TRIQUILAR 28 TABLET

Canada - English - Health Canada

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Active ingredient:
LEVONORGESTREL; ETHINYL ESTRADIOL; ETHINYL ESTRADIOL; LEVONORGESTREL; ETHINYL ESTRADIOL; LEVONORGESTREL
Available from:
BAYER INC
ATC code:
G03AB03
INN (International Name):
LEVONORGESTREL AND ESTROGEN
Dosage:
125MCG; 30MCG; 40MCG; 50MCG; 30MCG; 75MCG
Pharmaceutical form:
TABLET
Composition:
LEVONORGESTREL 125MCG; ETHINYL ESTRADIOL 30MCG; ETHINYL ESTRADIOL 40MCG; LEVONORGESTREL 50MCG; ETHINYL ESTRADIOL 30MCG; LEVONORGESTREL 75MCG
Administration route:
ORAL
Units in package:
28
Prescription type:
Prescription
Therapeutic area:
CONTRACEPTIVES
Product summary:
Active ingredient group (AIG) number: 0618648001; AHFS: 68:12.00
Authorization status:
APPROVED
Authorization number:
00707503
Authorization date:
2007-03-08

Documents

TRIQUILAR Product Monograph

Page 1 of 54

PRODUCT MONOGRAPH

Pr

TRIQUILAR

®

21

Pr

TRIQUILAR

®

28

0.05 mg levonorgestrel and 0.03 mg ethinyl estradiol tablets

0.075 mg levonorgestrel and 0.04 mg ethinyl estradiol tablets

0.125 mg levonorgestrel and 0.03 mg ethinyl estradiol tablets

Oral Contraceptive

Bayer Inc.

2920 Matheson Boulevard East

Mississauga, Ontario

L4W 5R6

www.bayer.ca

Date of Revision:

May 26, 2017

Submission Control No: 202824

© 2017, Bayer Inc.

® TM see www.bayer.ca/tm-mc

TRIQUILAR Product Monograph

Page 2 of 54

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ..........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................3

WARNINGS AND PRECAUTIONS ..................................................................................4

ADVERSE REACTIONS ..................................................................................................13

DRUG INTERACTIONS ..................................................................................................17

DOSAGE AND ADMINISTRATION ..............................................................................23

OVERDOSAGE ................................................................................................................26

ACTION AND CLINICAL PHARMACOLOGY ............................................................27

STORAGE AND STABILITY ..........................................................................................30

SPECIAL HANDLING INSTRUCTIONS .......................................................................30

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................30

PART II: SCIENTIFIC INFORMATION ...............................................................................32

PHARMACEUTICAL INFORMATION ..........................................................................32

CLINICAL TRIALS ..........................................................................................................33

DETAILED PHARMACOLOGY .....................................................................................36

TOXICOLOGY .................................................................................................................38

REFERENCES ..................................................................................................................41

PART III: CONSUMER INFORMATION ..............................................................................46

TRIQUILAR Product Monograph

Page 3 of 54

Pr

TRIQUILAR

®

21

Pr

TRIQUILAR

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levonorgestrel and ethinyl estradiol

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Table 1: Product Information Summary

Route of

Administration

Dosage Form / Strength

Clinically Relevant

Nonmedicinal Ingredients

Oral

0.05 mg levonorgestrel and 0.03 mg ethinyl estradiol tablets

0.075 mg levonorgestrel and 0.04 mg ethinyl estradiol tablets

0.125 mg levonorgestrel and 0.03 mg ethinyl estradiol tablets

Lactose monohydrate.

For a complete listing see

DOSAGE FORMS,

COMPOSITION AND

PACKAGING section.

INDICATIONS AND CLINICAL USE

TRIQUILAR (levonorgestrel and ethinyl estradiol) is indicated for:

Conception control

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 (eg, 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 (eg, 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

TRIQUILAR Product Monograph

Page 4 of 54

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 WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic and DRUG INTERACTIONS, Drug-Drug Interactions);

active liver disease, or history of or actual benign or malignant liver tumours;

known or suspected carcinoma of the breast;

carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia;

undiagnosed abnormal vaginal bleeding;

steroid-dependent jaundice, cholestatic jaundice, history of jaundice of pregnancy;

any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss

of vision, or defect in visual fields;

known or suspected pregnancy;

current or history of migraine with focal aura;

history of or actual pancreatitis if associated with severe hypertriglyceridemia;

hypersensitivity to this drug or to any ingredient in the formulation or component of the

container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND

PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels.

This risk increases with age, 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 WARNINGS AND PRECAUTIONS -

Cardiovascular section below).

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.

>

General

Discontinue Medication at the Earliest Manifestation of:

A. Thromboembolic and cardiovascular disorders such as, thrombophlebitis, pulmonary

embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis,

retinal thrombosis.

TRIQUILAR Product Monograph

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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 WARNINGS

AND PRECAUTIONS - Peri-operative Considerations.

C. Visual defects, partial or complete.

D. Papilledema, or ophthalmic vascular lesions.

E.

Severe headache of unknown etiology or worsening of pre-existing migraine headache.

F.

Increase in epileptic seizures.

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

The use of combination hormonal contraceptives is associated with increased risks of several

serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia

and gallbladder disease, although the risk of serious morbidity and mortality is small in healthy

women without underlying risk factors. The risk of morbidity and mortality increases

significantly if associated with the presence of other risk factors such as hypertension,

hyperlipidemias, obesity and diabetes. Other medical conditions which have been associated

with adverse circulatory events include, systemic lupus erythematosus, (1) hemolytic uremic

syndrome, (2-5) chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis), (6,

7) sickle cell disease, (8) valvular heart disease and atrial fibrillation (9, 10).

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, (11) systemic lupus erythematosus, (12) hemolytic uremic syndrome, (2) Sydenham’s

chorea, (13, 14) herpes gestationis, (15, 16) and otosclerosis-related hearing loss (17).

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 Mutagenesis

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

TRIQUILAR Product Monograph

Page 6 of 54

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, eg, cervical screening and sexual behaviour

including use of barrier contraceptives. (18)

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 Product Monograph Part II: PART II: SCIENTIFIC INFORMATION: TOXICOLOGY,

Chronic Toxicity 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.

TRIQUILAR Product Monograph

Page 7 of 54

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.

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

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. (19-24)

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.

TRIQUILAR Product Monograph

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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 (eg, 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 (eg, “shortness of breath”, “coughing”) are non-specific and

might be misinterpreted as more common or less severe events (eg, respiratory tract infections).

TRIQUILAR Product Monograph

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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/m

), 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.

TRIQUILAR Product Monograph

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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

CONTRAINDICATIONS and DRUG INTERACTIONS, 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. (25-27)

TRIQUILAR Product Monograph

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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 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.

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.

TRIQUILAR Product Monograph

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Sexual Function/Reproduction

Return to 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, 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 DOSAGE AND ADMINISTRATION and

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.

Special Populations

Pregnant Women

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.

TRIQUILAR Product Monograph

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Nursing Women

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. (28) Published studies have

indicated that during lactation, 0.1% of the daily maternal dose of levonorgestrel (29) and 0.02%

of the daily maternal dose of ethinyl estradiol (30) 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.

Pediatrics

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.

Geriatrics

TRIQUILAR is not indicated for use in postmenopausal women. Oral contraceptives may mask

the onset of the climacteric.

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 (eg, 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.

ADVERSE REACTIONS

Adverse Drug 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

TRIQUILAR Product Monograph

Page 14 of 54

cerebral hemorrhage

cerebral thrombosis

congenital anomalies

gallbladder disease

hypertension

mesenteric thrombosis

myocardial infarction

neuro-ocular lesions (eg, 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

TRIQUILAR Product Monograph

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gallstone formation

gastrointestinal symptoms (such as abdominal cramps and bloating)

headache

hemolytic uremic syndrome

hemorrhagic eruption

herpes gestationis

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

liver function disturbances

loss of scalp hair

migraine

nervousness

optic neuritis

otosclerosis-related hearing loss

pancreatitis

porphyria

possible diminution in lactation when given immediately postpartum

premenstrual-like syndrome

pruritus related to cholestasis

rash (allergic)

Raynaud’s phenomenon

reduced tolerance to carbohydrates

retinal thrombosis

rhinitis

spotting

Sydenham’s chorea

Systemic lupus erythematosus

temporary infertility after discontinuation of treatment

ulcerative colitis

urticaria

vaginal candidiasis

vaginal discharge

vaginitis

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

TRIQUILAR Product Monograph

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Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates

observed in the clinical trials may not reflect the rates observed in practice and should not be

compared to the rates in the clinical trials of another drug. Adverse drug reaction information

from clinical trials is useful for identifying drug-related adverse events and for approximating

rates.

