by Health Canada, Health Canada has authorized an indication in women of reproductive age. TRIQUILAR is not indicated for use before menarche (see 7.1.3 Pediatrics).

1.2 Geriatrics

Geriatrics: TRIQUILAR is not indicated for use in postmenopausal women. No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 Contraindications

TRIQUILAR should not be used in women with:

• a history of or actual thrombophlebitis or thromboembolic disorders;
• a history of or actual cerebrovascular disorders;
• a history of or actual myocardial infarction or coronary artery disease;
• a history of or actual prodromi of a thrombosis (e.g., transient ischemic attack, angina pectoris)

• 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, if over age 35
  • diabetes mellitus with vascular involvement
  • major surgery associated with an increased risk of postoperative thromboembolism
  • prolonged immobilization
• valvular heart disease with complications;
• concomitant use of the Hepatitis C virus combination drug regimen ombitasvir, paritaprevir, ritonavir, with or without dasabuvir (see 7 Hepatic/Biliary/Pancreatic and 9.4 Drug-Drug Interactions);
• active liver disease, or history of or actual benign or malignant liver tumors;
• 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 hypertriglyceridemia;
• hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.

3 Serious Warnings and Precautions Box

• Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including TRIQUILAR, should not be used by women who are over 35 years of age and smoke. Women should be counselled not to smoke (see 7 Cardiovascular).
• Patients should be counselled that birth control pills DO NOT PROTECT against sexually transmitted infections (STIs) including HIV/AIDS. For protection against STIs, patients should be counselled to use latex or polyurethane condoms IN COMBINATION WITH birth control pills.>

4 Dosage and Administration

4.2 Recommended Dose and Dosage Adjustment

Take one tablet by mouth at the same time every day. The failure rate may increase when pills are missed or taken incorrectly.

It is recommended that TRIQUILAR tablets should be taken every day at about the same time regardless of mealtimes and as directed on the package.

4.4 Administration

Tablets must be taken in the order directed on the package every day at about the same time with some liquid as needed. The patient may begin using TRIQUILAR (levonorgestrel and ethinyl estradiol) on Day 1 of her menstrual cycle (i.e., the first day of menstrual flow), on Day 5, or on the first Sunday after her period begins. If the patient’s period begins on Sunday, she should start that same day. An additional (barrier) method of birth control is recommended for the first seven days of use.

TRIQUILAR 21 (21-day Regimen)

One tablet is to be taken daily for 21 consecutive days. Tablets are then discontinued for 7 consecutive days. Withdrawal bleeding usually occurs within 2 to 3 days following discontinuation.

The patient begins each subsequent course of TRIQUILAR 21 tablets on the same day of the week that she began her first course. She begins taking her next course on the 8th day after discontinuation, regardless of whether or not withdrawal bleeding is still in progress.

TRIQUILAR 28 (28-day Regimen)

Tablet taking is continuous. One tablet is to be taken daily for 28 consecutive days. Withdrawal bleeding usually occurs within 2 to 3 days of starting the placebo tablets (i.e., while the patient is taking the last row of the slightly larger, hormone-free white tablets).

The patient begins each subsequent course of TRIQUILAR 28 tablets on the same day of the week that she began her first course. She begins taking her next course immediately after completion of the last course, regardless of whether or not withdrawal bleeding is still in progress. There is no need for the patient to count days between cycles because there are no “off tablet days”.

Special Notes on Administration

Switching from Another Combined Hormonal Contraceptive (Combined Oral Contraceptive (COC), Vaginal Ring or Transdermal Patch)

The patient should start TRIQUILAR on the day she would normally start her next pack of combination oral contraceptives. In case a vaginal ring or transdermal patch has been used, the woman should start using TRIQUILAR 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) or from a Progestogen-releasing Intrauterine System (IUS)

The patient may switch from the mini-pill to TRIQUILAR on any day of her cycle. Patients using a progestogen injection should start TRIQUILAR on the day the next injection is due. Patients using an IUS should start TRIQUILAR on the day the IUS is removed. In all cases, the patient should be advised to use an additional (barrier) method for the first 7 days of TRIQUILAR use.

