TRI-JORDYNA 28 TABLET

Canada - English - Health Canada

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Active ingredient:
ETHINYL ESTRADIOL; NORGESTIMATE; NORGESTIMATE; ETHINYL ESTRADIOL; NORGESTIMATE; ETHINYL ESTRADIOL
Available from:
GLENMARK PHARMACEUTICALS CANADA INC.
ATC code:
G03AB11
INN (International Name):
NORGESTIMATE AND ESTROGEN
Dosage:
0.035MG; 0.18MG; 0.215MG; 0.035MG; 0.25MG; 0.035MG
Pharmaceutical form:
TABLET
Composition:
ETHINYL ESTRADIOL 0.035MG; NORGESTIMATE 0.18MG; NORGESTIMATE 0.215MG; ETHINYL ESTRADIOL 0.035MG; NORGESTIMATE 0.25MG; ETHINYL ESTRADIOL 0.035MG
Administration route:
ORAL
Units in package:
84 TABS (3 X 28)
Prescription type:
Prescription
Therapeutic area:
CONTRACEPTIVES
Product summary:
Active ingredient group (AIG) number: 0636783002; AHFS: 68:12.00
Authorization status:
APPROVED
Authorization number:
02486318
Authorization date:
2019-03-01

Documents in other languages

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PRODUCT MONOGRAPH

Pr

TRI-JORDYNA™ 21

Pr

TRI-JORDYNA ™ 28

Norgestimate and Ethinyl Estradiol Tablets USP

0.18 mg norgestimate and 0.035 mg ethinyl estradiol

0.215 mg norgestimate and 0.035 mg ethinyl estradiol

0.25 mg norgestimate and 0.035 mg ethinyl estradiol

Oral Contraceptive

Glenmark Pharmaceuticals Canada Inc.

1600 Steeles Ave. West,

Suite 407, Concord, ON

L4K 4M2

Canada

Date of Revision:

October 4, 2019

Submission Control No.: 231016

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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 ......................................................................................................... 18

DOSAGE AND ADMINISTRATION ..................................................................................... 25

OVERDOSAGE ....................................................................................................................... 31

ACTION AND CLINICAL PHARMACOLOGY ................................................................... 32

STORAGE AND STABILITY ................................................................................................. 33

DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................... 34

PART II: SCIENTIFIC INFORMATION .................................................................................... 35

PHARMACEUTICAL INFORMATION ................................................................................. 35

CLINICAL TRIALS ................................................................................................................. 36

DETAILED PHARMACOLOGY ............................................................................................ 40

TOXICOLOGY ........................................................................................................................ 40

REFERENCES ......................................................................................................................... 48

PART III: CONSUMER INFORMATION .................................................................................. 53

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PRODUCT MONOGRAPH

Pr

TRI-JORDYNA™ 21

Pr

TRI-JORDYNA ™ 28

Norgestimate and Ethinyl Estradiol Tablets USP

0.18 mg norgestimate and 0.035 mg ethinyl estradiol

0.215 mg norgestimate and 0.035 mg ethinyl estradiol

0.25 mg norgestimate and 0.035 mg ethinyl estradiol

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form / Strength

All Nonmedicinal

Ingredients

Oral

Tablets,

0.18 mg norgestimate and 0.035 mg ethinyl estradiol

0.215 mg norgestimate and 0.035 mg ethinyl

estradiol

0.25 mg norgestimate and 0.035 mg ethinyl estradiol

Lactose

monohydrate

For a complete

listing see Dosage

Forms,

Composition and

Packaging section.

INDICATIONS AND CLINICAL USE

TRI-JORDYNA™ Tablets are indicated for:

Conception control.

The treatment of moderate acne vulgaris in females, ≥ 15 years of age, who have no known

contraindications to oral contraceptive therapy, desire contraception, and have achieved

menarche.

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CONTRAINDICATIONS

History of or actual thrombophlebitis or thromboembolic disorders.

Known thrombophilic conditions.

History of or actual cerebrovascular disorders.

History of or actual myocardial infarction or coronary arterial disease.

History of or actual prodromi of a thrombosis (e.g., transient ischemic attack, angina pectoris).

Active liver disease or history of or actual benign or malignant liver tumours.

Use with the Hepatitis C virus (HCV) combination drug regimen ombitasvir,

paritaprevir, ritonavir, with or without dasabuvir (see WARNINGS AND

PRECAUTIONS).

Known or suspected carcinoma of the breast.

Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.

Undiagnosed abnormal vaginal bleeding.

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

of vision or defect in visual fields.

When pregnancy is suspected or diagnosed.

Valvular heart disease with complications.

Steroid-dependent jaundice, cholestatic jaundice or history of jaundice of pregnancy.

Current or history of migraine with focal aura.

History of or actual pancreatitis if associated with severe hypertriglyceridemia.

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

persistent blood pressure values ≥160 mm Hg systolic or ≥100 mm Hg diastolic

hereditary or acquired predisposition for venous or arterial thrombosis, such as

Factor V Leiden mutation and activated protein C (APC-) resistance, antithrombin-

III- deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia

(e.g., due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A,

and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant)

severe dyslipoproteinemia

over age 35 and smoke

diabetes mellitus with vascular involvement

major surgery associated with an increased risk of postoperative thromboembolism

prolonged immobilization

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

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

AND PACKAGING section of the Product Monograph.

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WARNINGS AND PRECAUTIONS

General

Discontinue Medication at the Earliest Manifestation of the Following:

A.

Thromboembolic and Cardiovascular Disorders such as thrombophlebitis, pulmonary

embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis, and

retinal thrombosis.

B.

Conditions that Predispose to Venous Stasis and to Vascular Thrombosis (e.g.,

immobilization after accidents or confinement to bed during long-term illness). Other

non-hormonal methods of contraception should be used until regular activities are

resumed. For use of oral contraceptives when surgery is contemplated, see

WARNINGS AND PRECAUTIONS, Peri-Operative Considerations.

C.

Visual Defects – Partial or Complete

D.

Papilledema or Ophthalmic Vascular Lesions

E.

Severe Headache of Unknown Etiology or Worsening of Pre-existing Migraine

Headache

F.

Increase in Epileptic Seizures

The following information is provided from studies of combination oral contraceptives

(COCs):

The use of COCs is associated with increased risks of several serious conditions including

myocardial infarction, thromboembolism, stroke, hepatic neoplasia and gallbladder disease,

although the risk of serious morbidity and mortality is small in healthy women without

underlying risk factors. The risk of morbidity and mortality increases significantly if associated

with the presence of other risk factors such as hypertension, hyperlipidemias, obesity and

diabetes. Other examples of medical conditions which have been associated with adverse

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious cardiovascular events from combination oral

contraceptive use. 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 TRI-JORDYNA™, should not be used by women who are over 35 years of age and

smoke (see Cardiovascular section below).

Oral contraceptives DO NOT PROTECT against sexually transmitted infections (STIs)

including HIV/AIDS. For protection against STIs, it is advisable to use latex or polyurethane

condoms IN COMBINATION WITH oral contraceptives.

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circulatory events e.g., systemic lupus erythematosus

, hemolytic uremic syndrome

, chronic

inflammatory bowel disease (Crohn’s disease or ulcerative colitis)

, sickle cell disease

, valvular

heart disease and atrial fibrillation

The following conditions have been reported to occur or deteriorate with both pregnancy and

COC use, although a direct association with COCs has not been firmly established: porphyria

systemic lupus erythematosus

, hemolytic uremic syndrome

, Sydenham’s chorea

12,13

, herpes

gestationis

14,15

and otosclerosis-related hearing loss

The information contained in this section is principally from studies carried out in women who

used COCs with higher formulations of estrogen and progestogens than those in common use

today. The effect of long-term use of COCs with lower doses of both estrogen and progestogen

administered orally remains to be determined.

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Carcinogenesis and Mutagenesis

Breast Cancer

Increasing age and a strong family history are the most significant risk factors for the

development of breast cancer. Other established risk factors include obesity, nulliparity and late

age for first full-term pregnancy. The identified groups of women that may be at increased risk

of developing breast cancer before menopause are long-term users of oral contraceptives (more

than eight years) and starters at an early age. In a few women, the use of oral contraceptives may

accelerate the growth of an existing but undiagnosed breast cancer. Since any potential

increased risk related to oral contraceptive use is small, there is no reason to change prescribing

habits at present.

Women receiving oral contraceptives should be instructed in self-examination of their breasts.

Their physicians should be notified whenever any masses are detected. A yearly clinical breast

examination is also recommended because, if a breast cancer should develop, drugs that contain

estrogen may cause a rapid progression.

Cervical Cancer

The most important risk factor for cervical cancer is persistent human papilloma virus (HPV)

infection. Some epidemiological studies have indicated that long-term use of COCs may further

contribute to this increased risk but there continues to be controversy about the extent to which

this finding is attributable to confounding effects, e.g., cervical screening and sexual behaviour

including use of barrier contraceptives.

Hepatocellular Carcinoma

Hepatocellular carcinoma may be associated with oral contraceptives. The risk appears to

increase with duration of hormonal contraceptive use. However, the attributable risk (the excess

incidence) of liver cancers in oral contraceptive users is extremely small.

Cardiovascular

Predisposing Factors for Coronary Artery Disease

Cigarette smoking increases the risk of serious cardiovascular events and mortality from

combination oral contraceptive (COC) use. This risk increases with age, particularly in women

over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs,

including TRI-JORDYNA™, 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.

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Hypertension

Patients with essential hypertension whose blood pressure (BP) is well controlled may be given

oral contraceptives but only under close supervision. If a significant and persistent 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 and an alternate method of

contraception should be prescribed (see CONTRAINDICATIONS).

An increase in BP 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 combination oral

contraceptives use and the development of Crohn’s disease and ulcerative colitis, although this

has not been firmly established

17-22

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.

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Hematologic

Venous and Arterial Thrombosis and Thromboembolism

Venous thrombosis and thromboembolism

Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in

users of oral contraceptives with low estrogen content (<50 mcg ethinyl estradiol) ranges

from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to

the progestogen. This compares with 5 to 10 cases per 100,000 women-years for non-users.

The use of any combined oral contraceptive (COC) carries an increased risk of VTE compared

with no use. The excess risk of VTE is highest during the first year a woman ever uses a COC or

restarts (following a 4-week or greater pill-free interval) the same or a different COC. The

increased risk is less than the risk of VTE associated with pregnancy, which is estimated as 60

cases per 100,000 pregnancies. VTE is fatal in 1–2% of cases.

If a hereditary or acquired predisposition for VTE is suspected, the woman should be referred to

a specialist for advice before deciding on any COC use.

Arterial thrombosis and thromboembolism

The use of COCs increases the risk of arterial thrombotic and thromboembolic events. Reported

events include myocardial infarction and cerebrovascular events (ischemic and hemorrhagic

stroke and transient ischemic attack).

The risk of arterial thrombotic and thromboembolic events is further increased in women with

underlying risk factors. Caution must be exercised when prescribing COCs for women with risk

factors for arterial thrombotic and thromboembolic events.

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 for

venous or arterial thromboembolism is suspected, the woman should be referred to a specialist

for advice before deciding on any COC use. The risk of VTE/ATE may be temporarily increased

with prolonged immobilization, major surgery, or trauma. In these situations, it is advisable to

discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to

resume COC use until 2 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 and antiphospholipid

antibodies (anticardiolipin antibodies, lupus anticoagulant).