The most frequently reported adverse events in the 8,748 patients (50,793 cycles) monitored

during clinical trials have been tabulated below (see Table 2). The reported frequencies are the

numbers of patients exhibiting a certain symptom per total number of cycles monitored.

Table 2: Clinical Trial Adverse Drug Reactions with a Reported Frequency of >1%

Adverse Events

Frequency of Observations per Cycle (%)

Gastrointestinal disorders

Nausea and/or vomiting

Nervous system disorders

Headache

Migraine

Psychiatric disorders

Libido, increase-decrease

Depression

Reproductive system and breast disorders

Dysmenorrhea

Spotting

Breast tension or pain

Breakthrough bleeding

Skin and subcutaneous tissue disorders

Acne

Chloasma

Vascular disorders

Varicose veins

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.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

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

TRIQUILAR Product Monograph

Page 17 of 54

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 12

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 3). Overall the incidence of spotting was greater

than that of breakthrough bleeding in most cycles.

Table 3: Intermenstrual Bleeding

Spotting

Breakthrough Bleeding

Spotting & Breakthrough Bleeding

Pill error – 1211 cycles

187 (14.6%)

(9.0%)

(2.2%)

All cycles – 50,793 cycles

2946

(5.8%)

(1.8%)

(0.9%)

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 4 and Table 5).

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.

Drug-Drug Interactions

Table 4: Drugs Which May Decrease the Efficacy of Oral Contraceptives

Class of

Compound

Drug

Proposed Mechanism

Suggested Management

Antacids

Decreased intestinal absorption of

progestins.

Dose two hours apart.

Antibiotics (31, 32)

Ampicillin

Cotrimoxazole

Penicillin

Enterohepatic circulation

disturbance, intestinal hurry.

For short course, use additional

non-hormonal method of

contraception or use another

drug. For long course, use

another non-hormonal method

of contraception.

Rifampin

Rifabutin

Increased metabolism of

progestins. Suspected acceleration

of estrogen metabolism.

Use another non-hormonal

method of contraception.

Chloramphenicol

Metronidazole

Neomycin

Nitrofurantoin

Sulfonamides

Tetracyclines

Induction of hepatic microsomal

enzymes. Also disturbance of

enterohepatic circulation.

For short course, use additional

non-hormonal method of

contraception or use another

drug. For long course, use

another non-hormonal method

of contraception.

TRIQUILAR Product Monograph

Page 18 of 54

Table 4: Drugs Which May Decrease the Efficacy of Oral Contraceptives

Class of

Compound

Drug

Proposed Mechanism

Suggested Management

Troleandomycin

May retard metabolism of oral

contraceptives, increasing the risk

of cholestatic jaundice.

Anticonvulsants

(33-39)

Carbamazepine

Ethosuximide

Felbamate

Lamotrigine

Oxcarbazepine

Phenobarbital

Phenytoin

Primidone

Topiramate

Induction of hepatic microsomal

enzymes. Rapid metabolism of

estrogen and increased binding of

progestin and ethinyl estradiol to

SHBG.

Use higher dose oral

contraceptives (50 μg ethinyl

estradiol), another drug or

another non-hormonal method

of contraception.

Antifungals (40)

Griseofulvin

Stimulation of hepatic metabolism

of contraceptive steroids may

occur.

Use another non-hormonal

method of contraception.

Cholesterol

Lowering Agents

Clofibrate

Reduces elevated serum

triglycerides and cholesterol; this

reduces oral contraceptive

efficacy.

Use another non-hormonal

method of contraception.

HCV Protease

Inhibitors

Boceprevir

Telaprevir

Remains to be confirmed.

Use another drug or another

non-hormonal method of

contraception.

HIV Protease

Inhibitors (41)

Ritonavir

Induction of hepatic microsomal

enzymes.

Use another drug or another

non-hormonal method of

contraception.

Non-nucleoside

reverse

transcriptase

inhibitors (28, 42)

Nevirapine

Induction of hepatic microsomal

enzymes.

Use another drug or another

non-hormonal method of

contraception.

Sedatives and

Hypnotics

Benzodiazepines

Barbiturates

Chloral hydrate

Glutethimide

Meprobamate

Induction of hepatic microsomal

enzymes.

For short course, use additional

non-hormonal method of

contraception or another drug.

For long course, use another

non-hormonal method of

contraception or higher dose

oral contraceptives.

Other Drugs

Analgesics

Antihistamines

Antimigraine

preparations

Phenylbutazone

Vitamin E

Reduced oral contraceptive

efficacy has been reported.

Remains to be confirmed.

TRIQUILAR Product Monograph

Page 19 of 54

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 (eg, ketoconazole,

itraconazole, voriconazole, fluconazole), verapamil, macrolides (eg, 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 (eg, ritonavir, telaprevir, boceprevir) and non-

nucleoside reverse transcriptase inhibitors (eg, 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. Health care 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 (eg,

midazolam) while plasma concentrations of CYP1A2 substrates can increase weakly (eg,

theophylline) or moderately (eg, melatonin and tizanidine).

Oral contraceptives may also interfere with the metabolism of other drugs (see Table 5).

Accordingly, plasma and tissue concentrations may either increase (eg, cyclosporine) or decrease

(eg, lamotrigine).

TRIQUILAR Product Monograph

Page 20 of 54

Table 5: Modification of Other Drug Action by Oral Contraceptives

Class of

Compound

Drug

Modification of Drug Action

Suggested Management

Alcohol

Possible increased levels of

ethanol or acetaldehyde

Use with caution.

Alpha-II

adrenoreceptor

agents

Clonidine

Sedation effect increased.

Use with caution.

Anticoagulants

Oral contraceptives increase

clotting factors, decrease

efficacy. However, oral

contraceptives may potentiate

action in some patients.

Use another non-hormonal

method of contraception.

Anticonvulsants

Estrogens may increase risk of

seizures.

Use another non-hormonal

method of contraception.

Lamotrigine

Decreased lamotrigine levels

may lead to breakthrough

seizures.

Use another non-hormonal

method of contraception.

Antidiabetic drugs

Oral

hypoglycemics and

insulin

Oral contraceptives may impair

glucose tolerance and increase

blood glucose.

Use low-dose estrogen and

progestin oral contraceptive or

another non-hormonal method of

contraception. Monitor blood

glucose.

Antihypertensive

agents

Guanethidine and

methyldopa

Estrogen component causes

sodium retention, progestin has

no effect.

Use low-dose estrogen oral

contraceptive or use another non-

hormonal method of

contraception.

Beta blockers

Increased drug effect

(decreased metabolism).

Adjust dose of drug if necessary.

Monitor cardiovascular status.

Antipyretics

Acetaminophen

Increased metabolism and renal

clearance.

Dose of drug may have to be

increased.

Antipyrine

Impaired metabolism.

Decrease dose of drug.

Effects of ASA may be

decreased by the short-term use

of oral contraceptives.

Patients on chronic ASA therapy

may require an increase in ASA

dosage.

Aminocaproic acid

Theoretically, a

hypercoagulable state may

occur because oral

contraceptives augment clotting

factors.

Avoid concomitant use.

Betamimetic agents

Isoproterenol

Estrogen causes decreased

response to these drugs.

Adjust dose of drug as necessary.

Discontinuing oral contraceptives

can result in excessive drug

activity.

Caffeine

The actions of caffeine may be

enhanced as oral contraceptives

may impair the hepatic

metabolism of caffeine.

Use with caution.

TRIQUILAR Product Monograph

Page 21 of 54

Table 5: Modification of Other Drug Action by Oral Contraceptives

Class of

Compound

Drug

Modification of Drug Action

Suggested Management

Cholesterol

lowering agents

Clofibrate

Their action may be

antagonized by oral

contraceptives. Oral

contraceptives may also

increase metabolism of

clofibrate.

May need to increase dose of

clofibrate.

Corticosteroids

Prednisone

Markedly increased serum

levels.

Possible need for decrease in

dose.

Cyclosporine

(43)

May lead to an increase in

cyclosporine levels and

hepatotoxicity.

Monitor hepatic function. The

cyclosporine dose may have to be

decreased.

Direct-acting

antiviral (DAA)

medicinal products

Ombitasvir,

Paritaprevir,

Ritonavir, with and

without Dasabuvir

Has been shown to be

associated with increases in

ALT levels 5 to >20 times the

upper limit of normal in healthy

female subjects and HCV

infected women.

see CONTRAINDICATIONS

and WARNINGS AND

PRECAUTIONS,

Hepatic/Biliary/Pancreatic.