Following First Trimester Abortion

The patient may start using TRIQUILAR immediately. When doing so, she need not take additional contraceptive measures.

Following Delivery or Second Trimester Abortion

Patients should be advised to start TRIQUILAR on day 21 to 28 after delivery or second trimester abortion, after consulting with their physician. When starting later, the patient should be advised to use an additional (barrier) method for the first seven days of TRIQUILAR use. 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 next menstrual period prior to starting TRIQUILAR. When the tablets are administered in the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (see 7.1.2 Breastfeeding).

Withdrawal/Breakthrough Bleeding

Withdrawal bleeding usually occurs within 3 days following the last hormone-containing tablet. If spotting or breakthrough bleeding occurs while taking TRIQUILAR, the patient should be instructed to continue taking TRIQUILAR as instructed and by the regimen described above. She should be instructed that this type of bleeding is usually transient and without significance; however, if the bleeding is persistent or prolonged, the patient should be advised to consult her physician.

Although the occurrence of pregnancy is unlikely if TRIQUILAR 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 dosing schedule (missed one or more hormone-containing 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 before the medication is resumed. If the patient has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing the contraceptive regimen.

Advice in Case of Vomiting

If vomiting occurs within 3 to 4 hours after a tablet is taken, absorption may not be complete. In such an event, the advice concerning management of missed tablets is applicable.

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 (see Table 1). She should be told to match the number of tablets missed with the appropriate starting time for her dosing regimen. The risk of pregnancy increases with each hormone-containing light brown, white or ochreous tablet missed.

Table 1 - Management of Missed Hormone-containing Light Brown, White or Ochreous Tablets

Patients taking TRIQUILAR 28

If the patient forgets any of the seven slightly larger, hormone-free white tablets in Week 4, she should be advised to safely dispose of the tablets she missed, and then to keep taking one tablet each day until the pack is empty. A backup method of birth control is not required.

5 Overdose

Symptoms

With levonorgestrel and ethinyl estradiol, acute doses in excess of clinical levels, when administered to experimental animals, have been shown to have a minimal deleterious effect. In humans, however, the extent of ill effects to be expected following accidental ingestion of a large dose of any oral contraceptive has not been firmly established.

Overdosage may cause nausea and vomiting. Depending upon the amount ingested, liver toxicity, temporary interference with the function of the seminiferous tubules, or in the case of females, possible withdrawal bleeding within a few days of consumption, are theoretically possible. Withdrawal bleeding may even occur in girls before their menarche, if they have accidentally taken the medicinal product. Case histories of both male and female children, some of whom ingested more than half a month's supply of oral contraceptive pills, indicate that the effects are asymptomatic and without immediate consequence. Despite the frequency of nausea and vomiting in adult females during the first few cycles of use, none of these children presented such symptoms.

Treatment

There is no known antidote to overdosage. Treatment should be symptomatic, based on the knowledge of the pharmacological action of the constituents. Liver function tests should be conducted, particularly transaminase levels, 2 to 3 weeks after consumption.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 Dosage, Strengths, Composition, and Packaging

Table 2 – Dosage Forms, Strengths, and Composition

TRIQUILAR tablets are available in a 21 day regimen (TRIQUILAR 21) and a 28 day regimen (TRIQUILAR 28) in blister pack.

Each pack contains three different combinations of levonorgestrel [(-)-isomer of norgestrel] and ethinyl estradiol.

"TRIQUILAR 21"

Days 1 - 6

Each hormone-containing light brown tablet contains levonorgestrel 0.05 mg and ethinyl estradiol 0.03 mg.

Days 7 - 11

Each hormone-containing white tablet contains levonorgestrel 0.075 mg and ethinyl estradiol 0.04 mg.

Days 12 - 21

Each hormone-containing ochreous tablet contains levonorgestrel 0.125 mg and ethinyl estradiol 0.03 mg.