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Postpartum Period

Since the immediate postpartum period is also associated with an increased risk of

thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery

in women who elect not to breast-feed (see DOSAGE AND ADMINISTRATION, Special

Notes on Administration).

Post-abortion/Post-miscarriage

After an induced or spontaneous abortion that occurs at or after 20 weeks gestation, hormonal

contraceptives may be started either on Day 21 post-abortion or on the first day of the first

spontaneous menstruation, whichever comes first (see DOSAGE AND ADMINISTRATION,

Special Notes on Administration).

Hepatic/Biliary/Pancreatic

Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use

until markers of liver function return to normal.

Jaundice

Patients who have had jaundice, including a history of cholestatic jaundice during pregnancy,

should be given oral contraceptives 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 oral 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 of use.

Gallbladder disease including cholecystitis and cholelithiasis has been reported with oral

contraceptive use.

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

TRI-JORDYNA

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). During clinical trials with

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ombitasvir, paritaprevir, ritonavir, with or 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. Physicians

are advised to consult the labelling of concurrently-used HCV combination drug regimen

ombitasvir, paritaprevir, ritonavir with or without dasabuvir to obtain further information about

restartingTRI-JORDYNA

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in

women with hereditary angioedema

24-27

Neurologic

Migraine and Headache

The onset or exacerbation of migraine or the development of headache of a new pattern that is

recurrent, persistent or severe requires discontinuation of oral 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 reports of retinal thrombosis associated with the use of oral

contraceptives. Oral contraceptives should be discontinued if there is unexplained transient,

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

Thromboembolic Complications – Post-surgery

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has

been reported with the use of hormonal contraceptives. The relative risk of venous thrombosis in

women who have predisposing conditions is twice that of women without such medical

conditions.

Hormonal contraceptives should be discontinued and an alternative method substituted at least

four weeks prior to elective surgery of a type associated with an increase in risk of

thromboembolism and during prolonged immobilization. Hormonal contraceptives should not be

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resumed until the first menstrual period after hospital discharge following surgery or following

prolonged immobilization.

Psychiatric

Emotional Disorders

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 alternative 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.

Sexual Function/Reproduction

Amenorrhea

In the event of amenorrhea, pregnancy should be ruled out.

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.

Return to Fertility

After discontinuing oral contraceptive therapy, the patient should delay pregnancy until at least

one normal spontaneous cycle has occurred in order to date the pregnancy. An alternative

contraceptive method should be used during this time.

Reduced Efficacy

The efficacy of COCs may be reduced in the event of missed tablets, gastro-intestinal

disturbances or concomitant medication (see DRUG INTERACTIONS).

Skin

Chloasma may occasionally occur, 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 this preparation. Chloasma is often not fully reversible.

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Special Populations

Pregnant Women:

TRI-JORDYNA™ is contraindicated during pregnancy. If pregnancy occurs during treatment

with

TRI-JORDYNA

, 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.

Nursing Women:

Contraceptive steroids and/or their metabolites may be excreted in breast milk. In addition,

combination hormonal contraceptives given in the postpartum period may interfere with lactation

by decreasing the quantity and quality of breast milk. If possible, the nursing mother should be

advised not to use TRI-JORDYNA™ or other combination hormonal contraceptives but to use

other forms of contraception until the child is fully weaned.

Pediatrics (<16 years of age):

Safety and efficacy of norgestimate and ethinyl estradiol tablets have been established in women

of reproductive age. Use of this product before menarche is not indicated.

Geriatrics (> 65 years of age):

TRI-JORDYNA™ are not indicated for use in post-menopausal women.

Monitoring and Laboratory Tests

Physical Examination and Follow-up

Before oral contraceptives are used, a thorough history and physical examination should be

performed, including a blood pressure determination and the family case history carefully noted.

In addition, disturbances of the clotting system must be ruled out if any members of the family

have suffered from thromboembolic diseases (e.g., deep vein thrombosis, stroke, myocardial

infarction) at a young age. Breasts, liver, extremities, and pelvic organs should be examined. A

Papanicolaou (PAP) smear should be taken if the patient has been sexually active.

The first follow-up visit should be 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

Periodic Health Examination. Their suggestion was that, for women who had two consecutive

negative PAP smears, screening could be continued every three years up to the age of 69.

Tissue Specimens

Pathologists should be advised of oral contraceptive therapy when specimens obtained from

surgical procedures and PAP smears are submitted for examination.

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ADVERSE REACTIONS

Adverse Drug Reaction Overview

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

oral contraceptives:

Thrombophlebitis and venous thrombosis with or without embolism

Arterial thromboembolism

Pulmonary embolism

Mesenteric thrombosis

Neuro-ocular lesions (e.g., retinal thrombosis)

Myocardial infarction

Cerebral thrombosis

Cerebral hemorrhage

Hypertension

Benign hepatic tumours

Gallbladder disease

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

contraceptives. Nausea and vomiting, usually the most common adverse reaction, occurs in

approximately 10 per cent or less patients during the first cycle. Other reactions, as a general

rule, are seen less frequently or only occasionally, as follows:

Cardiovascular System:

Edema

Slight rise of blood pressure

Genital Tract:

Breakthrough bleeding

Spotting

Change in menstrual flow

Dysmenorrhea

Amenorrhea during and after treatment

Vaginal candidiasis

Premenstrual-like syndrome

Temporary infertility after discontinuance of treatment

Vaginitis

Endocervical hyperplasias

Increase in cervical erosion and secretion

Neoplasms:

Malignant hepatic tumours

Cervical cancer

Increase in size of uterine leiomyomata

Breast cancer

Breast:

Pain, tenderness, enlargement, and secretion

Possible diminution in lactation when given immediately

postpartum

Skin and Subcutaneous Tissue:

Chloasma or melasma which may persist

Rash (allergic)

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Hirsutism

Loss of scalp hair

Erythema multiforme

Erythema nodosum

Raynaud's phenomenon

Hemorrhagic eruption

Porphyria

Acne

Seborrhea

Pemphigoid (herpes gestationis)

Urticaria

Angioedema

CNS:

Migraine

Depression

Headache

Nervousness

Dizziness

Changes in libido

Chorea

Metabolic:

Reduced tolerance to carbohydrates

Change in weight (increase or decrease)

Changes in appetite

Gastro-intestinal Tract:

Gastrointestinal symptoms (such as abdominal cramps and

bloating)

Colitis

Pancreatitis

Hepatobiliary:

Cholestatic jaundice

Budd-Chiari syndrome

Eyes:

Intolerance to contact lenses

Change in corneal curvature (steepening)

Cataracts

Optic neuritis

Retinal thrombosis

Urinary:

Impaired renal function

Hemolytic uremic syndrome

Cystitis-like syndrome

Others:

Rhinitis

Auditory disturbances

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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 safety of norgestimate and ethinyl estradiol

tablets was evaluated in 4,826 healthy women

of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of

norgestimate and ethinyl estradiol

tablets for contraception. Two trials were randomized, active-

controlled trials and 4 were uncontrolled, open-label trials. In 3 trials, subjects were followed

for up to 24 cycles; in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial,

subjects were followed for up to 6 cycles. The most frequent Adverse Drug Reactions (ADRs)

reported in >5% of subjects were headache, breast pain and vaginal infection. ADRs reported

by ≥1% of subjects treated with norgestimate and ethinyl estradiol tablets in these trials are

shown in Table 1.

Table 1: Adverse Drug Reactions Reported by ≥1% of Subjects Treated with

Norgestimate and Ethinyl Estradiol Tablets in 6 Clinical Trials of

Norgestimate and Ethinyl Estradiol Tablets

System/Organ Class

Adverse Reaction

(N=4,826)

Infections and Infestations

Vaginal infection

Metabolism and Nutrition Disorders

Fluid retention

Psychiatric Disorders

Mood altered

Nervousness

Depression

Nervous System Disorders

Headache

31.7

Migraine

Gastrointestinal Disorders

Abdominal pain

Gastrointestinal pain

Flatulence

Skin and Subcutaneous Tissue Disorders

Rash

Reproductive System and Breast Disorders

Breast pain

Genital discharge

General Disorders and Administration Site Conditions

Edema

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Investigations

Weight increased

Additional ADRs reported by <1% of subjects (N=4,826) treated with norgestimate and

ethinyl estradiol tablets in the above clinical dataset are shown in Table 2.

Table 2: Adverse Drug Reactions Reported by <1% of Subjects Treated with

Norgestimate and Ethinyl Estradiol Tablets in 6 Clinical Trials of

Norgestimate and Ethinyl Estradiol

System/Organ Class

Adverse Reaction

Metabolism and Nutrition Disorders

Increased appetite, Decreased appetite, Weight fluctuation, Appetite disorder

Psychiatric Disorders

Libido disorder

Vascular Disorders

Hypertension

Skin and Subcutaneous Tissue Disorders

Alopecia, Rash popular, Skin discolouration, Erythema

Reproductive System and Breast Disorders

Breast enlargement, Breast discharge, Menstruation irregular, Menstrual disorder

Investigations

Weight decreased

In the above trials with norgestimate and ethinyl estradiol tablets, details for specific ADRs,

namely nausea, vomiting, gastrointestinal disorder (reported as nausea or vomiting),

dysmenorrhea, metrorrhagia, abnormal withdrawal bleeding, amenorrhea and premenstrual

syndrome, were solicited or determined from bleeding pattern or cycle characteristics data on a

by-cycle basis, e.g., using menstrual calendars or diary cards. These ADRs are not included in

Tables 1 and 2, as the incidence of each ADR was reported separately by treatment cycle only

and no overall subject incidence for the whole trial was reported. In general, solicited events are

associated with higher reporting rates than events spontaneously reported by subjects.

By-cycle ADRs reported by ≥1% of subjects treated with norgestimate and ethinyl estradiol

tablets in cycle 1 are shown in Table 3. With the exception of premenstrual syndrome and

dsymenorrhea, the incidence of these ADRs was highest in cycle 1 and decreased over time with

further treatment cycles. Premenstrual syndrome remained relatively stable over time and

dysmenorrhea remained relatively stable, with a slight decrease over time (based on incidence

data from cycles 1, 3, 6, 12 and 24).

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Table 3: Adverse Drug Reactions Reported by ≥1% of Subjects Treated with Norgestimate and

Ethinyl Estradiol Tablets in Cycle 1 in 6 Clinical Trials (Except Where Specified) of

Norgestimate and Ethinyl Estradiol

System/Organ Class

Adverse Reaction

Total Subjects

1

(N)

Cycle 1 (%)

Gastrointestinal Disorders

Gastrointestinal disorder

1,779

25.9

Nausea

19.1

Vomiting

Reproductive System and Breast

Disorders

Dysmenorrhea

2,675

37.0

Premenstrual syndrome

2,673

32.0

Metrorrhagia

2,912

22.7

Abnormal withdrawal bleeding

2,912

14.8

Amenorrhea

2,334

Number of subjects with available data for cycle 1.

Based on data from 2 trials.

Reported as nausea or vomiting.

Based on data from 3 trials.

Based on data from 5 trials.

Post-Market Adverse Drug Reactions

Adverse drug reactions first identified during post-marketing experience with norgestimate/ethinyl

estradiol (NGM/EE) are included in Table 4.