Folic acid

Oral contraceptives have been

reported to impair folate

metabolism.

May need to increase dietary

intake, or supplement.

Meperidine

Possible increased analgesia

and CNS depression due to

decreased metabolism of

meperidine.

Use combination with caution.

Phenothiazine

tranquilizers

All phenothiazines,

reserpine and

similar drugs

Estrogen potentiates the

hyperprolactinemia effect of

these drugs.

Use other drugs or lower dose oral

contraceptives. If galactorrhea or

hyperprolactinemia occurs, use

other non-hormonal method of

contraception.

Sedatives and

hypnotics

Chlordiazepoxide

Diazepam

Lorazepam

Oxazepam

Increased effect (increased

metabolism).

Use with caution.

Theophylline

Decreased oxidation, leading to

possible toxicity.

Use with caution. Monitor

theophylline levels.

Tricyclic

antidepressants

Clomipramine

(possibly others)

Increased side effects:

ie, depression

Use with caution.

Vitamin B

Oral contraceptives have been

reported to reduce serum levels

of Vitamin B

May need to increase dietary

intake, or supplement.

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

Drug-Food Interactions

Interactions with food have not been established.

TRIQUILAR Product Monograph

Page 22 of 54

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.

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 T

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.

Drug-Lifestyle Interactions

No studies on the effects of TRIQUILAR on the ability to drive or use machines have been

performed.

TRIQUILAR Product Monograph

Page 23 of 54

Noncontraceptive Benefits of Oral Contraceptives

Several health advantages other than contraception have been reported.

Combination oral contraceptives reduce the incidence of cancer of the endometrium and

ovaries.

Oral contraceptives reduce the likelihood of developing benign breast disease, and as a result

decrease the incidence of breast biopsies.

Oral contraceptives reduce the likelihood of development of functional ovarian cysts.

Pill-users have less menstrual blood loss and have more regular cycles, thereby reducing the

chance of developing iron-deficiency anemia.

The use of oral contraceptives may decrease the severity of dysmenorrhea and premenstrual

syndrome, and may improve acne vulgaris, hirsutism, and other androgen-mediated

disorders.

Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and thereby

reduce as well the incidence of ectopic pregnancy.

Oral contraceptives have potential beneficial effects on endometriosis.

DOSAGE AND 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 (ie, 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 (ie, while the patient is

taking the last row of the slightly larger, hormone-free white tablets).

TRIQUILAR Product Monograph

Page 24 of 54

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”.

Management of Missed Tablets:

The patient should be instructed to use the following chart if she misses one or more of her birth

control pills (see Table 6). 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 6: Management of Missed Hormone-containing Light Brown, White or Ochreous Tablets

Sunday Start

Other than Sunday Start

Miss One Light Brown, White or Ochreous Tablet

At Any Time

Miss One Light Brown, White or Ochreous Tablet

At Any Time

Take it as soon as you remember, and take the next

tablet at the usual time. This means that you might take

two tablets in one day.

Take it as soon as you remember, and take the next

tablet at the usual time. This means that you might take

two tablets in one day.

Miss Two Light Brown, White or Ochreous Tablets

in a Row

Miss Two Light Brown, White or Ochreous Tablets

in a Row

First Two Weeks:

Take two tablets the day you remember and two

tablets the next day.

Then take one tablet a day until you finish the

pack.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

First Two Weeks:

Take two tablets the day you remember and two

tablets the next day.

Then take one tablet a day until you finish the

pack.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

Third Week

Keep taking one tablet a day until Sunday.

On Sunday, safely discard the rest of the pack

and start a new pack that day.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

You may not have a period this month.

If you miss two periods in a row, call your doctor or

clinic.

Third Week

Safely dispose of the rest of the pill pack and

start a new pack that same day.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

You may not have a period this month.

If you miss two periods in a row, call your doctor or

clinic.

TRIQUILAR Product Monograph

Page 25 of 54

Table 6: Management of Missed Hormone-containing Light Brown, White or Ochreous Tablets

Sunday Start

Other than Sunday Start

Miss

Three

or

More

Light

Brown,

White

or

Ochreous Tablets in a Row

Miss

Three

or

More

Light

Brown,

White

or

Ochreous Tablets in a Row

Anytime in the cycle

Keep taking one tablet a day until Sunday.

On Sunday, safely discard the rest of the pack

and start a new pack that day.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

You may not have a period this month.

If you miss two periods in a row, call your doctor or

clinic.

Anytime in the cycle

Safely dispose of the rest of the pill pack and

start a new pack that same day.

Use a back-up (barrier) method of birth control

if you have sex in the seven days after you miss

the tablets.

You may not have a period this month.

If you miss two periods in a row, call your doctor or

clinic.

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.

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.

TRIQUILAR Product Monograph

Page 26 of 54

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.

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.

OVERDOSAGE

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

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.

TRIQUILAR Product Monograph

Page 27 of 54

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.

ACTION AND CLINICAL PHARMACOLOGY

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

g/day, corresponding to 5

g/kg.

Levonorgestrel at a dose of 125

g/day was also shown to be twice as potent as norethindrone in

the delay of menstruation test by "Swyer and Greenblatt".

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.

TRIQUILAR Product Monograph

Page 28 of 54

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.

Pharmacokinetics

Levonorgestrel

Absorption

Orally administered levonorgestrel is rapidly and completely absorbed. (44-46) 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. (47)

Levonorgestrel is almost completely bioavailable after oral administration. (44, 46, 48)

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. (47) 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. (49) The volume of distribution of levonorgestrel (V

) is about 128 L after single oral

administration of the highest levonorgestrel dose of TRIQUILAR. (47)

Metabolism

Levonorgestrel is extensively metabolized. The major metabolites in plasma are the

unconjugated and conjugated forms of 3α, 5β-tetrahydrolevonorgestrel (50). Based on in vitro

and in vivo studies, CYP3A4 is the main enzyme involved in the metabolism of levonorgestrel

(51). The clearance rate from serum is approximately 1.0 mL/min/kg (47).

Elimination

Levonorgestrel serum levels decrease in two phases. The terminal disposition phase is

characterized by a half-life of approximately 22 hours. (47) Levonorgestrel is not excreted in

unchanged form. Its metabolites are excreted at a urinary to biliary ratio of about 1:1. (45) The

half-life of metabolite excretion is about 1 day. (45)

TRIQUILAR Product Monograph

Page 29 of 54

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. (47)

Ethinyl Estradiol

Absorption

Orally administered ethinyl estradiol is rapidly and completely absorbed. (52-54) 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. (47) 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%. (53)

Distribution

Ethinyl estradiol is highly but non-specifically bound to serum albumin (approximately 95-98%),

(55) and induces an increase in the serum concentrations of SHBG. (53) An apparent volume of

distribution of about 2.8-8.6 L/kg was reported after intravenous administration. (53)

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. (53)

Elimination

Ethinyl estradiol serum levels decrease in two disposition phases characterized by half-lives of

about 1 hour and 10-20 hours, respectively. (53) 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. (54)

Steady-state Conditions

According to the variable half-life of the terminal disposition phase from serum, (53) 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. (47)

TRIQUILAR Product Monograph

Page 30 of 54

Special Populations and Conditions

Pediatrics

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.

Geriatrics

TRIQUILAR is not indicated for use in postmenopausal women. Oral contraceptives may mask

the onset of the climacteric.

Hepatic Insufficiency

TRIQUILAR is contraindicated in women with active liver diseases (see

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.

STORAGE AND STABILITY

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.

SPECIAL HANDLING INSTRUCTIONS

There are no special handling instructions.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Availability

TRIQUILAR tablets are available:

For 21-day regimens in "TRIQUILAR 21".

For 28-day regimens in "TRIQUILAR 28".

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

ethinyl estradiol. Non-medicinal ingredients: calcium carbonate, maize starch, glycerine,

lactose, magnesium stearate, montanglycol wax, polyethylene glycol, polyvinylpyrrolidone, red

ferric oxide, sucrose, talc, titanium dioxide and yellow ferric oxide.

TRIQUILAR Product Monograph

Page 31 of 54

"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.

TRIQUILAR Product Monograph

Page 32 of 54

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name:

Levonorgestrel

Ethinyl estradiol

Chemical Name:

Levonorgestrel:

18,19-Dinorpregn-4-en-20-yn-3-one,13-ethyl-

17-hydroxy-,(17

)-(-)

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

diol,(17

Structural Formula:

Levonorgestrel:

Ethinyl estradiol:

Molecular Formula

and Molecular Mass:

Levonorgestrel:

312.45

Ethinyl estradiol:

296.41

Physicochemical properties:

Solubility: (USP Classification):

Levonorgestrel:

Slightly soluble in alcohol; insoluble in water.