"TRIQUILAR 28"

Days 1 - 6

Each hormone-containing light brown tablet contains levonorgestrel 0.05 mg and ethinyl estradiol 0.03 mg.

Days 7 - 11

Each hormone-containing white tablet contains levonorgestrel 0.075 mg and ethinyl estradiol 0.04 mg.

Days 12 - 21

Each hormone-containing ochreous tablet contains levonorgestrel 0.125 mg and ethinyl estradiol 0.03 mg.

Days 22 - 28

Each slightly larger inert white tablet is hormone-free.

7 Warnings and Precautions

Please see 3 Serious Warnings and Precautions Box.

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, retinal thrombosis.
2. B. 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 7 Perioperative 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.

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

The use of combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia and gallbladder disease, although the risk of serious morbidity and mortality is small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly if associated with the presence of other risk factors such as hypertension, hyperlipidemias, obesity and diabetes. 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 COC’s 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 COCs with higher formulations of estrogens and progestogens than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestogen administered orally remains to be determined.

Carcinogenesis and Genotoxicity

Malignancies may be life-threatening or may have a fatal outcome.

Breast Cancer

The frequency of diagnosis of breast cancer is very slightly increased among COC users. As breast cancer is rare in women under 40 years of age, the excess number is small in relation to the overall risk of breast cancer. Causation with COC use is unknown.

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 8 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 contraceptives 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, drugs that contain estrogen may cause a rapid progression.

Cervical Cancer

The most important risk factor for cervical cancer is persistent human papillomavirus infection (HPV). Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour including use of barrier contraceptives.

Hepatocellular Carcinoma

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. 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 16 Non-Clinical Toxicology for discussion of animal data.

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, 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. For this reason, combination oral contraceptives, including TRIQUILAR, should not be used by women who are over 35 years of age and 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. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use.

Driving and Operating Machinery

No studies on the effects of TRIQUILAR 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 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 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. These events occur rarely.

The use of any combined oral contraceptive carries an increased risk of venous thromboembolism (VTE) compared with no use. The excess risk of VTE is highest during the first year a woman ever uses a combined oral contraceptive 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 life-threatening and is fatal in 1-2% 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 µg 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 woman-years in pregnant women or postpartum.

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

VTE, manifesting as deep venous thrombosis (DVT) and/or pulmonary embolism (PE), may occur during the use of all COCs.

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.

Symptoms of DVT can include: unilateral swelling of the leg or along a vein in the leg; pain or tenderness in the leg which may be felt only when standing or walking, increased warmth in the affected leg; red or discolored skin on the leg.

Symptoms of PE can include: sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may bring up blood; sharp chest pain which may increase with deep breathing; sense of anxiety; severe light headedness or dizziness; rapid or irregular heartbeat. Some of these symptoms (e.g., “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g., respiratory tract infections).

The risk for arterial thromboembolism (ATE) in users of oral contraceptives with low estrogen content (<50 µg ethinyl estradiol) ranges from about 1 to 3 cases per 10,000 woman-years. An arterial thromboembolic event can include cerebrovascular accident, vascular occlusion or myocardial infarction (MI). Symptoms of a cerebrovascular accident can include: sudden numbness or weakness of the face, arm, or leg., especially on one side of the body; sudden confusion, trouble speaking or understanding; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, loss of balance or coordination; sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity; acute abdomen.

Symptoms of MI can include: pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; discomfort radiating to the back, jaw, throat, arm, stomach; fullness, indigestion or choking feeling; sweating, nausea, vomiting or dizziness; extreme weakness, anxiety, or shortness of breath; rapid or irregular heartbeats.

Arterial thromboembolic events are life-threatening and may have a fatal outcome.

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 of 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 Activated Protein C (APC) resistance, hyperhomocysteinemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, 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 low-dose COCs (<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.

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 with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.