Table 4: Adverse Drug Reactions Identified During Post-Marketing Experience with

NGM/EE from Spontaneous Reports

Infections and Infestations

Urinary tract infection

Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps)

Breast cancer, Cervical dysplasia, Benign breast neoplasm, Hepatic adenoma, Focal

nodular hyperplasia, Fibroadenoma of breast, Breast cyst

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Dyslipidaemia

Psychiatric Disorders

Anxiety, Insomnia

Nervous System Disorders

Cerebrovascular accident, Syncope, Convulsion, Paraesthesia, Dizziness

Eye Disorders

Retinal vascular thrombosis, Visual impairment, Dry eye, Contact lens intolerance

Ear and Labyrinth Disorders

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Vertigo

Cardiac Disorders

Myocardial infarction, Tachycardia, Palpitations

Vascular Disorders

Arterial thromboembolism, Deep vein thrombosis, Hot flush, Venous thrombosis

Respiratory, Thoracic and Mediastinal Disorders

Pulmonary embolism, Dyspnea

Gastrointestinal Disorders

Pancreatitis, Abdominal distension, Diarrhea, Constipation

Hepatobiliary Disorders

Hepatitis

Skin and Subcutaneous Tissue Disorders

Angioedema, Erythema nodosum, Hirsutism, Night sweats, Hyperhidrosis, Photosensitivity

reaction, Urticaria, Pruritus, Acne

Musculoskeletal, Connective Tissue, and Bone Disorders

Muscle spasms, Pain in extremity, Myalgia, Back pain

Reproductive System and Breast Disorders

Ovarian cyst, Suppressed lactation, Vulvovaginal dryness

General Disorders and Administration Site Conditions

Chest pain, Asthenic conditions

The bundled terms for venous thrombosis include Budd Chiari Syndrome and hepatic vein thrombosis.

DRUG INTERACTIONS

Overview

The concurrent administration of oral contraceptives with other drugs may result in an altered

response to either agent (see Tables 5 and 6). Reduced effectiveness of the oral contraceptive,

should it occur, is more likely with the low-dose formulations.

It is important to ascertain all drugs that a patient is taking, both prescription and non-

prescription, including herbal preparations/remedies, before oral contraceptives are prescribed.

Physicians are advised to consult the labelling of concurrently used drugs to obtain further

information about interactions with hormonal contraceptives or the potential for enzyme

alterations and the possible need to adjust dosages.

Refer to Oral Contraceptives 1994 (Chapter 8), Health Canada, for other possible drug

interactions with OCs.

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Drug-Drug Interactions

Table 5: Drugs That 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.

Anticonvulsants

Carbamazepine

Eslicarbazepine acetate

Ethosuximide

Felbamate

Lamotrigine

Oxcarbazepine

Phenobarbital

Phenytoin

Primidone

Rufinamide

Topiramate

Induction of hepatic microsomal

enzymes. Rapid metabolism of estrogen

and increased binding of progestin and

ethinyl estradiol to SHBG.

Use higher dose OCs (50 mcg

ethinyl estradiol), another drug or

another method.

Antibiotics

Ampicillin

Cotrimoxazole

Penicillin

Enterohepatic circulation disturbance,

intestinal hurry.

For short course, use additional

method or use another drug.

For long course, use another

method.

Rifabutin

Rifampin

Increased metabolism of progestins.

Suspected acceleration of estrogen

metabolism.

Use another method.

Chloramphenicol

Metronidazole

Neomycin

Nitrofurantoin

Sulfonamides

Tetracyclines

Induction of hepatic microsomal

enzymes. Also disturbance of

enterohepatic circulation.

For short course, use additional

method or use another drug.

For long course, use another

method.

Troleandomycin

May retard metabolism of OCs,

increasing the risk of cholestatic jaundice.

Antifungals

Griseofulvin

Stimulation of hepatic metabolism of

contraceptive steroids may occur.

Use another method.

Cholesterol-

Lowering

Agents

Cholestyramine

May result in hastened elimination and

impaired effectiveness.

Clofibrate

Reduces elevated serum triglycerides and

cholesterol; this reduces oral

contraceptive efficacy.

Use another method.

Protease

Inhibitors

Boceprevir

Telaprevir

Uncertain, but may be due to an effect on

GI transporters, leading to a decrease in

the AUC of ethinyl estradiol.

Exposure to ethinyl estradiol was

decreased when co-administered

with telaprevir or boceprevir.

Additional methods of non-

hormonal contraception should be

used when hormonal

contraceptives are co-administered

with telaprevir or boceprevir.

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HIV Protease

Inhibitors

Nelfinavir

Ritonavir

Ritonavir-boosted

protease inhibitors

Induction of hepatic microsomal

enzymes.

Use another drug or another

method.

Non-nucleoside

Reverse

Transcriptase

Inhibitors

Nevirapine

Induction of hepatic microsomal

enzymes.

Use another drug or another

method.

Sedatives

Hypnotics

Benzodiazepines

Barbiturates

Chloral hydrate

Glutethimide

Meprobamate

Induction of hepatic microsomal

enzymes.

For short course, use

additional method or another

drug.

For long course, use

another method or higher

dose OCs.

Other Drugs

Phenylbutazone

Antihistamines

Analgesics

Antimigraine

preparations

Vitamin E

Modafinil

Reduced OC efficacy has been reported.

Remains to be confirmed.

Bosentan

Induction of hepatic microsomal

enzymes.

Consider switching to a non-

hormonal contraceptive method or

adding a barrier method to oral

contraceptive therapy.

Colesevelam

A bile acid sequestrant, given together

with a combined oral hormonal

contraceptive, has been shown to

significantly decrease the AUC of

ethinyl estradiol.

Take contraceptive 4 hours

before colesevelam.

(fos)aprepitant

Induction of hepatic microsomal

enzymes.

Use another method.

Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and

antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics

on plasma concentrations of synthetic steroids.

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Table 6: 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

OCs increase clotting factors,

decrease efficacy. However, OCs

may potentiate action in some

patients.

Use another method.

Anticonvulsants

Fluid retention may increase risk of

seizures.

Use another method.

Lamotrigine

Significantly decreased lamotrigine

levels (due to induction of

lamotrigine glucuronidation) may

lead to breakthrough seizures.

Adjust dose of drug if necessary.

Antidiabetic

Drugs

Oral

hypoglycemics

and Insulin

OCs may impair glucose tolerance

and increase blood glucose.

Use low-dose estrogen and progestin

OC or another method. Monitor blood

glucose.

Antihypertensive

Agents

Guanethidine and

Methyldopa

Estrogen component causes

sodium retention, progestin has no

effect.

Use low-dose estrogen OC or use

another method.

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.

Salicylic acid

Plasma levels may be decreased

(due to induction of

glucuronidation).

Use with caution.

Effects of ASA may be decreased

by the short-term use of OCs.

Patients on chronic ASA therapy may

require an increase in ASA dosage.

Aminocaproic

Acid

Theoretically, a hypercoagulable

state may occur because OCs

augment clotting factors.

Avoid concomitant use.

Betamimetic

Agents

Isoproterenol

Estrogen causes decreased

response to these drugs.

Adjust dose of drug as necessary.

Discontinuing OCs can result in

excessive drug activity.

Caffeine

The actions of caffeine may be

enhanced as OCs may impair the

hepatic metabolism of caffeine.

Use with caution.

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Table 6 (cont’d): Modification of Other Drug Action by Oral Contraceptives

Class of

Compound

Drug

Modification of Drug

Action

Suggested Management

Corticosteroids

Prednisone

Prednisolone

Markedly increased serum levels.

Possible need for decrease in dose.

Cyclosporine

May lead to an increase in

cyclosporine levels and

hepatotoxicity.

Monitor hepatic function. The

cyclosporine dose may have to be

decreased.

Folic Acid

OCs 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.

Morphine

Decreased morphine levels (due to

induction of glucuronidation).

Use with caution.

Phenothiazine

Tranquilizers

Phenothiazines,

Reserpine and

similar drugs

Estrogen potentiates the

hyperprolactinemia effect of these

drugs.

Use other drugs or lower dose OCs. If

galactorrhea or hyperprolactinemia

occurs, use other method.

Proton Pump

Inhibitors

Omeprazole

May lead to an increase in

omeprazole plasma levels (due to

CYP inhibition).

Use with caution.

Sedatives and

Hypnotics

Chlordiazepoxide

Lorazepam

Oxazepam

Diazepam

Increased effect (increased

metabolism).

Use with caution.

Temazepam

Decreased temazepam plasma level

(due to induction of

glucuronidation).

Use with caution.

Theophylline

Decreased oxidation, leading to

possible toxicity.

Use with caution. Monitor theophylline

levels.

Tricyclic

Antidepressants

Clomipramine

(possibly others)

Increased side effects; i.e.,

depression.

Use with caution.

Vitamin B

OCs have been reported to reduce

serum levels of Vitamin B

May need to increase dietary intake, or

supplement.

Other Drugs

Selegiline

May lead to an increase in

selegiline plasma levels (due to

CYP inhibition).

Avoid concomitant use.

Tizanidine

May lead to an increase in

tizanidine plasma levels (due to

CYP inhibition).

Use with caution.

Voriconazole

May lead to an increase in

voriconazole plasma levels (due to

CYP inhibition).

Use with caution.

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Several of the anti-HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse

transcriptase inhibitors (e.g., nevirapine) have been studied with co-administration of oral

combination hormonal contraceptives; significant changes (both increases and decreases) in the

mean AUC of the estrogen and progestin and the potential to affect hepatic metabolism have

been noted in some cases. The efficacy and safety of oral contraceptive products may be

affected. Health care providers should refer to the label of the individual anti-HIV protease

inhibitor for further drug-drug interaction information.

Increase in Plasma Hormone Levels Associated with Co-Administered Drugs:

Some drugs and grapefruit juice may increase the plasma levels of ethinyl estradiol if co-

administered. Examples include:

acetaminophen

ascorbic acid

CYP3A4 inhibitors (including itraconazole, ketoconazole, voriconazole, fluconazole and

grapefruit juice)

some HIV protease inhibitors (e.g., atazanavir and indinavir)

HMG-CoA reductase inhibitors (including atorvastatin and rosuvastatin)

some non-nucleoside reverse transcriptase inhibitors (e.g., etravirine)

Contraindicated co-administration

Ombitasvir, paritaprevir, ritonavir, with or without dasabuvir (direct-acting antiviral medicinal

products) have been shown to be associated with increases in ALT levels 5 to >20 times the

upper limit of normal in healthy female subjects and HCV infected women using ethinyl

estradiol-containing medications such as COCs (see CONTRAINDICATIONS and

WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

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 in light of the fact that the patient is on oral

contraceptives. The following laboratory tests are modified.

A.

Liver Function Tests

Bromsulphthalein Retention Test (BSP)

Moderate increase

AST (SGOT) and GGT

Minor increase

Alkaline Phosphatase

Variable increase

Serum Bilirubin

Increased, particularly in conditions

predisposing to or associated with

hyperbilirubinemia

B.

Coagulation Tests

Factors II, VII, IX, X, XII and XIII

Increased

Factor VIII

Mild increase

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Platelet Aggregation and Adhesiveness

Mild increase in response to common

aggregating agents

Fibrinogen

Increased

Plasminogen

Mild increase

Antithrombin III

Mild decrease

Prothrombin Time

Increased

C.