Ethinyl estradiol:

Insoluble in water; soluble in alcohol,

chloroform, ether, vegetable oil, and in alkaline

solutions.

Melting Points:

Levonorgestrel:

C - 240

Ethinyl estradiol:

C - 186

Biological Properties:

Levonorgestrel:

This entire synthetic progestogen is the (-)-

isomer of norgestrel. It is the active form of the

racemic norgestrel.

Ethinyl estradiol:

synthetic estrogen.

TRIQUILAR Product Monograph

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CLINICAL TRIALS

Study Demographics and Trial Design

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

Study

Trial Design

Number of

Subjects

Age Distribution (Years)

<20

20-29

30-39

>40

Carlborg

Multicentre, double-blind, controlled

vs. levonorgestrel 150 mcg + ethinyl

estradiol 50 mcg

Aydinlik 70015

Multicentre, double-blind, controlled

vs. levonorgestrel 150 mcg + ethinyl

estradiol 50 mcg

Lachnit 81182

Multicentre, double-blind, controlled

vs. desogestrel 150 mcg + ethinyl

estradiol 30 mcg

Lachnit 1124

Multicentre, open

Ulstein 79184

Multicentre, open

Lachnit 70127

Multicentre, open

Aydinlik 70101

Multicentre, open

Lachnit 70124

Multicentre, open

6272

2284

2772

Total

9025

2963

4179

1574

309

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.

TRIQUILAR Product Monograph

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Table 8: Duration of Treatment (Cycles)

Study

Patients

6 Cycles

12 Cycles

24 Cycles

Total

Carlborg

3194

70015

1440

81182

1529

1124

6628

79184

3588

70127

3521

70101

2252

70124

6271

4595

28,638

Total

8748

6673

943

54

50,793

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 6

cycle.

Table 9: Discontinuation During the First 6 Cycles

Study

Total

Side Effects

Carlborg

67/417

(16%)

47/417

(11%)

70015

85/254

(33%)

23/254

(9%)

81182

30/258

(11%)

17/258

(6%)

1124

185/696

(27%)

85/696

(12%)

79184

122/367

(33%)

62/367

(16%)

70127

63/258

(24%)

20/258

(8%)

70101

44/210

(22%)

70124

1883/6272

(30%)

824/6272

(13%)

Overall

2479/8732

(28%)

1078/8732

(12%)

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%).

TRIQUILAR Product Monograph

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Table 10: Tablet Error - Cycles

Study

Total Number of Cycles

Number of Cycles with Tablet Error

Carlborg

3197

(8%)

70015

1440

(0.9%)

81182

1529

(1.5%)

1124

6628

(1.7%)

79184

3588

(0.2%)

70127

3521

(3.0%)

70101

2252

(4.0%)

70124

28,638

(2.1%)

Total

50,793

1211

(2.4%)

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

Study

Patients

Pregnancy Patient Error

Pregnancy No Error

Total

Carlborg

70015

81182

1124

79184

70127

70101

70124

6271

Total

8748

10

11

21

Pearl Index = 0.3

Table 12: Overall Pregnancy Rate

Method

Method Failure + Patient Failure

Method Failure

Lifetable analysis

0.65

0.40

Pearl Index

0.60

0.30

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.

TRIQUILAR Product Monograph

Page 36 of 54

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

Combination pill

less than 1 to 2

Intrauterine device (IUD)

less than 1 to 6

Condom with spermicidal foam or gel

1 to 6

Mini-pill

3 to 6

Condom

2 to 12

Diaphragm with spermicidal foam or gel

3 to 18

Spermicide

3 to 21

Sponge with spermicide

3 to 28

Cervical cap with spermicide

5 to 18

Periodic abstinence (rhythm), all types

2 to 20

No birth control

60 to 85

DETAILED PHARMACOLOGY

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.

TRIQUILAR Product Monograph

Page 37 of 54

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, ie, 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 ie, 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.

TRIQUILAR Product Monograph

Page 38 of 54

TOXICOLOGY

Acute Toxicity

Acute oral toxicity studies have been carried out with oral, intraperitoneal (i.p.) and

subcutaneous (s.c.) doses of levonorgestrel alone, ethinyl estradiol alone and in a combination of

5:1 ratio.

Table 14 represents the findings of these studies:

Table 14: Summary of Acute Toxicity Results

Species

Route of

Administration

LD

50

Levonorgestrel

LD

50

Ethinyl Estradiol

LD

50

Levonorgestrel +

Ethinyl Estradiol

(5:1)

Mice

oral

> 4.0 g/kg

> 2.5 g/kg

> 2.5 g/kg

Mice

i.p.

> 3.9 g/kg

0.69 g/kg

1.32 - 1.65 g/kg

Mice

s.c.

> 4.0 g/kg

> 2.6 g/kg

> 2.5 g/kg

Rats

oral

> 4.0 g/kg

susp. > 5.0 g/kg

solu. 1.5 g/kg

> 2 g/kg

Rats

i.p.

> 5.0 g/kg

0.97 g/kg

approx. 2 g/kg

Rats

s.c.

> 4.0 g/kg

hair loss

> 2 g/kg

Dogs

oral

> 1.0 g/kg

Both compounds were found to be almost non-toxic in the acute toxicity studies.

Page 39 of 54

Chronic Toxicity

Table 15: Chronic Toxicity Studies

Species

Drugs, Route of Administration and

Dose

Duration of

Administration

Symptoms

Histopathology

16/sex/group

Norgestrel, Oral

0.0001%, 0.0005%, 0.0025%

26 weeks

No signs and symptoms of toxicity.

No histopathological changes.

Levonorgestrel, Oral

0.00005%, 0.00025%, 0.00125%

26 weeks

Significant less weight gain in low-

dose females, no other signs of

toxicity.

No abnormal histopathology.

6/sex/group

Levonorgestrel, Oral

0.05 - 0.1 - 0.5 mg/kg

26 weeks

No estrus in any dog. Mammary

enlargement: in all but 2 females

and 8 males. Dose related clitoral

reddening and enlargement.

Significant decrease in cholesterol

in all dosage groups.

No drug-related effects on

ophthalmology, ECG, hemostatic

functions, urinalysis or organ weight.

16 females/dose

Norgestrel, Oral

0, 3.0, 15.0, 37.5

g/kg

continuous

7 years

Estrus inhibited in all but low

dosage group. Uterine enlargement

and endometrial hyperplasia at 15

and 37.5

g/kg.

Norgestrel 37.5

g group - many dogs

with cysts and absence of luteal phase.

1 dog mammary carcinoma (37.5

g/kg).

Levonorgestrel, Oral

0.5 mg/kg

cyclic - 7 years

Enlarged clitoris on majority of

dogs. Hematocrit and hemoglobin

low or SGPT increased

significantly. Fibrinogen increased.

Increase in benign mammary adenomas.

1 dog adenocarcinoma. Many vaginal

cysts and absence of luteal phase.

RHESUS

MONKEY

16 females/dose

Norgestrel, Oral

0 , 3, 15, 75

g/kg

continuous

10 years

(78 months)

Red vaginal discharge less frequent

in 15 and 75

g/kg group.

Mammary nodules in 3 animals at

g/kg. 1 animal at 3 and 15

g/kg.

Levonorgestrel, Oral

1 mg/kg

cyclic - (21 days)

10 years (78 months)

Red vaginal discharge more

frequent in withdrawal period.

Fibrinogen levels increased.

1 animal mammary nodules.

Page 40 of 54

Table 15: Chronic Toxicity Studies

Species

Drugs, Route of Administration and

Dose

Duration of

Administration

Symptoms

Histopathology

MICE

40/sex/dose

Norgestrel

Ethinyl Estradiol

Norgestrel +

Ethinyl Estradiol (10 + 1) Oral,

0.02 + 0.002 mg/kg;

0.7 + 0.07 mg/kg;

2.0 + 0.2 mg/kg;

3.0 + 0.3 mg/kg

80 weeks

Ethinyl Estradiol depressed weight

gain in 3 highest dosage groups.

Norgestrel + Ethinyl Estradiol -

depressed weight gain in 3 highest

dosage groups. Norgestrel - no

effects.

Ethinyl Estradiol - significant increase in

malignant tumors. Lymphocarcinoma -

males interstitial tumors - females.

Ethinyl Estradiol + Norgestrel - same.

Norgestrel - no significant tumorigenic

effect.