Hepatitis C

TRIQUILAR must be discontinued prior to starting therapy with the Hepatitis C virus (HCV) combination drug regimen ombitasvir, paritaprevir, ritonavir, with or without dasabuvir (see 2 Contraindications and 9.4 Drug-Drug Interactions). During clinical trials with ombitasvir, paritaprevir, ritonavir, with and without dasabuvir, ALT elevations 5 to >20 times the upper limit of normal (ULN) were significantly more frequent in healthy female subjects and HCV infected women using ethinyl estradiol-containing medications such as COCs. TRIQUILAR 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 angioedema, in particular in women with hereditary 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. 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

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

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained partial or complete loss of vision, onset of proptosis or diplopia, papilledema, or retinal vascular lesions. Appropriate diagnostic and therapeutic measures should be undertaken immediately.

Perioperative 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

• 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.

• Amenorhea

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

• Reduced Efficacy

The efficacy of COCs may be reduced in the event of missed tablets, gastrointestinal disturbances or concomitant medication (see 4 Dosage and Administration and 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 Pregnancy

Oral contraceptives should not be taken by pregnant women. If pregnancy occurs during treatment with TRIQUILAR, 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. Published studies have indicated that during lactation, 0.1% of the daily maternal dose of levonorgestrel and 0.02% of the daily maternal dose of ethinyl estradiol could be transferred to the newborn via milk. Adverse effects on the child have been reported, including jaundice and breast enlargement.

The nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child. There have been no formal studies of TRIQUILAR in nursing women.

7.1.3 Pediatrics

Pediatrics (˂16 years of age): Safety and efficacy of TRIQUILAR has not been established in women under the age of 16 years. Use of this product before menarche is not indicated.

7.1.4 Geriatrics

TRIQUILAR is not indicated for use in postmenopausal women. Oral contraceptives may mask the onset of the climacteric.

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 thromboembolic events
• being diagnosed with breast cancer
• 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 have also 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:

• abdominal pain
• amenorrhea during and after treatment
• angioedema (exogenous estrogens may induce or exacerbate symptoms of angioedema in women with hereditary angioedema)
• 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
• mental depression
• 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
• 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
• 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

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

The most frequently reported adverse events in the 8,748 patients (50,793 cycles) monitored during clinical trials have been tabulated below (see Table 3). The reported frequencies are the numbers of patients exhibiting a certain symptom per total number of cycles monitored.

Table 3 - Clinical Trial Adverse Drug Reactions with a Reported Frequency of >1%

In all studies, there was a decline in the incidence of symptoms with time. Most side effects were observed in the first three months of therapy, particularly such symptoms as nausea, dizziness, breast tension, headache and changes in libido occurred more frequently during Cycles 1 to 3 than during the pretreatment phase. However, from Cycles 4 to 24, the frequencies of all symptoms were lower than the pretreatment values.

8.3 Less Common Clinical Trial Adverse Reactions

General disorders and administration site condition: Edema

Investigations: Weight increased

Metabolism and nutrition disorders: Increased appetite

Reproductive system and breast disorders: Amenorrhea

Vascular disorders: Thrombophlebitis

Intermenstrual Bleeding

The incidence of intercyclic bleeding irregularities (defined as either spotting or breakthrough bleeding) was higher during the first cycle. The frequency of intercyclic bleeding episodes decreased with time, so that after the 12th cycle with TRIQUILAR bleeding irregularities were rarely encountered.

In the patient population studied, bleeding irregularities occurred during 8.5% of all cycles monitored. However, bleeding irregularities for those cycles associated with admitted pill errors were generally much higher (25.6%) (see Table 4). Overall the incidence of spotting was greater than that of breakthrough bleeding in most cycles.

Table 4 - Intermenstrual Bleeding

Spotting

Breakthrough Bleeding

Spotting & Breakthrough Bleeding

Pill error – 1211 cycles

187

(14.6%)

107

(9.0%)

27

(2.2%)

All cycles – 50,793 cycles

2946

(5.8%)

901

(1.8%)

455

(0.9%)

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 5 and Table 6). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before oral contraceptives are prescribed.