Thyroid Function Tests

Protein-bound Iodine (PBI)

Increased

Total Serum Thyroxine (T

Increased

Thyroid Stimulating Hormone (TSH)

Unchanged

Resin-uptake

Decreased

Free T4 Concentration

Unchanged

D.

Adrenocortical Function Tests

Plasma Cortisol

Increased

E.

Miscellaneous Tests

Serum Folate

Occasionally decreased

Glucose Tolerance Test

May be decreased

Insulin Response

Mild to moderate increase

c-Peptide Response

Mild to moderate increase

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 at least two weeks

after discontinuing the use of oral contraceptives before measurements are made.

NON-CONTRACEPTIVE 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.

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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. TRI-JORDYNA™ is also used to treat moderate

acne in females who are able to take oral contraceptives.

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

INFORMATION TO PATIENTS ON HOW TO TAKE THE BIRTH CONTROL PILL

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 active pills (with hormones) taken daily for three weeks, and

then no pills taken for one week or

28-Pill Pack: 21 active pills (with hormones) taken daily for three weeks,

and then seven "reminder" pills (no hormones) taken daily for one week.

ALSO CHECK the pill pack for instructions on 1) where to start and 2)

direction to take pills.

21-Day Package 28-Day Package

You may wish to use a second method of birth control (e.g., 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.

When receiving any medical treatment, be sure to tell your doctor that you are

using birth control pills.

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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.

MISSING PILLS ALSO 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.

ALWAYS BE SURE YOU HAVE READY:

ANOTHER KIND OF BIRTH CONTROL (such as latex or polyurethane condoms

and spermicidal foam or gel) to use as a back-up in case you miss pills, and

AN EXTRA, FULL PACK OF 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

back-up method, such as latex or polyurethane condoms and spermicidal foam or gel,

until you can check with your doctor or clinic.

IF YOU FORGET MORE THAN ONE PILL TWO MONTHS IN A ROW, talk to

your doctor or clinic about how to make pill-taking easier or about using another method

of birth control.

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 is the best day for you to start taking your first pack of

pills. Your pills may be either a 21-day or a 28-day type.

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DIRECTIONS FOR 21-DAY AND 28-DAY PILL PACKS

THE FIRST DAY OF YOUR MENSTRUAL PERIOD (BLEEDING) IS DAY 1

OF YOUR CYCLE. The pills may be started up to Day 6 of your cycle. Your starting

day will be chosen in discussion with your doctor. You will always begin taking your

pill on this day of the week. 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.

IF YOU ARE USING A:

21-DAY Pill Pack:

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.

Take one pill at approximately the same time every day for 21 days. THEN DO NOT

TAKE A PILL FOR SEVEN DAYS. Start a new pack on the eighth day. You will

probably have a period during the seven days off the pill. (This bleeding may be lighter

and shorter than your usual period.)

28-DAY Pill Pack:

With this type of birth control pill, you take 21 pills that contain hormones and seven

pills that contain no hormones.

Take one pill at approximately the same time every day for 28 days. Begin a new pack

the next day, NOT MISSING ANY DAYS ON THE PILLS. Your period should

occur during the last seven days of using that pill pack.

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INSTRUCTIONS FOR USING YOUR PACKAGE FOR BOTH 21-DAY AND 28-DAY

PACKS.

FOLLOW THESE INSTRUCTIONS CAREFULLY:

The pill package indicates Sunday as the day you start your pills.

If you are starting the pills on any other day but Sunday, peel the

appropriate day label from the enclosed stickers and place the label

over the pre-printed days of the week.

For Day 1 start: Label the pill package by selecting the

day label that starts with Day 1 of your menstrual period

(the first day of menstruation is Day 1). For example, if

your first day of menstruation is Tuesday, attach the day

label that begins with TUE over the pre-printed days of

the week.

OR

For Day 5 start: Label the pill package by selecting the day

label that starts with the day that is 5 days after your period

begins. (Count 5 days including the first day of

menstruation.) For example, if your first day of

menstruation is Saturday, place the day label that starts with

WED over the pre-printed days of the week.

OR

For Sunday start: No day label is required. The

package is printed for a Sunday start. (The first Sunday

after your period begins, or, if your period starts on

Sunday, start that same day.)

Ensure the day label lines up with the pills. Having the

package labelled with the days of the week will help

remind you to take your pill every day.

To begin taking your pills, start with the pill inside the circle

(beside the word START). This pill should correspond to

the day of the week that you are taking your first pill. To

remove the pill, push through the back of the package.

On the following day, take the next pill in the same row,

always proceeding from left to right (

). Each row will

always begin on the same day of the week.

21-Day Package

28-Day Package

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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.

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.

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SUNDAY START

MISS ONE PILL

OTHER THAN SUNDAY START

MISS ONE PILL

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

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

pills in one day.

Take it as soon as you remember, and take the next pill at the usual

time. This means that you might take two pills in one day.

MISS TWO PILLS IN A ROW

MISS TWO 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 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 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.

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 method of birth control if you have sex in the

seven days after you miss the pills.

Third Week

Safely dispose of the rest of the pill pack and start a new

pack that same day.

Use a back-up 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 PILLS IN A ROW

MISS THREE OR MORE PILLS IN A ROW

Any Time in the Cycle

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 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.

Any Time in the Cycle

Safely dispose of the rest of the pill pack and start a new

pack that same day.

Use a back-up 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.

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NOTE: 28-DAY PACK – If you forget any of the seven "reminder" pills (without hormones) 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 CLINIC about ways to make pill-taking easier or about using another

method of birth control.

Special Notes on Administration

Use after childbirth:

TRI-JORDYNA™ should be started no earlier than 4 weeks postpartum in women who elect not

to breastfeed due to increased risk of thromboembolism (see WARNINGS AND

PRECAUTIONS, Hematologic). The possibility of ovulation and conception prior to initiation

of medication should also be considered.

Use after abortion or miscarriage:

After an abortion or miscarriage that occurs prior to 20 weeks gestation,TRI-JORDYNA™

be started immediately. An additional method of contraception is not needed. Be advised that

ovulation may occur within 10 days of an abortion or miscarriage.

After an induced or spontaneous abortion that occurs at or after 20 weeks gestation,TRI-

JORDYNA™ may be started either on Day 21 post-abortion or on the first day of the first

spontaneous menstruation, whichever comes first. The incidence of ovulation on Day 21 post-

abortion (at 20 weeks gestation) is not known. A non-hormonal contraceptive must be used

concurrently for the first 7 days of the first cycle.

OVERDOSAGE

In case of overdose or accidental ingestion by children, the physician should observe the patient

closely, although generally no treatment is required.

Overdosage may cause nausea and

vomiting and withdrawal bleeding may occur in females. There are no antidotes and treatment

should be symptomatic.

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

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ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Oral Contraception

The primary mechanism of action of norgestimate and ethinyl estradiol

is an inhibition of

ovulation. Additionally, other effects caused by the treatment (for example, alteration of the

endometrium and the thickening of the cervical mucus) appear to interfere with implantation

and conception.

Studies evaluating the effect of the combination on cervical mucus characteristics, hormonal

levels and also on the endometrial tissue yielded results that were consistent with the known

mechanism of action (i.e., suppression of ovulation) of the combination.

Acne

Acne is an androgen dependent skin condition with a multifactorial etiology. Elevation in serum

sex hormone binding globulin (SHBG), the main testosterone-carrier protein in women, is an

indicator of the potential anti-androgenic effects associated with oral contraceptives. The

combination of ethinyl estradiol and norgestimate has been shown to increase SHBG and

decrease free testosterone in healthy women. The combination of ethinyl estradiol and

norgestimate in tablets has been associated with a decrease in the severity of facial acne in

otherwise healthy women with this skin condition.

Pharmacodynamics

Norgestimate plus ethinyl estradiol elevated HDL levels across all studies. Norgestimate plus

ethinyl estradiol exhibited minimal androgenicity. Sex hormone binding globulin levels were

increased and testosterone was not readily displaced from its binding sites by norgestimate.

Pharmcokinetics

Investigations of norgestimate alone and of norgestimate plus ethinyl estradiol tablets were

carried out to study the pharmacokinetics of the drug in oral dosage forms.

Absorption:

Orally administered norgestimate plus ethinyl estradiol in tablets has been shown to be absorbed

rapidly. Peak plasma concentrations (C

), areas under the plasma level vs time curve (AUC),

time to peak plasma levels (T

), and half-life (t

) of norgestimate and ethinyl estradiol were

as follows:

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0.25 mg Norgestimate

(blue) tablet x 2

0.215 mg Norgestimate

(light blue) tablet x 2

0.18 mg Norgestimate

(white) tablet x 2

Norgestimate

Ethinyl Estradiol

278 + 140 pg/mL

119 + 50 pg/mL

529 + 220 pg/mL

113 + 39 pg/mL

778 + 420 pg/mL

117 + 56 pg/mL

Norgestimate

Ethinyl Estradiol

1.1 hr

1.8 hr

1.2 hr

1.8 hr

1.1 hr

1.9 hr

AUC + SD

- Norgestimate

1064 + 425 hrpg/mL

1649 + 604 hrpg/mL

2264 + 962 hrpg/mL

- Ethinyl Estradiol

984 + 476 hrpg/mL

873 + 489 hrpg/mL

815 + 450 hrpg/mL

Norgestimate

Ethinyl Estradiol

6.5 hr

7.3 hr

7.6 hr

4.3 hr

5.3 hr

5.5 hr

Distribution:

It has been shown that norgestimate, like ethinyl estradiol, is highly bound to plasma proteins

(99% as determined in vitro for norgestimate); this is consistent with literature reports on other

progestational agents.

Elimination:

The elimination of norgestimate has been shown to be unaffected by ethinyl estradiol. While

some biliary excretion and enterohepatic circulation is seen with norgestimate (similar to that

seen with other contraceptive steroids),

29,30

elimination is primarily renal.

29-31

Special Populations and Conditions

Pediatrics

The safety and efficacy of norgestimate and ethinyl estradiol tablets has been established in

women of reproductive age. Use of this product before menarche is not indicated.

Geriatrics

TRI-JORDYNA

is not indicated for use in postmenopausal women.

Hepatic Insufficiency

The effects of hepatic impairment on the pharmacokinetics of norgestimate and ethinyl

estradiol tablets have not been studied. However, steroid hormones may be poorly

metabolized in women with impaired liver function.

Renal Insufficiency

The effects of renal impairment on the pharmacokinetics of norgestimate and ethinyl estradiol

tablets have not been studied.

STORAGE AND STABILITY

Store between 15°C – 30°C. Leave contents in protective packaging until time of use. Keep out

of the sight and reach of children.