40/sex/dose

Norgestrel

Ethinyl Estradiol

Norgestrel +

Ethinyl Estradiol (10 + 1)

Oral,

0.02 + 0.002 mg/kg;

0.5 + 0.05 mg/kg;

2.0+ 0.2 mg/kg

104 weeks

Norgestrel - no effects. Ethinyl

Estradiol - dosage related decrease

in body weight gain. Norgestrel +

Ethinyl Estradiol - dosage related

decrease in body weight gain.

Malignant and benign mammary tumors

were significantly increased over controls

in both males and females at the two

highest dosage levels of Ethinyl Estradiol

either alone or in combination with

Norgestrel. Hematological changes

included are one case of Leukemia in low

dosage group of Norgestrel + Ethinyl

Estradiol.

12 females/dose

Norgestrel

Ethinyl Estradiol

Norgestrel +

Ethinyl Estradiol Oral - mg/kg

0.1 - 0.25

0.01

0.1 + 0.025

0.1 + 0.01

0.25 + 0.025

7 years

Norgestrel - increase in body weight

at 0.1 mg/kg. Slight to moderate

increase SGPT values in treated

groups also increase in fibrinogen in

some animals. Norgestrel alone or

in combination with Ethinyl

Estradiol also suppressed estrus.

Dose related increase in mammary

adenomas in the Norgestrel treated

groups. Possible indication of an increase

in benign adenomas and intraductal

papillomas after high doses of Norgestrel.

RHESUS

MONKEY

16 females/dose

Norgestrel

Ethinyl Estradiol

Norgestrel +

Ethinyl Estradiol

Oral - mg/kg

0.02, 0.1, 0.5

0.002, 0.01, 0.05

0.02 + 0.002

0.1 + 0.01

0.5 + 0.05

10 years

Increase in body weight gain in the

Norgestrel 0.5 mg/kg group.

Fibrinogen levels increased in

monkeys receiving Norgestrel alone

or in combination with Ethinyl

Estradiol. A higher rate with retinal

depigmentation in the groups treated

with Ethinyl Estradiol alone or in

combination with Norgestrel.

No abnormal findings.

TRIQUILAR Product Monograph

Page 41 of 54

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clinicians. Arch Intern Med. 2001 Nov 12;161(20):2417-29.

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Heikkila M, Haukkamaa M, Luukkainen T. Levonorgestrel in milk and plasma of breast-

feeding women with a levonorgestrel-releasing IUD. Contraception. 1982 Jan;25(1):41-9.

Nilsson S, Nygren KG, Johansson ED. Ethinyl estradiol in human milk and plasma after

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Barditch-Crovo P, Trapnell CB, Ette E, Zacur HA, Coresh J, Rocco LE, et al. The effects

of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of a

combination oral contraceptive. Clin Pharmacol Ther. 1999 Apr;65(4):428-38.

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Pharmacol. 1998 Nov;38(11):1042-50.

Geurts TBP, Goorissen EM, Sitsen JMA. Anticonvulsants. Summary of drug interactions

with oral contraceptives. Carnforth: The Parthenon Publishing Group; 1993. p. 49-57.

Geurts TBP, Goorissen EM, Sitsen JMA. Mechanisms of Drug Interactions. Summary of

drug interactions with oral contraceptives. Carnforth: The Parthenon Publishing Group;

1993. p. 11-22.

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and oral contraceptive interactions: a national survey of neurologists and obstetricians.

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Saano V, Glue P, Banfield CR, Reidenberg P, Colucci RD, Meehan JW, et al. Effects of

felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin

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Geurts TBP, Goorissen EM, Sitsen JMA. Griseofulvin. Summary of drug interactions

with oral contraceptives. Carnforth: The Parthenon Publishing Group; 1993. p. 70-1.

Ouellet D, Hsu A, Qian J, Locke CS, Eason CJ, Cavanaugh JH, et al. Effect of ritonavir

on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers. Br J Clin

Pharmacol. 1998 Aug;46(2):111-6.

Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M, et al.

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when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr.

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interactions with oral contraceptives. Carnforth: The Parthenon Publishing Group; 1993.

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linearity of levonorgestrel pharmacokinetics in 18 healthy, young women1994 Aug. 24.

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pharmacokinetic parameters of d-norgestrel, lynestrenol and cyproterone acetate in 6

women. Contraception. 1977;16(2):199-215.

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pharmacokinetics of levonorgestrel to specific consideration of a possible first-pass effect

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Kuhnz W, Staks T, Jutting G. Pharmacokinetics of levonorgestrel and ethinylestradiol in

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contraceptive: serum protein binding of levonorgestrel and influence of treatment on free

and total testosterone levels in the serum. Contraception. 1994 Dec;50(6):563-79.

Fotherby K. Bioavailability of orally administered sex steroids used in oral contraception

and hormone replacement therapy. Contraception. 1996 Aug;54(2):59-69.

Kuhnz W, Schutt B, Woloszczak R. Influence of changes in the concentration of sex

hormone-binding globulin in human serum on the protein binding of the contraceptive

steroids levonorgestrel, 3-keto-desogestrel and gestodene. J Steroid Biochem Mol Biol.

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Stanczyk FZ, Roy S. Metabolism of levonorgestrel, norethindrone, and structurally

related contraceptive steroids. Contraception. 1990 Jul;42(1):67-96.

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gestodene, 3-keto desogestrel, levonorgestrel, norethisterone and norgestimate on the

oxidation of ethinyloestradiol and other substrates by human liver microsomes. The

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ethinyloestradiol to specific consideration of a possible first-pass effect in women.

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antiestrogens. Berlin: Springer-Verlag; 1999. p. 281-91.

Speck U, Wendt H, Schulze PE, Jentsch D. Bio-availability and pharmacokinetics of

cyproterone acetate-14C and ethinyloestradiol-3H after oral administration as a coated

tablet (SH B 209 AB). Contraception. 1976 Aug;14(2):151-63.

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gestodene, 3-keto-desogestrel and ethinylestradiol in human serum. J Steroid Biochem.

1990 Feb;35(2):313-8.

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May;75(5):344-54.

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 46 of 54

PART III: CONSUMER INFORMATION

Pr

TRIQUILAR

®

(levonorgestrel and ethinyl estradiol tablets USP)

This leaflet is Part III of a three-part “Product Monograph"

published when TRIQUILAR was approved for sale in

Canada and is designed specifically for Consumers. This

leaflet is a summary and will not tell you everything about

TRIQUILAR. Contact your doctor or pharmacist if you have

any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

To prevent pregnancy

What it does:

TRIQUILAR is a birth control pill (oral contraceptive) that

contains two female sex hormones (levonorgestrel and ethinyl

estradiol). It has been shown to be highly effective in

preventing pregnancy when taken as prescribed by your doctor.

Pregnancy is always more risky than taking birth control pills,

except in smokers older than age 35.

Birth control pills work in two ways:

1. They inhibit the monthly release of an egg by the ovaries.

2. They change the mucus produced by the cervix. This slows

the movement of the sperm through the mucus and through

the uterus (womb).

Effectiveness of Birth Control Pills

Combination birth control pills are more than 99 percent

effective in preventing pregnancy when:

the pill is TAKEN AS DIRECTED, and

the amount of estrogen is 20 micrograms or more.

A 99 percent effectiveness rate means that if 100 women used

birth control pills for one year, one woman in the group would

get pregnant.

The chance of becoming pregnant increases with incorrect use.

Other Ways to Prevent Pregnancy

Other methods of birth control are available to you. They are

usually less effective than birth control pills. When used

properly, however, other methods of birth control are effective

enough for many women.

The following table gives reported pregnancy rates for various

forms of birth control, including no birth control. The reported

rates represent the number of women out of 100 who would

become pregnant in one year.

Reported Pregnancies per 100 Women per Year:

Combination pill

less than 1 to 2

Intrauterine device (IUD)

less than 1 to 6

Condom with spermicidal foam or gel

1 to 6

Mini-pill

3 to 6

Condom

2 to 12

Diaphragm with spermicidal foam or gel

3 to 18

Spermicide

3 to 21

Sponge with spermicide

3 to 28

Cervical cap with spermicide

5 to 18

Periodic abstinence (rhythm), all types

2 to 20

No birth control

60 to 85

Pregnancy rates vary widely because people differ in how

carefully and regularly they use each method. (This does not

apply to IUDs since they are implanted in the uterus). Regular

users may achieve pregnancy rates in the lower ranges. Others

may expect pregnancy rates more in the middle ranges.

The effective use of birth control methods other than birth

control pills and IUDs requires more effort than taking a single

pill every day. It is an effort that many couples undertake

successfully.