9.3 Drug-Behaviour Interactions

See 7 Driving and Operating Machinery. No studies on the effects of TRIQUILAR on the ability to drive or use machines have been performed.

9.4 Drug-Drug Interactions

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

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

Interactions can occur with drugs that induce microsomal enzymes which can result in increased clearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be sustained for about 4 weeks.

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase plasma concentrations of the estrogen or the progestin or both.

Several of the anti-HIV/HCV protease inhibitors (e.g., ritonavir, telaprevir, boceprevir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase or decrease) in the mean AUC of the estrogen or progestogen have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected. Healthcare professionals should refer to the label of the individual anti-HIV/HCV protease inhibitor for further drug-drug interaction information.

In vitro, ethinyl estradiol is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. In clinical studies, administration of a hormonal contraceptive containing ethinyl estradiol did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (e.g., theophylline) or moderately (e.g., melatonin and tizanidine).

Oral contraceptives may also interfere with the metabolism of other drugs (see Table 6). Accordingly, plasma and tissue concentrations may either increase (e.g., cyclosporine) or decrease (e.g., lamotrigine).

Table 6 - Modification of Other Drug Action by Oral Contraceptives

No formal drug-drug interaction studies have been conducted with TRIQUILAR.

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

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

9.7 Drug-Laboratory Test Interactions

Results of laboratory tests should be interpreted with the knowledge that the patient is on oral contraceptives. 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

Glucose tolerance may be 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

TRIQUILAR, a triphasic oral contraceptive, contains as active ingredients levonorgestrel and ethinyl estradiol. It acts primarily through the mechanism of gonadotrophin suppression by the estrogenic and progestational activity of the active ingredients. Although the primary activity is inhibition of ovulation, alterations in the genital tract, including changes in the cervical mucus (which make sperm penetration more difficult), and the endometrium (which reduce the likelihood of implantation) may also contribute to contraceptive effectiveness.

Levonorgestrel has been evaluated extensively in women to assess its progestational activity.

In women, the endometrium is transformed by the oral administration of 2.5 mg levonorgestrel given over a period of 10 days (total dose after pretreatment with estrogen). The endometrial transformation dose is 250 μg/day, corresponding to 5 μg/kg.

Levonorgestrel at a dose of 125 μg/day was also shown to be twice as potent as norethindrone in the delay of menstruation test by "Swyer and Greenblatt".

10.2 Pharmacodynamics

Effects on central and peripheral function before, during and after the use of TRIQUILAR were evaluated in 5 women.

The first and third cycles under TRIQUILAR differed considerably from the control cycle. Serum LH values remained at the level of the early follicular phase as a sign of central inhibitory effect, furthermore there was no increase at mid-cycle.

The 17 β-estradiol also failed to peak and serum progesterone reflected the absence of ovulation. As a result, cervical function was limited, the spinnbarkeit and degree of crystallization of the secretion were greatly reduced. The Caryopyknotic index ran in waves to achieve 25%. Finally, the basal body temperature increased as a result of the thermogenic effect of the progesterone, although this occurred later and more slowly than with preparations which contain a higher dose of progesterone in the first half of the cycle.

Upon discontinuation of TRIQUILAR after the third cycle of use, the serum values of LH, 17 β-estradiol and progesterone again displayed all signs of a normal ovulatory cycle pattern.

Overall the study results confirm that ovulation is inhibited and a distinct antifertile effect is exerted in the peripheral cycle function during therapy with TRIQUILAR.

10.3 Pharmacokinetics

Levonorgestrel

Absorption:

Orally administered levonorgestrel is rapidly and completely absorbed. Following single ingestion of 0.125 mg levonorgestrel together with 0.03 mg ethinyl estradiol (which represents the combination with the highest levonorgestrel content of the triphasic formulation), peak serum concentrations of 4.3 ng/mL are reached at about one hour after single ingestion. Levonorgestrel is almost completely bioavailable after oral administration.