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DOSAGE FORMS, COMPOSITION AND PACKAGING

TRI-JORDYNA

Tablets are available in:

21-day package that contains:

7 WHITE to OFF WHITE tablets each containing 0.18 mg norgestimate and 0.035 mg

ethinyl estradiol

7 LIGHT BLUE tablets each containing 0.215 mg norgestimate and 0.035 mg ethinyl

estradiol

7 BLUE tablets each containing 0.25 mg norgestimate and 0.035 mg ethinyl estradiol

day package that contains:

7 WHITE to OFF WHITE tablets each containing 0.18 mg norgestimate and 0.035 mg

ethinyl estradiol

7 LIGHT BLUE tablets each containing 0.215 mg norgestimate and 0.035 mg ethinyl

estradiol

7 BLUE tablets each containing 0.25 mg norgestimate and 0.035 mg ethinyl estradiol

7 LIGHT GREEN tablets with inert ingredients

Each white to off white TRI-JORDYNA

Tablet contains 0.18 mg norgestimate plus 0.035 mg

ethinyl estradiol. Each white to off white tablet also contains lactose monohydrate, povidone

K-30, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, purified water and

talc.

Each light blue TRI-JORDYNA™ Tablet contains 0.215 mg norgestimate plus 0.035 mg ethinyl

estradiol. Each light blue tablet also contains FD & C Blue # 2-5625 Aluminum Lake, lactose

monohydrate, povidone K-30, pregelatinized starch, colloidal silicon dioxide, magnesium stearate,

purified water and talc.

Each blue TRI-JORDYNA™ Tablet contains 0.25 mg norgestimate plus 0.035 mg ethinyl

estradiol. Each blue tablet also contains FD & C Blue # 2 -5625 Aluminum Lake, lactose

monohydrate, povidone K-30, pregelatinized starch, colloidal silicon dioxide, magnesium

stearate, purified water and talc.

Each light green tablet contains inert ingredients FD & C Blue # 2 -5625 Aluminum Lake, D

& C Yellow # 10, lactose monohydrate, microcrystalline cellulose, magnesium stearate,

pregelatinized starch, purified water and talc.

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

(i)

Norgestimate:

Chemical Name:

18,19-dinor-17-pregn-4-en-20-yn-3-one, 17-(acetyloxy)-13-ethyl-, oxime,

(17α)-(+)-

Structural Formula:

OCOCH

Molecular Weight:

369.51 g/mol

Molecular Formula: C

Description:

Norgestimate is a white to off-white fine granular powder. Melting and decomposition begin at

Solubility:

Solvent

Solubility

Criteria for USP

Distilled Water (DW)

0.076 mcg/mL

Insoluble

Methanol

20.9 mg/mL

Sparingly Soluble

Ethanol

18.0 mg/mL

Sparingly Soluble

Octanol

10.5 mg/mL

Sparingly Soluble

Acetonitrile

10.6 mg/mL

Sparingly Soluble

Methylene Chloride

>80 mg/mL

Freely to Very Soluble

Heptane

29.9 mcg/mL

Insoluble

Sesame Oil

1.4 mg/mL

Slightly Soluble

Norgestimate has a partition coefficient of Log P = 5.28 (Octanol/water). No pKa was

determined because of its poor solubility in water.

Norgestimate is an optically active mixture of syn and anti isomers having a specific rotation of

+ 40

to + 46

(1% in chloroform at 25

C at the sodium D line).

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(ii)

Ethinyl Estradiol:

Chemical Name:

19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol

Structural Formula:

Molecular Weight: 296.41 g/mol

Molecular Formula: C

Description:

Ethinyl estradiol is a white to creamy white, odourless, crystalline powder with a melting range

of 183

C - 184

C. It is insoluble in water and soluble in alcohol, chloroform, ether, vegetable

oils and solutions of fixed alkali hydroxides.

CLINICAL TRIALS

Comparative Bioavailability study

A randomized, double-blinded, single dose, two-way crossover comparative bioavailability study

of 2 x 0.25 mg/0.035 mg TRI-JORDYNA

(Glenmark) and 2 x 0.25 mg/0.035 mg of

TRI-

CYCLEN® (Norgestimate and Ethinyl Estradiol Tablets, Janssen Inc., Canada) was conducted in

48 healthy female subjects under fasting conditions. Summaries of the pharmacokinetic

parameters for norgestimate and ethinyl estradiol are presented in the following tables:

Norgestimate

(2 x 0.25 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Test*

Reference

Δ

% Ratio of

Geometric Means

90% Confidence

Intervals

(pg.hr/mL)

213.05

227.02 (35.1)

211.22

227.34 (39.6)

100.87

94.42 - 107.75

(pg.hr/mL)

223.60

238.83 (36.4)

222.62

239.72 (40.1)

100.44

93.92 - 107.42

Cmax

(pg/mL)

131.18

146.55 (46.4)

112.06

124.61 (46.3)

117.06

101.98 - 134.37

Tmax

0.83

(0.25 – 2.50)

1.00

(0.33 – 2.50)

T½ (h)

3.08 (101.7)

3.43 (101.5)

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Norgestimate

(2 x 0.25 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Test*

Reference

Δ

% Ratio of

Geometric Means

90% Confidence

Intervals

*TRI-JORDYNA™, 0.25 mg/0.035 mg (Glenmark)

Δ

Tri-cyclen (Norgestimate and Ethinyl Estradiol Tablets, House Std.), 0.25 mg/0.035 mg (Janssen Inc., Canada)

Expressed as the median (range)

Expressed as the arithmetic mean (CV%)

Norgestimate: N=46

Ethinyl Estradiol

(2 x 0.035 mg)

From measured data

Geometric Mean

Arithmetic Mean (CV%)

Parameter

Test*

Reference

Δ

% Ratio of

Geometric Means

90% Confidence

Intervals

(pg.hr/mL)

2102.73

2192.75 (29.9)

2163.29

2253.94 (29.6)

97.20

93.64 – 100.90

(pg.hr/mL)

2241.21

2353.36 (32.5)

2324.12

2432.23 (31.5)

96.43

92.75 – 100.26

Cmax

(pg/mL)

202.29

214.59 (35.3)

203.47

213.04 (30.3)

99.42

95.15 – 103.88

Tmax

1.50

(0.83 – 2.00)

1.50

(0.83 – 2.50)

T½ (h)

18.74 (19.6)

19.94 (23.8)

TRI-JORDYNA™, 0.25 mg/0.035 mg (Glenmark)

Δ

Tri-cyclen (Norgestimate and Ethinyl Estradiol Tablets, House Std.), 0.25 mg/0.035 mg (Janssen Inc., Canada)

Expressed as the median (range)

Expressed as the arithmetic mean (CV%)

Ethinyl Estradiol: N=44

Clinical Efficacy of Norgestimate and Ethinyl Estradiol

Tablets

Contraception

In four major clinical trials with norgestimate and ethinyl estradiol tablets, 4,756 subjects

completed 45,244 cycles and a total of 42 pregnancies were reported. This represents an overall

use-efficacy (typical user efficacy) pregnancy rate of 1.11 per 100 woman-years. This rate

includes patients who did not take the drug correctly. The Pearl Rates for the individual studies

ranged from 0.63 to 1.36.

Acne

In two double-blind, placebo-controlled, multicentre clinical trials, norgestimate and ethinyl

estradiol tablets showed a statistically significantly greater improvement for all primary efficacy

measures: inflammatory lesion count, total lesion count, and investigator's global assessment

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(Table 7). In the secondary efficacy measures, norgestimate and ethinyl estradiol tablets also

showed a statistically greater improvement for the end-of-therapy subject's self-assessment. The

adverse reaction profile of norgestimate and ethinyl estradiol tablets from these two controlled

clinical trials is consistent with what has been noted from previous studies involving

norgestimate and ethinyl estradiol tablets and the known risks associated with oral

contraceptives.

Table 7: Acne Vulgaris Indication Combined Results: Two Multicentre, Placebo-

Controlled TrialsPrimary Efficacy Variables: Evaluable-for-Efficacy Population

Norgestimate and Ethinyl

Estradiol

PLACEBO

N=163

N=161

Mean Age at Enrollment

27.3 years

28.0 years

Inflammatory Lesions -

Mean Percent Reduction

56.6

36.6

p=0.0001

Total Lesions - Mean

Percent Reduction

49.6

30.3

p=0.0001

Investigator's Global

Progress of Treatment

Percent of Subjects improved

Percent of Subjects not improved

88.3

11.7

64.0

36.0

p<0.001

Clinical Safety of Norgestimate and Ethinyl Estradiol Tablets

U.S. Multicentre, Comparative, Phase III Study

In the major comparative U.S. study, 8.6% (182 of 2115) of the subjects receiving

norgestimate and ethinyl estradiol discontinued due to adverse experiences, while 6.8%

(145 of 2132) of subjects receiving the norgestrel-containing product discontinued due to

adverse experiences. The difference between the groups was not statistically significant and

the adverse experiences were characteristic of those expected among women taking low-

dose combination oral contraceptives.

Among all patients, 70.50% (1491 of 2115) receiving norgestimate and ethinyl estradiol

tablets and 67.64% (1442 of 2132) receiving levonorgestrel and ethinyl estradiol reported at

least one adverse experience during the trial. The most common adverse experiences in the

norgestimate triphasic regimen were headaches (29.3%), upper respiratory infection (12.2%),

dysmenorrhea (11.6%), and nausea (10.87%). The incidences of such experiences in the

norgestrel regimen were 29.5%, 11.9%, 11.9%, and 10.32% respectively.

U.S. Multicentre, Non-comparative, Phase III Studies

In the two non-comparative, U.S. studies combined, 296 of 1,783 (16.6%) subjects

discontinued for medical use-related reasons. Only 77 (4.3%) discontinued treatment due to

bleeding events.

A perspective on patient tolerance to effects reported during the course administration of

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norgestimate and ethinyl estradiol tablets can be obtained from an examination of the

incidence of "drop-out" from the studies for the undesirable effects reported as follows:

SUBJECT FREQUENCY OF ADVERSE EXPERIENCES CAUSING

DISCONTINUATION (COMBINED NON-COMPARATIVE STUDIES, N=1783)

Adverse

Experience

Number (Percent)

Breakthrough Bleeding

or Spotting

77 (4.32)

Headache

54 (3.03)

Nausea and/or Vomiting

39 (2.19)

Menstrual Disturbances

Other than Amenorrhea,

Breakthrough Bleeding or

Spotting

38 (2.13)

Mood Alterations

28 (1.57)

Weight Gain

23 (1.29)

Fluid Retention

21 (1.18)

Gastrointestinal Disorders

19 (1.07)

Lab Abnormalities

16 (0.90)

Hypertension

13 (0.73)

Other OB/Gyn

13 (0.73)

Skin Problems

8 (0.45)

Eye Abnormalities

8 (0.45)

Amenorrhea*

4 (0.22)

All Other

41 (2.30)

*The statistical definition of amenorrhea is two consecutive valid cycles with no bleeding or spotting. According to this definition, no

subjects receiving norgestimate and ethinyl estradiol had amenorrhea.

Laboratory Tests

A broad range of clinical laboratory data have been collected in a number of studies.

Statistically significant laboratory changes were generally clinically insignificant and

consistent with use of low-dose oral contraceptives.

Lipid profile changes are relevant due to their relationship to cardiovascular disease.

Norgestimate and ethinyl estradiol tablets are associated with minimal adverse effect on

triglycerides, LDL, and total cholesterol. Uncharacteristic of most currently approved

products, norgestimate and ethinyl estradiol tablets are associated with a salutary increase in

HDL and HDL/LDL ratios.

Changes observed in thyroid analytes were clinically insignificant and consistent with those

expected for low-dose oral contraceptive use.