When it should not be used:

The birth control pill is not suitable for every woman. In a

small number of women, serious side effects may occur. Your

doctor can advise you if you have any conditions that would

pose a risk to you. The use of the birth control pill should

always be supervised by your doctor.

You should not use TRIQUILAR if you have or have had any

of the following conditions:

blood clots in the legs, lungs, eyes, or elsewhere, or

thrombophlebitis (inflammation of the veins)

stroke, heart attack, or coronary artery disease

(eg, angina pectoris), or a condition that may be a first

sign of a stroke (such as a transient ischemic attack or

small reversible stroke)

disease of the heart valves with complications

known abnormalities of the blood clotting system that

increases your risk for developing blood clots

severe high blood pressure

diabetes with complications

very high blood cholesterol or triglyceride levels

you smoke and are over age 35

migraine headache

you are scheduled for major surgery

prolonged bed rest

you are taking ombitasvir, paritaprevir, ritonavir, with

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 47 of 54

or without dasabuvir for the treatment of Hepatitis C

(an infectious disease that affects the liver, caused by

the hepatitis C virus)

jaundice (yellowing of the eyes or skin), liver disease

or liver tumor

known or suspected cancer of the breast or uterus

(womb) or other estrogen-dependent cancer

unusual vaginal bleeding without a known reason

loss of vision due to blood vessel disease of the eye

you are pregnant or suspect you may be pregnant

pancreatitis (inflammation of the pancreas) associated

with high levels of fatty substances in your blood

allergy (hypersensitivity) to ethinyl estradiol,

levonorgestrel or to any of the other ingredients in

TRIQUILAR (see What the Medicinal Ingredients

Are and What the Nonmedicinal Ingredients Are)

What the medicinal ingredients are:

levonorgestrel and ethinyl estradiol

What the nonmedicinal ingredients are:

calcium carbonate, cornstarch, glycerine, lactose, magnesium

stearate, montanglycol wax, polyethylene glycol,

polyvinylpyrrolidone, red ferric oxide, sucrose, talc, titanium

dioxide and yellow ferric oxide

What dosage forms it comes in:

TRIQUILAR is a combined oral contraceptive that contains

three different combinations of levonorgestrel and ethinyl

estradiol as described in the charts below. TRIQUILAR is

available in a 21-day or 28-day treatment cycle. Each phase of

pills is a different strength and should be taken successively.

TRIQUILAR 21 (21-day Treatment Cycle)

Pill

Description

Amount of

Levonorgestrel

Amount of

Ethinyl Estradiol

1 – 6

light brown

0.05 mg

0.03 mg

7 – 11

white

0.075 mg

0.04 mg

12 – 21

ochreous

0.125 mg

0.03 mg

TRIQUILAR 28 (28-day Treatment Cycle)

Pill

Description

Amount of

Levonorgestrel

Amount of

Ethinyl Estradiol

1 – 6

light brown

0.05 mg

0.03 mg

7 – 11

white

0.075 mg

0.04 mg

12 – 21

ochreous

0.125 mg

0.03 mg

22 – 28

slightly

larger,

white

no active ingredients

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious adverse

effects on the heart and blood vessels. This risk increases

with age and becomes significant in hormonal

contraceptive users older than 35 years of age, 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 not smoke.

Birth control pills DO NOT PROTECT against sexually

transmitted diseases (STIs), including HIV/AIDS.

For protection against STIs, it is advisable to use latex or

polyurethane condoms IN COMBINATION WITH birth

control pills.

Do not use

TRIQUILAR if you are taking ombitasvir,

paritaprevir, ritonavir, with or without dasabuvir for the

treatment of Hepatitis C. Using these drugs at the same

time as TRIQUILAR has the potential to cause liver

problems, such as an increase in the ALT liver enzyme. You

can usually start TRIQUILAR about 2 weeks after finishing

treatment with this combination of drugs used for Hepatitis

C, but always consult with your doctor or pharmacist.

BEFORE you use TRIQUILAR, talk to your doctor or

pharmacist if you:

smoke

are overweight

have a history of breast disease (eg, breast lumps) or a

family history of breast cancer

have high blood pressure

have high cholesterol

have diabetes

have heart or kidney disease

have a history of seizures/epilepsy

have a history of depression

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 48 of 54

have a history of liver disease or jaundice

wear contact lenses

have uterine fibroids (benign tumors of the uterus)

may be pregnant or are breastfeeding

have systemic lupus erythematosus

have inflammatory bowel disease such as Crohn’s disease

or ulcerative colitis

have hemolytic uremic syndrome

have sickle cell disease

have any problems with the valves in your heart and/or

have an irregular heart rhythm

have been told that you have a condition called hereditary

angioedema or if you have had episodes of swelling in

body parts such as hands, feet, face or airway passages

You should also inform your doctor about a family history of

blood clots, heart attacks, or strokes.

If you see a different doctor, inform him or her that you are

using TRIQUILAR.

Tell your doctor if you are scheduled for any laboratory tests

since certain blood tests may be affected by hormonal

contraceptives.

Also tell your doctor if you are scheduled for MAJOR surgery.

You should consult your doctor about stopping the use of

TRIQUILAR four weeks before surgery and not using

TRIQUILAR for a time period after surgery or during bed rest.

TRIQUILAR should be used only under the supervision of a

doctor, with regular follow-up to identify side effects associated

with its use. Your visits may include a blood pressure check, a

breast exam, an abdominal exam and a pelvic exam, including a

Pap smear. Visit your doctor three months or sooner after the

initial examination. Afterward, visit your doctor at least once a

year. Use TRIQUILAR only on the advice of your doctor and

carefully follow all directions given to you. You must use the

birth control pill exactly as prescribed. Otherwise, you may

become pregnant.

If you and your doctor decide that, for you, the benefits of

TRIQUILAR outweigh the risks, you should be aware of the

following:

THE RISKS OF USING TRIQUILAR

1.

Circulatory disorders (including blood clot in legs,

lungs, heart, eyes or brain)

Women who use hormonal contraceptives have a higher

incidence of blood clots. Blood clots are the most common

serious side effects of birth control pills. The risk of

developing blood clots is especially high during the first year a

woman ever uses a hormonal contraceptive or restarts the same

or a different hormonal contraceptive. Clots can occur in many

parts of the body.

Be alert for the following symptoms and signs of serious

adverse effects. Call your doctor immediately if they occur:

sharp pain in the chest which may increase with deep

breathing; coughing blood; sudden shortness of breath or

rapid breathing; sense of anxiety; severe light headedness

or dizziness; rapid or irregular heartbeat. These symptoms

could indicate a possible blood clot in the lung.

pain and/or swelling in the calf 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 discoloured skin on the leg. These symptoms could

indicate a possible blood clot in the leg.

crushing chest 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. These symptoms could indicate a possible

heart attack.

sudden severe or worsening headache or vomiting; sudden

trouble walking, dizziness, loss of balance or coordination;

loss of consciousness or fainting with or without seizure;

sudden confusion, disturbances of vision, speech or

understanding; sudden weakness or numbness of the face,

arm or leg. These symptoms could indicate a possible

stroke.

sudden partial or complete loss of vision. This symptom

could indicate a blood clot in the eye.

other signs of a blood clot can include: sudden pain,

swelling, slight blue discoloration of an extremity; acute

abdomen

Any of these conditions can cause death or disability. Clots

also occur rarely in the blood vessels of the eye, resulting in

blindness or impaired vision or in a blood vessel leading to an

arm or leg, resulting in damage to or loss of a limb.

The risk of clotting seems to increase with higher estrogen

doses. It is important, therefore, to use as low a dosage of

estrogen as possible.

Cancer of the breast, cervix, or liver may be life-threatening

or may result in death.

2. Breast cancer

The most significant risk factors for breast cancer are

increasing age and a strong history of breast cancer in the

family (mother or sister). Other established risk factors include

obesity, never having children, and having your first full-term

pregnancy at a late age.

Some women who use hormonal contraceptives may be at

increased risk of developing breast cancer before menopause,

which occurs around age 50. These women may be long-term

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 49 of 54

users of birth control pills (more than eight years) or women

who start using birth control pills at an early age. In a few

women, the use of birth control pills may accelerate the growth

of an existing but undiagnosed breast cancer. Early diagnosis,

however, can reduce the effect of breast cancer on a woman’s

life expectancy. The potential risks related to birth control pills

seem to be small, however. A yearly breast examination by a

health care professional is recommended for all women.

ASK YOUR DOCTOR FOR ADVICE AND

INSTRUCTIONS ON REGULAR SELF-EXAMINATION

OF YOUR BREASTS.