Distribution:

Levonorgestrel is bound to serum albumin and to sex hormone binding globulin (SHBG). Only 1.4% of the total serum drug concentrations are present as free steroid, 55% are specifically bound to SHBG and about 44% are non-specifically bound to albumin. The ethinyl estradiol induced increase in SHBG influences the proportion of levonorgestrel bound to the serum proteins, causing an increase of the SHBG-bound fraction and a decrease of the albumin-bound fraction. The volume of distribution of levonorgestrel (Vz) is about 128 L after single oral administration of the highest levonorgestrel dose of TRIQUILAR.

Metabolism:

Levonorgestrel is extensively metabolized. The major metabolites in plasma are the unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel. Based on in vitro and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel. The clearance rate from serum is approximately 1.0 mL/min/kg.

Elimination:

Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is characterized by a half-life of approximately 22 hours. Levonorgestrel is not excreted in unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. The half-life of metabolite excretion is about 1 day.

Steady-state Conditions

Levonorgestrel pharmacokinetics are influenced by SHBG levels, which are increased about twofold during the 21-day treatment period with TRIQUILAR. Following daily ingestion drug serum levels increase about fourfold as compared to single oral administration of the highest levonorgestrel dose of TRIQUILAR, reaching steady-state conditions during the second half of a treatment cycle. At steady-state, the volume of distribution and the clearance rate are reduced to 52 L and 0.5 mL/min/kg, respectively, as compared to single oral administration of the highest levonorgestrel dose of TRIQUILAR.

Ethinyl Estradiol

Absorption:

Orally administered ethinyl estradiol is rapidly and completely absorbed. Peak serum concentrations of about 116 pg/mL are reached within 1.3 hours after single oral ingestion of 0.03 mg ethinyl estradiol in combination with 0.125 mg levonorgestrel. During absorption and first liver passage, ethinyl estradiol is metabolized extensively, resulting in a mean oral bioavailability of about 45% with a large inter-individual variation of about 20-65%.

Distribution:

Ethinyl estradiol is highly but non-specifically bound to serum albumin (approximately 95-98%), and induces an increase in the serum concentrations of SHBG. An apparent volume of distribution of about 2.8-8.6 L/kg was reported after intravenous administration.

Metabolism:

Ethinyl estradiol is subject to presystemic conjugation in both small bowel mucosa and the liver. Ethinyl estradiol is primarily metabolized by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed, and these are present as free metabolites and as conjugates with glucuronides and sulfate. The clearance rate was reported to be 2.3 - 7 mL/min/kg after intravenous administration.

Elimination:

Ethinyl estradiol serum levels decrease in two disposition phases characterized by half-lives of about 1 hour and 10-20 hours, respectively. Unchanged drug is not excreted. Ethinyl estradiol metabolites are excreted at a urinary to biliary ratio of 4:6 with a half-life of about 1 day.

Steady-state Conditions

According to the variable half-life of the terminal disposition phase from serum, and the daily ingestion, steady-state serum levels of ethinyl estradiol will be reached after about one week. After three cycles, the maximum ethinyl estradiol concentration of about 132 pg/mL is reached after about 1.3 h.

Special populations and conditions

• Pediatrics (<16 years of age): There is no PK data available. Use of this product before menarche is not indicated.
• Geriatrics: There is no PK data available. TRIQUILAR is not indicated for use in postmenopausal women. Oral contraceptives may mask the onset of the climacteric.

• Pregnancy and breastfeeding

  • Pregnancy: TRIQUILAR is not indicated for use in pregnancy (see 2 Contraindications and 7.1.1 Pregnancy).
  • Breastfeeding: 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 (see 7.1.2 Breastfeeding).
• Hepatic Insufficiency: TRIQUILAR is contraindicated in women with active liver diseases (see 2 Contraindications).
• Renal Insufficiency: TRIQUILAR has not been specifically studied in renally impaired patients. Available data do not suggest a change in treatment in this patient population.