Liver function test mean values generally decreased with time on therapy and, consistent with

results from other low-dose products, showed no adverse clinical impact.

No unusual findings for thyroid function, kidney function, or hematology values were noted

with norgestimate and ethinyl estradiol tablets and normal coagulability of the blood was

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maintained.

Norgestimate and ethinyl estradiol tablets also exhibited minimal androgenicity. Sex hormone

binding globulin levels were increased and testosterone was not readily displaced from its

binding sites by norgestimate.

As both progestins and estrogens may modify carbohydrate metabolism, this area was

investigated. No clinically significant changes were observed in fasting serum or blood glucose

levels and associated blood insulin levels of subjects receiving norgestimate and ethinyl estradiol

tablets. Measurement of glycosylated hemoglobin confirmed these results demonstrating that

there was no adverse change in carbohydrate metabolism.

DETAILED PHARMACOLOGY

Oral Contraception

Norgestimate, alone and in combination with ethinyl estradiol, is an effective antiovulatory

agent.

It is moderately potent in the standard in vivo progestational assay which measures

endometrial proliferation in rabbits, and it effectively blocks ovulation in rats, hamsters and

rabbits. In rats, this blockade correlates well with suppression of the proestrus LH surge and the

antiovulatory activity of norgestimate is overcome by LHRH. The blockade appears, like that of

other progestational agents, to be the result of inhibition of the hypothalamic/pituitary axis.

Norgestimate is an active progestin when administered either orally or parenterally and binds to

progestational receptors in vitro. Like other progestins, norgestimate inhibits the action of estrogen

but is not estrogenic itself. Studies measuring the stimulation of ventral prostate growth in rats, the

ability to bind to human SHBG in vitro, and the effects on serum SHBG levels in rabbits

demonstrate that in contrast to levonorgestrel, norgestimate is not androgenic. It also does not

inhibit the action of androgen in rats. No adverse effects on the reproductive, thyroid or adrenal

endocrine systems were seen in rats given norgestimate orally for 7 days at doses up to 100 times

the clinical dose. In vitro studies indicate that norgestimate does not directly alter ovarian

aromatase activity. Norgestimate does not exhibit central nervous system or autonomic nervous

system activities in rats and does not interfere with autonomic-mediated responses of the

cardiovascular system in dogs. In vitro studies indicate that norgestimate does not possess

antimicrobial activity against diverse pathogenic microorganisms. Ethinyl estradiol is a potent

estrogen, which stimulates the uterus and the vagina. Its preclinical pharmacology is well

established.

30,32

Acne

Acne is an androgen dependent skin condition with a multifactorial etiology. Elevation in serum

sex hormone binding globulin (SHBG), the main testosterone-carrier protein in women, is an

indicator of the potential anti-androgenic effects associated with oral contraceptives. The

combination of ethinyl estradiol and norgestimate has been shown to increase SHBG and

decrease free testosterone in healthy women. The combination of ethinyl estradiol and

norgestimate in norgestimate and ethinyl estradiol tablets has been associated with a decrease in

the severity of facial acne in otherwise healthy women with this skin condition.

TOXICOLOGY

Toxicology studies have evaluated norgestimate alone as well as in combination with ethinyl

estradiol in the mouse, rat, rabbit, dog and monkey.

Ethinyl estradiol has also been evaluated

both alone and in combination with synthetic steroidal progestogens in the rat, rabbit, dog and

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monkey.

29, 33-35

Compound-related gross and microscopic lesions have been minimal and show

the typical pathological changes that are known to occur with the administration of progestogen

and estrogen.

Acute Toxicity Studies

Mice

In HaM/1CR CD-1 mice oral norgestimate alone and oral norgestimate + ethinyl estradiol (5:1)

each had an LD

greater than 5 g/kg body weight. Norgestimate alone at 5 g/kg caused no overt

signs of toxicity while the combination caused transient changes in behaviour and one death (one

female out of 10 females and 10 males) at 5 g/kg. Oral ethinyl estradiol alone at 5 g/kg caused a

transient period of depression and slightly laboured breathing (in males only) with no mortality.

The drug was given as a single dose, suspended in carboxymethylcellulose or

carboxymethylcellulose and sesame oil.

Rats

In hooded Long-Evans rats no deaths or toxic signs were seen at 5 g/kg or 6.2 g/kg orally of

norgestimate alone. Norgestimate in combination with ethinyl estradiol (5:1) orally at 5 g/kg

caused no deaths or overt signs of toxicity other than a slight decrease in body weight compared

to controls. At autopsy prostate, seminal vesicles and testes were smaller in animals receiving

5g/kg of the combination than in controls. Ethinyl estradiol alone had an oral LD

of 5.3 g/kg

for males and 3.2 g/kg for females. Drug was administered suspended in

carboxymethylcellulose.

Dogs

Oral norgestimate at 5 g/kg caused no deaths or signs of toxicity in female beagles. Also, no

deaths or signs of toxicity were seen in female beagles given ethinyl estradiol 5 g/kg orally.

Drugs were given suspended in carboxymethylcellulose.

Norgestimate (14.3 mg/kg) plus ethinyl estradiol (2.0 mg/kg) in ethanol given by i.v. infusion

caused no deaths and the only toxic signs were those of acute ethanol intoxication and were also

seen in controls.

Subacute Toxicity Studies

Rats

In female hooded Long-Evans rats oral norgestimate at 10.0, 2.5, 1.0, 0.5 and 0 mg/kg/day for 90

days caused no deaths; and all animals appeared normal on the 90th day. Daily observation

showed no symptoms of drug-induced effect or toxicity. Hematological examination results

were within normal range and urinalysis results gave no indication of toxicity throughout the test

period. Biochemical evaluation showed blood components to be within normal range at

termination. A dose-related decrease in cholesterol levels was seen. Gross pathological and

histopathological examination did not reveal any toxic effects at any dose level.

Norgestimate plus ethinyl estradiol (10:1) was given orally at 11.0, 2.75, 1.10 and 0.55

mg/kg/day for 90 days, and caused no deaths or symptoms indicating drug-induced toxicity. Lab

testing and necropsy results were all in the normal range although treated animals appeared to

have an increased incidence of nephrocalcinosis and unilateral hydronephrosis.

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Dogs

Female beagles were given oral doses of norgestimate up to 5.0 mg/kg/day. No deaths were

seen. Hematological test results were normal as were clinical chemistry values except for a

slight depression of cholesterol in higher-dose animals early in the study. Urinalysis results were

normal.

Some test groups showed a decrease in organ weight or organ/body weight ratio for uterus and

ovaries when compared to controls, and test animals showed suppression of luteinization and/or

follicular maturation. Glandular cystic hyperplasia of gallbladder was seen in treated dogs. An

extremely low degree of toxicity was exhibited.

Female beagles were given oral doses of norgestimate + ethinyl estradiol (5:1) up to 5.5

mg/kg/day for 90 days. No deaths occurred. Hematological test values were normal for control

and low-dose (0.28 mg/kg) animals while WBC was elevated in the two higher-dose groups.

Clinical chemistry results were normal except for 1 dog in the high-dose and 2 in the middle-

dose groups which had slightly depressed BUN values. Uterus weight increased and ovary

weight decreased in test animals when compared to controls. Test animals showed suppression

of luteinization and/or follicular maturation and gallbladder glandular hyperplasia.

Monkeys

Female Rhesus monkeys given norgestimate orally at doses of 5.0, 1.50, 0.25 and 0 mg/kg/day

for 90 days showed no signs of toxicity in their behaviour, body weight, hematology results,

urinalysis, or clinical chemistry values.

Histological examination revealed no lesions attributable to the drug. The same was seen for

oral norgestimate + ethinyl estradiol (10:1) for doses of 5.5, 1.65, 0.275 and 0 mg/kg/day for 90

days except in high-dose animals. These animals showed hypertrophy of cervical mucus glands

and an increase in size and number of mammary acini. Evidence of hyperplasia and epithelial

sloughing of uterine endometrium was also noted. There was a dose-dependent stimulation of

mucus secretion of the cervix.

Long-Term Toxicity Studies

Rats

Adult female Long-Evans rats were given norgestimate + ethinyl estradiol (5:1) at doses of 3.00,

0.60, 0.15 and 0 mg/kg/day orally for 24 months. There were 70 animals in each group receiving

drug and 110 animals in the vehicle only group.

One hundred and five animals did not survive the dosing schedule. The highest mortality rate

was seen in controls. In drug-treated rats, the middle-dose group had the lowest mortality rate

while the low-dose group had the highest.

Mean body weights of all treated groups decreased slightly as compared to controls, while the

mean food consumption was not significantly different. In all test groups, there was a slight to

moderate decrease in RBCs, hematocrit and hemoglobin compared to controls. Clinical

chemistry showed a significant decrease in serum cholesterol in all drug-treated groups.

Hepatic changes were seen in all groups (including controls) at 2 years. The severity and

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incidence of these changes were higher in high- and mid-dose groups than in others. These

changes were: nodular or generalized hepatocyte hypertrophy and hyperplasia, hyperplasia foci

of hepatocyte coagulation necrosis, sinusoidal telangiectasis, and formation of hematocysts. The

reproductive organs showed little microscopic evidence of drug effect, although uterine

endometrial hyperplasia was increased in treated animals. The incidence of benign mammary

tumours was higher in treated animals than in controls. However, the incidence was statistically

significant only in the highest dose group. At 50 to 1000 times the human dose, this combination

produced effects remarkably similar to those of other progestin-estrogen combinations.

In a second study, female Long-Evans rats were given norgestimate + ethinyl estradiol (5:1) at

0.150, 0.0375 and 0.01875 mg/kg/day (6.5 to 50 times the human dose), norgestimate alone and

ethinyl estradiol alone each at 0.025 mg/kg/day (50 times the human dose) or d-norgestrel at

0.150, 0.075, and 0.0375 mg/kg/day (50 times human dose) for 104 weeks. There were 50 rats

in each test group and 100 vehicle controls. Mortality was 55.9% overall with no difference

between groups. Minor transient changes were seen for food consumption and body weight

early in the study. Periodic hematological examination showed no deviations beyond normal

range except for a slight decrease in hematocrit in the high-dose norgestimate + ethinyl estradiol

groups. All clinical chemistry parameters measured demonstrated large variations associated

with aging in all groups. The only statistically significant changes were a decrease in the

cholesterol in ethinyl estradiol only and norgestimate + ethinyl estradiol high-dose groups, and

an elevation of triglycerides in all combination groups. There was no significant difference

between control and test rats for either benign or malignant tumours.

Dogs

Adult female beagles were given norgestimate + ethinyl estradiol orally at doses of 0.60

mg/kg/day (16 dogs) and 0.15, 0.06, and 0 (vehicle controls) mg/kg/day (20 dogs/group) for two

years. This constitutes 20 to 200 times the human dose.

No deaths occurred. All animals were in good health at termination and no changes in behaviour

were noted. In year 1, estrus was seen in all controls. In year 2, it was seen in 13 of 16 controls

and was not seen in any test dog during the study. High-dose dogs had decreased RBCs and

hematocrit throughout the study and an increased WBC count from 3 to 18 months of study.