3. Cervical cancer

Some studies have found an increase of cancer of the cervix in

women who use hormonal contraceptives, although this finding

may be related to factors other than the use of oral

contraceptives. However, there is insufficient evidence to rule

out the possibility that oral contraceptives may cause such

cancers.

4. Liver tumors

The short and long-term use of birth control pills also have

been linked with the growth of liver tumors. Such tumors are

extremely rare.

Contact your doctor immediately if you experience severe pain

or a lump in the abdomen.

5. Gallbladder disease

Users of birth control pills 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 of use.

6. Use in pregnancy

Birth control pills should not be taken by pregnant women.

There is no evidence, however, that the birth control pill can

damage a developing child. You should check with your doctor

about risks to your unborn child from any medication taken

during pregnancy.

7. Use after pregnancy, miscarriage or an abortion

Your doctor will advise you of the appropriate time to start the

use of TRIQUILAR after childbirth, miscarriage, or therapeutic

abortion.

8. Pregnancy after stopping TRIQUILAR

You will have a menstrual period when you stop using

TRIQUILAR. You should delay pregnancy until another

menstrual period occurs within four to six weeks. In this way

the pregnancy can be more accurately dated. Contact your

doctor for recommendations on alternate methods of

contraception during this time.

9. Use while breastfeeding

If you are breastfeeding, consult your doctor before starting the

birth control pill. The hormones in birth control pills are

known to appear in breast milk. These hormones may decrease

the flow of breast milk. Adverse effects on the child have been

reported, including yellowing of the skin (jaundice) and breast

enlargement. You should use another method of contraception

and only consider starting the birth control pill once you have

weaned your child completely.

INTERACTIONS WITH THIS MEDICATION

There are some medicines you must not take with TRIQUILAR

(see When It Should Not Be Used). Certain drugs may interact

with

birth-control

pills

make

them

less

effective

preventing pregnancy or cause an increase in breakthrough

bleeding. Please inform your doctor or pharmacist if you are

taking

have

recently

taken

other

drugs

herbal

products, even those without a prescription. Also tell any other

doctor or dentist who prescribes another drug (or the dispensing

pharmacist) that you use TRIQUILAR. They can tell you if you

need to use an additional method of contraception and if so, for

how long.

Drugs that may interact with TRIQUILAR include:

drugs used for the treatment of epilepsy (eg, primidone,

phenytoin, barbiturates, carbamazepine, oxcarbazepine,

topiramate, felbamate); tuberculosis (eg, rifampin,

rifabutin), HIV infections (eg, ritonavir, nevirapine), and

Hepatitis C Virus infections (eg, boceprevir, telaprevir)

ombitasvir, paritaprevir, ritonavir, with or without

dasabuvir (used to treat Hepatitis C)

antibiotics (eg, penicillins, tetracyclines, clarithromycin,

erythromycin) for infectious diseases

cyclosporine

antifungals (eg, griseofulvin, fluconazole, itraconazole,

ketoconazole, voriconazole)

cholesterol-lowering drugs (eg, clofibrate)

drugs used for the treatment of certain heart diseases or for

high blood pressure (eg, diltiazem, verapamil)

antidiabetic drugs and insulin (for diabetes)

prednisone

sedatives and hypnotics (eg, benzodiazepines, barbiturates,

chloral hydrate, glutethimide, meprobamate)

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 50 of 54

meperidine (pain medication)

antidepressants (eg, clomipramine)

tizanidine (drugs used for multiple sclerosis [MS])

theophylline (drug used for asthma)

some nutritional supplements (eg, Vit. B

, folic acid)

antacids (use 2 hours before or after taking TRIQUILAR)

TRIQUILAR may also interfere with the working of other

drugs.

Herbal or food products that may interact with

TRIQUILAR include:

the herbal remedy St. John’s wort (primarily used for

the treatment of depressive moods)

grapefruit juice

This is not a complete list of possible drug interactions with

TRIQUILAR. Talk to your doctor for more information about

drug interactions.

PROPER USE OF THIS MEDICATION

Usual dose:

HOW TO TAKE TRIQUILAR

READ THESE DIRECTIONS

before you start taking your pills, and

any time you are not sure what to do.

LOOK AT YOUR PILL PACK to see if it has 21 or 28

pills:

21-Pill Pack: 21 hormone-containing (6 light brown, 5

white, and 10 ochreous) pills taken daily for three weeks,

and then no pills taken for one week.

OR

28-Pill Pack: 21 hormone-containing (6 light brown, 5

white and 10 ochreous) pills taken daily for three weeks,

and then seven hormone-free “reminder” (slightly larger,

white) pills taken daily for one week.

ALSO CHECK the pill pack for: 1) where to start, and

2) direction to take pills in (follow the arrows).

You should use a second method of birth control (eg, latex

or polyurethane 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 you are

getting used to taking them.

4.

When receiving any medical treatment, be sure to tell

your doctor that you are using birth control pills.

IF YOU EXPERIENCE VOMITING OR DIARRHEA,

OR IF YOU TAKE CERTAIN MEDICINES, such as

antibiotics, your pills may not work as well. Use a backup

method, such as latex or polyurethane condoms and

spermicidal foam or gel, until you can check with your

doctor or clinic.

Visit your doctor three months or sooner after the initial

examination. Afterwards, visit your doctor at least once a

year.

Take the pills only on the advice of your doctor and

carefully follow all directions given to you. You must take

the pills exactly as prescribed. Otherwise, you may become

pregnant.

Your doctor will advise you of the appropriate time to start

the use of birth control pills after childbirth, miscarriage, or

therapeutic abortion.

THERE IS NO NEED TO STOP TAKING BIRTH

CONTROL PILLS FOR A REST PERIOD.

10. IF YOUR QUESTIONS ARE NOT ANSWERED

HERE, CALL YOUR DOCTOR OR CLINIC.

WHEN TO START THE FIRST PACK OF PILLS

BE SURE TO READ THESE INSTRUCTIONS:

before you start taking your pills, and

any time you are not sure what to do.

Decide with your doctor or clinic what the best day is for you to

start taking your first pack of pills. Your pills may be either a

21-day or a 28-day type.

21-DAY COMBINATION

With this type of birth control pill, you are on pills for 21 days

and off pills for seven days. You must not be off the pills for

more than seven days in a row.

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 51 of 54

THE FIRST DAY OF YOUR MENSTRUAL PERIOD

(BLEEDING) IS DAY 1 OF YOUR CYCLE. Your

doctor may advise you to start taking the pills on Day 1, on

Day 5, or on the first Sunday after your period begins. If

your period starts on Sunday, start that same day.

On the back of the pill pack, there is an area shaded in red

which reads “I took my first pill on” followed by the days

of the week directly below. Under each day of the week,

there is a black circle which may be punctured in order to

remember the day you first took your pill.

Take your first pill starting at the circle shaded in red

marked “1.”

Take one pill each day, following the direction of the

arrows.

When you have taken all 21pills in this pack, wait seven

days and then start a new pack of TRIQUILAR 21. During

the seven days when you are not taking any pills, you

should have your period.

The first pill in every subsequent pack will always be taken

on the same day of the week that you first began taking

TRIQUILAR 21 pills.

28-DAY COMBINATION

With this type of birth control pill, you take 21 pills which

contain hormones and seven pills which contain no hormones.

THE FIRST DAY OF YOUR MENSTRUAL PERIOD

(BLEEDING) IS DAY 1 OF YOUR CYCLE. Your

doctor may advise you to start taking the pills on Day 1, on

Day 5, or on the first Sunday after your period begins. If

your period starts on Sunday, start that same day.

Select the calendar sticker that is blue coded with the day

you take your first pill and discard the rest.

Place the selected calendar sticker on the designated area,

aligning the blue section with the blue box marked

“START.”

Take your first pill starting at the blue box marked

“START.”

Take one pill each day, following the direction of the

arrows. Your period should usually occur during the last

week of pills.

When you have finished this pack, start a new pack of

TRIQUILAR 28 on the next day.

The first pill in every subsequent pack will always be taken

on the same day of the week that you first began taking

TRIQUILAR 28 pills.

WHAT TO DO DURING THE MONTH

TAKE A PILL AT APPROXIMATELY THE SAME

TIME EVERY DAY UNTIL THE PACK IS EMPTY.

Try to associate taking your pill with some regular activity,

such as eating a meal or going to bed.

Do not skip pills even if you have bleeding between

monthly periods or feel sick to your stomach (nausea).

Do not skip pills even if you do not have sex very often.

WHEN YOU FINISH A PACK

21 PILLS

WAIT SEVEN DAYS to start the next pack. You will

have your period during that week.

28 PILLS

Start the next pack ON THE NEXT DAY. Take one pill

every day. Do not wait any days between packs.