11 Storage, Stability, and Disposal

Store in original packaging between 15°C and 30°C. Keep out of reach of children and pets.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Levonorgestrel

Non-proprietary name of the drug substance:

Levonorgestrel

Chemical name:

18,19-Dinorpregn-4-en-20-yn-3-one,13-ethyl-17-hydroxy-,(17α)-(-)

Molecular formula:

C21 H28 O2

Structural formula:

Molecular weight:

312.45

Solubility: (USP Classification):

Slightly soluble in alcohol; insoluble in water.

Melting points:

234°C - 240°C

Biological properties:

This entire synthetic progestogen is the (-)-isomer of norgestrel. It is the active form of the racemic norgestrel.

Ethinyl estradiol

Non-proprietary name of the drug substance:

Ethinyl estradiol

Chemical name:

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

Molecular formula:

C20 H24 O2

Structural formula:

Molecular weight:

296.41

Solubility: (USP Classification):

Insoluble in water; soluble in alcohol, chloroform, ether, vegetable oil, and in alkaline solutions.

Melting points:

80°C - 186°C

Biological properties:

synthetic estrogen.

14 Clinical Trials

14.1 Clinical Trials by Indication

The safety and efficacy of TRIQUILAR were evaluated in eight multicentre, controlled and open clinical trials. The studies were carried out in eleven different countries in Europe and South America.

Two of the studies were controlled, double-blind comparisons of TRIQUILAR versus a monophasic oral contraceptive containing levonorgestrel 150 mcg and ethinyl estradiol 50 mcg. The third study was a double-blind comparison of TRIQUILAR with a monophasic oral contraceptive containing desogestrel 150 mcg and ethinyl estradiol 30 mcg. The remaining five studies were large open evaluations, including a German Phase IV study comprising some 6271 women. A total of 8748 women were included in the studies. All subjects were healthy women of whom the majority had a history of regular menstrual periods. Women with existing or previous contraindications to oral contraceptives were excluded from participating in the trials. A description of the trials is shown in Table 7. Nearly 80% of the women were in the <20 or 20-29 age brackets. The remainder were in their 30’s and 40’s.

Table 7 - Summary of Patient Demographics in TRIQUILAR Pivotal Clinical Efficacy Trials

¹ The total number of subjects (9025) includes those in the TRIQUILAR group (8748 subjects) plus the 277 subjects who were on another treatment in Study 81182

Study Results

In all studies, women were treated with TRIQUILAR for at least six cycles. As shown in Table 8, a total of 6673 patients were treated and monitored for six cycles with TRIQUILAR. In five of the eight studies, women were monitored for up to 12 cycles, and in one study, 54 women were followed for 24 cycles. A total of 50,793 individual cycles were monitored in the course of the eight studies.

Table 8 – Duration of Treatment (Cycles)

The rate of discontinuation of TRIQUILAR during the trials was carefully assessed. The overall dropout rate was 28%. However, the rate varied considerably from study to study, the lowest rate being 11% and the highest 33%.

Twelve percent (12%) of the patients discontinued for medical reasons and 16% for nonmedical reasons. The most common medical reasons given for dropping out of the trials were headaches, nausea and vomiting, and breakthrough bleeding.

The dropout rate for medical as well as nonmedical reasons was greatly reduced after the 6th cycle.

Table 9 – Discontinuation During the First 6 Cycles

In all studies there were patients that admitted to tablet omissions as shown in Table 10. Tablet error was admitted in 1211 cycles during TRIQUILAR administration (2.4%).

Table 10 – Tablet Error - Cycles

As shown in Table 11, a total of 21 pregnancies were recorded in the eight studies. Ten of these were considered due to patient failure (errors); however, the remaining eleven pregnancies were considered to be method failures. The results of the Lifetable Analysis and the Pearl Index are presented in Table 12.

Table 11 – Pregnancy

Table 12 – Overall Pregnancy Rate

In the large Phase IV multicentre study, there were ten reported pregnancies (method failure). The Pearl Index for this study was 0.4 and the Lifetable Analysis was 0.69.