Decreased lymphocytes were seen in high- and mid-dose dogs and cholesterol was decreased in

the low- and mid-dose dogs. Histologic changes were all estrogenic in nature with minimal

evidence of progestational response. In a 7-year study, 15 female beagles/group were given oral

doses of 0.1425, 0.057, 0.0057 and 0 mg/kg/day norgestimate + ethinyl estradiol in the 21 days

on followed by 7 days off cycle. There were 9 deaths during the study: 2 in the control, 2 in the

high-dose, 4 in the mid-dose and 1 in the low-dose group. Daily observation revealed no

unexpected adverse effects. Near the end of the study, slight to moderate alopecia and enlarged

uteri were palpated in some dogs from the high- and the intermediate-dose groups.

Hysterectomies resulting from pyometra were greatest in high-dose and least in low-dose and

control animals. Nodules palpated during mammary exams were greatest in number for the low-

dose group followed by controls and lowest in the high-dose groups; none appeared drug-related.

Heart rate, blood pressure and ECG intervals were all within normal range and no meaningful

differences were seen in mean body weights between treated and control dogs.

Hematology findings in the last year included decreases in hematocrit, hemoglobin, and red

blood cell mean values in the high-dose group. Throughout, a decline in hematocrit was

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observed in all groups, but was most evident in the high-dose group, and appears to be drug-

related. White blood cell counts were generally normal. Mean percent of segmented neutrophil

values were higher in the high-dose group at the 84-month interim, but over the course of the

study, this was not generally the case. Mean sedimentation rates at 84 months were increased,

primarily in the high-dose group. However, over the entire study, changes in sedimentation rates

noted were related to isolated individual increases observed in all test groups.

Coagulation parameters showed sporadic, statistically significant differences, but in general,

values over the study were within normal limits. No trends were observed. Decreases in

cholesterol and triglycerides and slight increases in potassium and albumin values occurred

during the study in treated dogs.

Urinalysis results were generally normal although near the end of the study some dogs from

control, high- and low-dose groups had trace to 4 + protein.

Monkeys

Norgestimate + ethinyl estradiol was given orally to female Rhesus monkeys (20/group except

for the high-dose group which had 16) at 0.60, 0.30, 0.06 and 0 mg/kg/day in a 21-day treatment

followed by a 7-day no-treatment cycle for 2 years. This dose represents 20 to 200 times the

human dose. During the study 1 control, 1 high-dose and 4 mid-dose monkeys died.

No changes in behaviour were observed. A grey mammary discharge was seen more frequently

in treated animals as compared to controls, and was seen mainly during withdrawal periods.

Early in the study, treated monkeys had lower mean RBC, hematocrit and hemoglobin values,

but were comparable to controls and within normal limits by month 12. All treated groups

showed elevated triglycerides and decreased alkaline phosphatase values throughout the study.

Decreased serum albumin and low total serum protein values were seen at various times during

the study. Other clinical chemistry results were within normal limits, as were clotting study

results, urinalysis and urinary steroid determinations. PAP smears produced no evidence of

neoplasia.

At autopsy, no drug-related gross or microscopic pathologic lesions were observed in any

monkeys, including those that died during the study. Isolated cases of focal hepatic sinusoidal

dilation, congestion and/or small hemorrhages were seen at the capsular surfaces. It is believed

that they are of little pathological importance due to an absence of any significant liver changes

over the 2-year dosing period and the high (up to 200 times the human dose) dose levels of drug.

Except for an increase in intralobular stromal tissue in a high-dose monkey, mammary nodules

found were focal nodular hyperplasia and these occurred in both control and treated animals.

The only organ weight changes seen were decreased ovarian and uterine weights in treated

monkeys from the 0.30 and 0.60 mg/kg/day groups.

In a 10-year study, female Rhesus monkeys (16/group) were given oral norgestimate + ethinyl

estradiol (5:1) at 150, 30, 3, and 0 mcg/kg/day in a 21 day on followed by 7 days off repeating

cycle for the first 4 years. For the remaining 6 years, the monkeys received the medications in a

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7:1 ratio, (285, 57, 5.7, 0 mg/kg/day) in the same cycle. Six (3 control, 1 low- and 2 high-dose)

monkeys died during the study.

While there were some early differences in weight gains all groups were similar from the second

year on. Mammary nodules were noted in all groups during the study and most regressed or

disappeared. At the end of the study, the number of animals with nodules was 0, 0, 1 and 1 in

the low, mid, high, and control dose groups, respectively. Mammary secretions were noted in

some mid- and high-dose monkeys throughout the study.

Hematocrit, erythrocytic parameter changes, mean corpuscular volume, mean leukocyte counts

and coagulation parameters were generally similar for all groups.

Clinical chemistry showed a dose-related increase in SGPT. All groups also showed an increase

with time, generally lower alkaline phosphatase values for treated monkeys and intermittent

slight decreases in serum protein for treated monkeys. BUN for all groups was well within

reference range and no difference between groups was noted for glucose. Reports from the

literature indicate a dose-related increase in triglycerides and a decrease in cholesterol for the

mid-dose group.

Thyroid function test results were typical of those expected for oral contraceptive use in humans.

Urinalysis results showed no difference between groups and the results for urinary steroids were

unremarkable.

Terminal organ weights for the liver and pituitary were increased while the ovary weights

decreased.

The salient non-neoplastic histologic findings consisted predominantly of genito-urinary

changes and multifocal myocardial fibrosis. Except for minor histopathologic differences in

the ovaries, findings affecting the lower dose animals were essentially comparable with those

of the controls. The findings seen in the tissues of the genital tracts and related tissues in the

mid- and high-dose animals included: ovarian atrophy associated with absence of active

corpora lutea and occasional reduction in the number of maturing follicles, varying degrees of

endometrial atrophy occasionally associated with stromal proliferation and/or decidualization

of the endometrial stroma, increased mucus secretion of the cervix often associated with

villous elongation and crypt dilation of the mucosa, atrophy and columnar cell metaplasia of

the vaginal mucosa, occasional atrophy of the oviduct, lobular hyperplasia of some of the

mammary glands and dose- related hypertrophy of the pars distalis of the pituitary gland.

Multifocal myocardial fibrosis was noted in animals of each group, including controls,

although in a slightly higher incidence in the treated groups. This finding was most prominent

in 4 of 7 affected high-dose animals. The significance of this lesion is uncertain based on its

presence in controls and the known spontaneous occurrence especially in aging animals.

Neoplasms of tissues other than the genito-urinary tract were few and all were considered to be

spontaneous. Neoplasms associated with the genito-urinary tract were as follows:

Neoplasm

Dose Group

One muco-epidermoid adenocarcinoma of cervix

high

One leiomyoma of vagina

high

One lobular carcinoma in situ of mammary gland

high

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One papilloma of mammary gland

high

One adenoma of mammary gland

high

One urinary bladder papilloma

a = Same Animal; b = Same Animal

The previously listed tumours of monkeys are single occurrences and are generally in different

organs. Each of these tumour types has been reported in the literature as spontaneous

occurrences. It is difficult to make a definitive etiologic association of the single cervical

adenocarcinoma in one high-dose monkey. However, in the absence of any antecedent changes

(dysplasia, carcinoma in situ) in any of the other 47 treated monkeys, the known spontaneous

occurrence (although rare in monkeys) suggests the tumour is probably spontaneous in origin.

REPRODUCTIVE STUDIES

A fertility and general reproductive performance study was conducted in female Long-Evans rats

to assess the effects of norgestimate + ethinyl estradiol (5:1) at 0.120, 0.0833, 0.060, 0.050 and

0.030 mg/kg/day on conception rates, fetal development, parturition and lactation and the

viability, growth and reproductive performance of the offspring.

Norgestimate + ethinyl estradiol results in a dose-related suppression of fertility, decreased

implantation efficiency and litter size, and an increased fetal resorption in the F

females at all

dose levels. Slight increases in the incidence of stillbirths were noted in all of the treated

females. In addition, there was a decrease in neonatal survival at 0.060, 0.0833 and 0.120

mg/kg/day.

Similar dose-related findings were observed for the F

females but to a lesser degree than the F

generation. Trends toward decreased fertility, decreased implantation, F

litter size, and

increased resorptions were noted in all dose groups. Dystocia and an increased number of

stillbirths occurred at the 0.060 mg/kg level. At the 0.060 and 0.0833 mg/kg dose levels,

survival of offspring was reduced.

TERATOLOGY AND FETAL TOXICITY

Female Long-Evans rats were treated orally with norgestimate + ethinyl estradiol (5:1) at 0

(vehicle), 0.012, 0.060, and 0.300 mg/kg/day dose levels on days 6-15 of gestation. An increase

in "wavy ribs" was noted in rats receiving 0.060 (3/159 fetuses) and 0.300 mg/kg/day (9/128

fetuses), which was statistically significant only in the high-dose group, compared to controls

(1/152 fetuses). A reduction in the implantation efficiency and an increase in the number of

resorptions were also noted in the high-dose group.

In addition, norgestimate + ethinyl estradiol (5:1) was administered orally to pregnant Long-

Evans rats from day 15 of pregnancy through day 21 of lactation at dose levels of 0 (vehicle),

0.03, 0.18, 0.30, and 0.060 mg/kg/day. These levels represent approximately 10, 60, 100, and

200 times the proposed human dose levels. In the F

generation, no significant adverse effects

were seen on maternal growth, behaviour and reproductive performance. However, there was

some evidence of lactational insufficiency at the high-dose level.

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In the F

generation, viability, growth and reproductive performance were unaffected in the 0.03

mg/kg/day group. At 0.18, 0.30 and 0.60 mg/kg/day, there was a dose-related reduction in

female fertility. The remaining drug effects were limited to the high-dose level which showed

significantly decreased offspring viability from birth to weaning and depressed pup weight

during the mid-lactation period.

There was no significant drug effect on F

generation development at any dose level.

Rabbit

Female New Zealand white rabbits were given oral doses of 0.5% sodium

carboxymethylcellulose suspensions of norgestimate + ethinyl estradiol (5:1) at concentrations of

0 (vehicle), 0.012, 0.060 or 0.300 mg/kg/day from day 7 through day 19 of gestation. The only

drug-related effect was the high rate of fetal resorptions observed in the high and intermediate

100% and 65.5% dose groups, respectively. No drug-related teratogenic changes were observed

in any of the fetuses examined.

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Morgan JK. Herpes gestationis influenced by an oral contraceptive. Br J Dermatol

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Product Monograph:

TRI-CYCLEN

(Norgestimate and Ethinyl Estradiol Tablets,

House Std.); Janssen Inc. (Canada); Date of Revision: June 21, 2018; Submission Control

No.: 214757

RELEVANT LITERATURE

Becker H. Supportive European data on a new oral contraceptive containing norgestimate.

Acta Obstet Gynecol Scand 1990; Suppl 152: 33-39.

Bingel AS, Benoit PS. Oral Contraceptives: Therapeutics Versus Adverse Reactions, with

an Outlook for the Future. Int J Pharm Sci 1973;62:179-200.

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an Outlook for the Future II. J Pharm Sci 1973;62:349-362.

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Thromboembolic Disease, Surgically Confirmed Gallbladder Disease, and Breast Tumors.

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Committee on the Safety of Medicines. Carcinogenicity Tests of Oral Contraceptives. Her

Majesty's Stationery Office, London, 1972.

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Fairweather FA. Toxicological Requirements of Oral Contraceptives. J Reprod Fertil

1968;(5 Suppl): 47-49.