Overdose:

Symptoms of overdose may include nausea, vomiting, or

vaginal bleeding. Even girls who have not yet had their first

menstrual period but have accidentally taken this medicine may

experience such bleeding. Available information from cases of

accidental ingestion of oral contraceptives by children indicates

no serious effects.

In case of drug overdose, contact a health care practitioner,

hospital emergency department, or regional Poison Control

Center immediately, even if there are no symptoms.

Missed dose:

MISSING PILLS CAN CAUSE SOME SPOTTING OR

LIGHT BLEEDING, even if you make up the missed pills.

You also could feel a little sick to your stomach on the days

you take two pills to make up for missed pills.

IF YOU MISS PILLS AT ANY TIME, YOU COULD GET

PREGNANT. THE GREATEST RISKS FOR

PREGNANCY ARE:

when you start a pack late, or

when you miss pills at the beginning or at the very end of

the pack.

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 52 of 54

WHAT TO DO IF YOU MISS PILLS

The following chart outlines the actions you should take if you

miss one or more of your birth control pills. Match the number

of pills missed with the appropriate starting time for your type

of pill pack.

Sunday Start

Other than Sunday Start

Miss One Light Brown, White

or Ochreous Pill At Any Time

Miss One Light Brown,

White or Ochreous Pill At

Any Time

Take it as soon as you remember,

and take the next pill at the usual

time. This means that you might

take two pills in one day.

Take it as soon as you

remember, and take the next

pill at the usual time. This

means that you might take two

pills in one day.

Miss Two Light Brown, White

or Ochreous Pills in a Row

Miss Two Light Brown,

White or Ochreous Pills in a

Row

First Two Weeks:

Take two pills the day you

remember and two pills the

next day.

Then take one pill a day until

you finish the pack.

Use a back-up (barrier)

method of birth control if you

have sex in the seven days

after you miss the pills.

First Two Weeks:

Take two pills the day you

remember and two pills

the next day.

Then take one pill a day

until you finish the pack.

Use a back-up (barrier)

method of birth control if

you have sex in the seven

days after you miss the

pills.

Third Week

Keep taking one pill a day

until Sunday.

On Sunday, safely discard the

rest of the pack and start a

new pack that day.

Use a back-up (barrier)

method of birth control if you

have sex in the seven days

after you miss the pills.

You may not have a period

this month.

If you miss two periods in a

row, call your doctor or clinic.

Third Week

Safely dispose of the rest of

the pill pack and start a new

pack that same day.

Use a back-up (barrier)

method of birth control if

you have sex in the seven

days after you miss the

pills.

You may not have a period

this month.

If you miss two periods in a

row, call your doctor or

clinic.

Miss Three or More Light

Brown, White or Ochreous

Pills in a Row

Miss Three or More Light

Brown, White or Ochreous

Pills in a Row

Anytime in the cycle

Keep taking one pill a day

until Sunday.

On Sunday, safely discard the

Anytime in the cycle

Safely dispose of the rest of

the pill pack and start a new

pack that same day.

Sunday Start

Other than Sunday Start

rest of the pack and start a

new pack that day.

Use a back-up (barrier)

method of birth control if you

have sex in the seven days

after you miss the pills.

You may not have a period

this month.

If you miss two periods in a

row, call your doctor or clinic.

Use a back-up (barrier)

method of birth control if

you have sex in the seven

days after you miss the

pills.

You may not have a period

this month.

If you miss two periods in a

row, call your doctor or

clinic.

NOTE: 28-DAY PACK - If you forget any of the seven

slightly larger, hormone-free white “reminder” pills in Week 4,

just safely dispose of the pills you missed. Then keep taking

one pill each day until the pack is empty. You do not need to

use a back-up method.

Always be sure you have on hand:

a back-up method of birth control (such as latex or

polyurethane condoms and spermicidal foam or gel) in

case you miss pills; and

an extra, full pack of pills.

IF YOU FORGET MORE THAN ONE PILL TWO

MONTHS IN A ROW, talk to your doctor or phone your

clinic about how to make pill-taking easier or about using

another method of birth control.

Noncontraceptive Benefits of Birth Control Pills

Several health advantages have been linked to the use of birth

control pills:

Combination estrogen and progestin birth control pills

reduce the incidence of cancer of the uterus and ovaries.

Birth control pills reduce the likelihood of developing

benign (non-cancerous) breast disease and ovarian cysts.

Users of birth control pills lose less menstrual blood and

have more regular cycles. The risk of developing

iron-deficiency anemia is thus reduced.

There may be a decrease in painful menstruation and in

premenstrual syndrome (PMS).

Acne, excessive hair growth and male-hormone-related

disorders also may be improved.

Ectopic (tubal) pregnancy may occur less frequently.

Acute pelvic inflammatory disease may occur less

frequently.

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 53 of 54

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The following side effects have been observed in studies of

women taking TRIQUILAR:

Common:

painful menstrual periods, spotting, breast pain, increased and

decreased libido, breakthrough bleeding, change in skin

pigmentation, nausea and/or vomiting, headache, migraine,

depression, varicose veins, acne

Uncommon:

increased appetite, swelling, thrombophlebitis (inflammation of

veins), weight gain

If you experience new onset of high blood pressure or

worsening of high blood pressure, contact your doctor or

pharmacist.

The following additional symptoms have been reported in

women taking hormonal contraceptives in general:

difficulty wearing contact lenses

vaginal irritation or infections

urinary tract infections or inflammation

upper respiratory tract infections (colds, bronchitis, runny

or stuffy nose, sore throat, etc)

severe headaches

depression, insomnia, nervousness

amenorrhea (lack of a period or breakthrough bleeding)

back pain

abdominal pain

flu-like symptoms

allergy, fatigue, fever

diarrhea, flatulence

rash

Many women have spotting or light bleeding or may feel sick

to their stomach during the first three months on the pill. If you

do feel sick, do not stop taking the pill. The problem will

usually go away. If it does not go away, check with your

doctor or clinic.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / Possible Side Effect

Talk With

Your Doctor

or

Pharmacist

Stop

Taking

Drug and

Call Your

Doctor or

Pharmacist

Only if

severe

In all

cases

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / Possible Side Effect

Talk With

Your Doctor

or

Pharmacist

Stop

Taking

Drug and

Call Your

Doctor or

Pharmacist

Only if

severe

In all

cases

Common

Persistent sad

mood

Uncommon

Abdominal pain,

nausea or vomiting

or lump in the

abdomen

Breast lump

Crushing chest pain

or heaviness

Pain or swelling in

the leg

Sharp pain in the

chest, coughing

blood, or sudden

shortness of breath

Sudden partial or

complete loss of

vision or double

vision

Sudden severe

headache or

worsening of

headache,

vomiting,

dizziness, fainting,

disturbance of

vision or speech, or

weakness or

numbness in the

face, arm or leg

Unexpected

vaginal bleeding

Unusual swelling

of the extremities

Yellowing of the

skin or eyes

(jaundice)

This is not a complete list of side effects. If you have any

unexpected effects while taking TRIQUILAR, contact your

doctor or pharmacist.

IMPORTANT: PLEASE READ

TRIQUILAR Product Monograph

Page 54 of 54

HOW TO STORE IT

Store in original packaging between 15ºC and 30ºC. 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.

REPORTING SUSPECTED SIDE EFFECTS

Canada Vigilance Program

You can report any suspected adverse reactions associated

with the use of health products to the Canada Vigilance

Program by one of the following 3 ways:

Report online at

www.healthcanada.gc.ca/medeffect

Call toll-free at 1-866-234-2345

Complete a Canada Vigilance Reporting Form

and:

Fax toll-free to 1-866-678-6789, or

Mail to:

Canada Vigilance Program

Health Canada

Postal Locator 0701D

Ottawa, ON K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and

the adverse reaction reporting guidelines are available on the

MedEffect™ Canada Web site at

www.healthcanada.gc.ca/medeffect.

NOTE: Should you require information related to the

management of side effects, contact your health

professional. The Canada Vigilance Program does not

provide medical advice.

MORE INFORMATION

For more information, please contact your health professional

or pharmacist first, or Bayer Medical Information at

1-800-265-7382 or canada.medinfo@bayer.com.

This document plus the full Product Monograph, prepared for

health professionals can be found at: http://www.bayer.ca or by

contacting the manufacturer at the above-mentioned phone

number and email address.

This leaflet was prepared by:

Bayer Inc.

2920 Matheson Boulevard East

Mississauga, Ontario L4W 5R6

Canada

Last revised: May 26, 2017

© 2017, Bayer Inc.

® TM see www.bayer.ca/tm-mc

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