In the other seven studies, comprising of 2,477 women treated for 22,155 cycles, there was just one method failure pregnancy. The Pearl Index resulting from these studies was 0.06 or approximately five times lower.

Endometrial biopsies obtained at variable times during the cycle were assessed according to the criteria of Noyes. Overall it was shown that this triphasic contraceptive causes a moderate degree of endometrial proliferation during the first phase, followed by premature secretory changes in the second phase, and minimal but continued development and maturation in the third phase that do not approach those seen in a normal cycle.

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.

Table 13 – Reported Pregnancies per 100 Women per Year

16 Non-Clinical Toxicology

Levonorgestrel

Levonorgestrel is a 19-nortestosterone derivative. Investigations with animals (rabbits, rats, mice) and man have shown it to be a very potent progestogen.

In rabbits (Clauberg test), evidence of transformation changes of the endometrium is found after subcutaneous administration of 0.01 mg levonorgestrel, corresponding to 2 μg/kg/day. Transformative effects are also histologically recognisable in the rabbit endometrium when levonorgestrel is administered orally in doses ranging from 0.03 to 0.3 mg/animal, corresponding to approximately 6 to 60 μg/kg/day.

In pregnant rats ovariectomised in the first 4 days after conception, the subcutaneous administration of levonorgestrel of 0.002 mg had a blastocyst-maintaining effect. The anti-estrogenic or progestogenic activity of levonorgestrel has also been demonstrated in various test models in rats and mice. The potency of levonorgestrel is significantly higher than progesterone and about 83 times stronger than chlormadinone acetate.

Levonorgestrel has not demonstrated any estrogenic activity and androgenic effects are only in evidence after large doses. Levonorgestrel also influences the gonadotropic partial function of the anterior lobe of the pituitary gland in all experimental tests (testes inhibition test, parabiosis test, inhibition of ovulation test).

Like other progestogens, relative large doses of levonorgestrel also leads to increases in insulin secretion in rats and dogs.

Ethinyl Estradiol

Ethinyl estradiol is a potent estrogen with qualities similar to estradiol in its oral efficacy. However, the relative oral potency is 3 - 30 times greater than estradiol in peripheral estrogenic effects, antigonadotropic effects and inhibition of ovulation and antifertility effects.

Ethinyl estradiol also exhibited the effects on carbohydrate and lipid metabolism similar to other estrogens, i.e., hepatic glycogen content was greatly increased, total glycerin in the serum was increased, serum cholesterol decreased. Phospholipids were also raised after 1 month's treatment.

The effect of ethinyl estradiol on carbohydrate and lipid metabolism also indicates an estrogenic effect on the pituitary/adrenal cortex system, such as increased secretion of ACTH and possibly somatotrophic hormone (STH).

Ethinyl Estradiol/Levonorgestrel

The estrogen/progestogen combinations which have been used in women in ratios varying between (1:1.67 to 1:4.17) are not optimal for use in laboratory testing in animals.

In animals (rats and rabbits) the relative estrogen doses are much lower than the required progestogen doses i.e., the optimal estrogen/progestogen doses are further apart. If an estrogen/progestogen combination which is optimal in women is tested in animals the progestogen compound has no or hardly any effect. Thus in the ovulation inhibiting test in the rat the orally effective dose range of ethinyl estradiol is between 30 and 300 μg/animal/day.

Levonorgestrel on the other hand is only slightly effective at dose of 3 mg/animal/day.

In the implantation inhibiting test in the rat, ethinyl estradiol produces a dose-related inhibition of nidation in an oral dose range between 7.6 and 11.4 μg/animal/day. In this test levonorgestrel does not show inhibiting effect below a dose of 2.5 mg/animal/day. In the testes inhibiting test in the rat 0.25 μg/animal/day, ethinyl estradiol (oral) is sufficient to significantly reduce the testicular weight. Levonorgestrel on the other hand has hardly any effect even in the high dose of 125 μg/animal/day orally.

Chronic toxicity

Table 14: – Chronic Toxicity Studies