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System Pharmacists, Inc. 2000.

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942.

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Contraceptives: An Epidemiologic Case-Control Study. Am J Epidemiol 1969;90:365-380.

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1982;142(B Part 2):717-816.

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Thromboembolic Disease. A Further Report. Br Med J 1969;2:651-657.

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Wu O, Robertson L, Langhorne P, Twaddle S, Lowe GD et al. Oral contraceptives, hormone

replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic

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Rossner S, Frankman O, Marsk L. Effects of Various Low Dose Contraceptive Pills On

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IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

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21 and

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Norgestimate and Ethinyl Estradiol Tablets USP

This leaflet is part III of a three-part “Product

Monograph” published when TRI-JORDYNA

approved for sale in Canada and is designed specifically

for Consumers. This leaflet is a summary and will not tell

you everything about TRI-JORDYNA

. Contact your

doctor or pharmacist if you have any questions about the

drug.

What the medication is used for:

prevention of pregnancy

to treat moderate acne

What it does:

TRI-JORDYNA

is a birth control pill (oral

contraceptive) that contains two female sex hormones

(norgestimate 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:

They inhibit the monthly release of an egg by the

ovaries.

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 per cent

effective in preventing pregnancy when:

the pill is TAKEN AS DIRECTED, and

the amount of estrogen is 20 micrograms or more.

A 99 per cent 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.

Do not use TRI-JORDYNA

if you have or have had

any of the following conditions:

unusual vaginal bleeding that has not yet been

diagnosed

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

thrombophlebitis (inflammation of the veins)

a stroke, heart attack, or coronary artery disease (chest

pain) 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

persistent high blood pressure

over age 35 and smoke

scheduled for major surgery

prolonged bed rest

loss of vision due to blood vessel disease of the eye

known or suspected cancer of the breast or sex organs;

liver tumour associated with the use of the pill or other

estrogen-containing products;

jaundice (yellowing of skin and eyes) or liver disease if

still present

diabetes with complications of the kidneys, eyes,

nerves, or blood vessels

migraines with visual and/or sensory disturbances

ABOUT THIS MEDICATION

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IMPORTANT: PLEASE READ

known abnormalities of blood clotting system that

increase your risk for developing blood clots

pancreatitis (inflammation of the pancreas) associated

with high levels of fatty substance (triglycerides) in

your blood

very high blood cholesterol or triglyceride levels

pregnant or if pregnancy is suspected

you are taking ombitasvir, paritaprevir, ritonavir,

with or without dasabuvir for the treatment of

Hepatitis C

allergic reaction to ethinyl estradiol, norgestimate or

to any of the other ingredients in

TRI-JORDYNA

(see What the nonmedicinal ingredients are).

What the medicinal ingredients are:

Norgestimate and ethinyl estradiol

What the nonmedicinal ingredients are:

WHITE to OFF WHITE tablet: lactose monohydrate,

povidone K-30, pregelatinized starch, colloidal silicon

dioxide, magnesium stearate, purified water and talc.

LIGHT BLUE tablet: FD & C Blue No. 2 -5625

Aluminum Lake, lactose monohydrate, povidone K-30,

pregelatinized starch, magnesium stearate, colloidal

silicon dioxide, purified water and talc.

BLUE tablet: FD & C Blue No. 2 -5625 Aluminum

Lake, lactose monohydrate, povidone K-30,

pregelatinized starch, magnesium stearate, colloidal

silicon dioxide, purified water and titanium dioxide.

LIGHT GREEN tablet: FD & C Blue No. 2 -5625

Aluminum Lake, D & C Yellow # 10, lactose monohydrate,

microcrystalline cellulose, magnesium stearate,

pregelatinized starch, purified water and talc.

What dosage forms it comes in:

TRI-JORDYNA

(norgestimate and ethinyl estradiol)

Tablets are available in a 21-day regimen and a 28-day

regimen.

21-day Package contains: 7 WHITE to OFF WHITE tablets,

each containing 0.18 mg norgestimate and 0.035 mg ethinyl

estradiol, 7 LIGHT BLUE tablets each containing

0.215 mg norgestimate and 0.035 mg ethinyl estradiol and

7 BLUE tablets each containing 0.25 mg norgestimate and

0.035 mg ethinyl estradiol

28-day Package contains: 7 WHITE to OFF WHITE

tablets each containing 0.18 mg norgestimate and 0.035

mg ethinyl estradiol, 7 LIGHT BLUE tablets each

containing 0.215 mg norgestimate and 0.035 mg ethinyl

estradiol, 7 BLUE tablets each containing 0.25 mg

norgestimate and 0.035 mg ethinyl estradiol and 7 LIGHT

GREEN tablets with inactive ingredients.

Do not use

TRI-JORDYNA

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 TRI-JORDYNA

has

the potential to cause problems with your liver, such

as an increase in the ALT liver enzyme. Consult with

your doctor or pharmacist about restarting TRI-

JORDYNA™ after finishing your Hepatitis C

treatment (see ABOUT THIS MEDICATION - When

it should not be used).

There are also conditions that your doctor will want

to watch closely or that might cause your doctor to

recommend a method of contraception other than

birth control pills.

BEFORE you use

TRI-JORDYNA™, talk to your

doctor or pharmacist if the following apply to you:

have a history of breast disease (e.g., breast lumps) or

a family history of breast cancer

diabetes

high blood pressure

abnormal levels of fats in the bloodstream

(high cholesterol or triglycerides)

are very overweight

cigarette smoking

migraine headaches

heart or kidney disease

epilepsy

depression

fibroid tumours of the uterus

wear contact lenses

pregnant or breast-feeding

systemic lupus erythematosus

inflammatory bowel disease such as Crohn’s disease

or ulcerative colitis

hemolytic uremic syndrome

Serious Warnings and Precautions

Cigarette smoking increases the risk of serious side

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

TRI-

JORDYNA™, should not be used by women who are

over 35 years of age and smoke.

Birth control pills DO NOT PROTECT against sexually

transmitted infections (STIs), including HIV/AIDS.

For protection against STIs, it is advisable to use latex

or polyurethane condoms IN COMBINATION WITH

birth control pills.

WARNINGS AND PRECAUTIONS

IMPORTANT: PLEASE READ

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sickle cell disease

problems with the valves in your heart and/or

have an irregular heart rhythm

hereditary angioedema or have had episodes of

swelling in body parts such as hands, feet, face,

or airway passages

gallbladder or pancreatic disease

history of jaundice (i.e., yellowing of skin and

eyes) or other liver disease

have or have previously had chloasmas

(yellow-brownish patches on your skin, pigment

spots during pregnancy, especially on your face). If

this happens, avoid sunlight and UV radiation

You should also inform your doctor about a family

history of blood clots, heart attacks or strokes.

TRI-JORDYNA™ is NOT to be used before menarche

(your first menstrual period) or in postmenopausal

women.

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

are using TRI-JORDYNA

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 TRI-JORDYNA

four weeks before surgery

and not using TRI-JORDYNA

for a time period after

surgery or during bed rest.

TRI-JORDYNA

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 TRI-JORDYNA

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 TRI-JORDYNA

outweigh the risks,

you should be aware of the following risks:

THE RISKS OF USING TRI-JORDYNA™

1.

Circulatory disorders (including blood clots in

legs, lungs, heart, eyes or brain)

Women who use hormonal contraceptives like TRI-

JORDYNA

have a higher incidence of blood clots

compared to non-users. 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

after a break of 4 weeks or more. Clots can occur in many

areas 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, coughing blood, or sudden

shortness of breath. These symptoms could indicate a

possible blood clot in the lung.

pain and/or swelling in the calf. These symptoms could

indicate a possible blood clot in the leg.

crushing chest pain or heaviness. These symptoms

could indicate a possible heart attack.

sudden severe or worsening headache or vomiting,

dizziness or fainting, disturbances of vision or speech,

or weakness or numbness in an 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.

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.

Women who use birth control pills have a higher incidence of

blood clots. 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.

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 birth control pills may be at increased

risk of developing breast cancer before menopause which

occurs around age 50. These women may be long-term 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 doctor is recommended for all women.

IMPORTANT: PLEASE READ

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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.

Chronic infection with the Human Papilloma Virus

(HPV) is believed to be the most important risk factor

for cervical cancer. In women who use combination oral

contraceptives (COCs) like TRI-JORDYNA

for a long

time, the chance of getting cervical cancer may be

slightly higher. This finding may not be caused by the

pill itself but may be related to sexual behaviour and

other factors.

4.

Gallbladder disease

Users of birth control pills have a greater risk of

developing gallbladder disease including inflammation

and gallstones requiring surgery within the first year of

use. The risk may double after four or five years of use.

5.

Liver tumours

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

has been linked with the growth of liver tumours. Such

tumours are EXTREMELY rare.

Contact your doctor immediately if you experience

nausea, vomiting, severe pain or a lump in the abdomen.

6.

Use during pregnancy

Birth control pills should never be taken if you think

you are pregnant. They will not prevent the pregnancy

from continuing. There is no evidence, however, that

the 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 TRI-JORDYNA

after childbirth,

miscarriage, or therapeutic abortion.

8.

Pregnancy after stopping TRI-JORDYNA™

You will have a menstrual period when you stop taking

TRI-JORDYNA™. You should delay pregnancy until

another menstrual period occurs within four to six

weeks. Contact your doctor for recommendations on

alternative methods of contraception during this time.

9.

Use while breast-feeding

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.

Certain drugs may interact with birth control pills to make

them less effective in preventing pregnancy or cause an

increase in breakthrough bleeding. You may also need to

use a nonhormonal method of contraception during any

cycle in which you take drugs that can make oral

contraceptives less effective.

Drugs that may interact with TRI-JORDYNA™ include:

drugs used for epilepsy (e.g., primidone, phenytoin,

phenobarbital, carbamazepine, lamotrigine,

oxcarbazepine, topiramate, rufinamide)

drugs used for tuberculosis (e.g., rifampin and rifabutin)

antibiotics (e.g., penicillins, tetracyclines) for

infectious diseases

(fos)aprepitant (used for nausea)

selegiline (used for Parkinson’s disease)

tizanidine (used for multiple sclerosis [MS])

drugs used for HIV/AIDS (e.g., atazanavir,

indinavir, nelfinavir, ritonavir, ritonavir-boosted

protease inhibitors, etravirine, nevirapine)

boceprevir, telaprevir (used to treat Hepatitis C)

ombitasvir, paritaprevir, ritonavir, with or

without dasabuvir (used to treat Hepatitis C)

salicylic acid

bosentan (used for pulmonary hypertension which is

high blood pressure in the blood vessels between the

heart and the lungs)

theophylline (used for asthma)

stimulants (e.g., modafinil)

lipid-lowering drugs (e.g., atorvastatin, rosuvastatin,)

colesevelam

cyclosporine

an immunosuppressive drug to

prevent graft rejection after transplantation)

omeprazole (used for gastric wound and heart burn)

antifungals (e.g., griseofulvin,

voriconazole, itraconazole, fluconazole,

ketoconazole)

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

for the treatment of depressive moods)

antihypertensive drugs (for high blood pressure)

antidiabetic drugs and insulin (for diabetes)

prednisone, prednisolone

sedatives and hypnotics (e.g.,

benzodiazepines, barbiturates, chloral

hydrate, glutethimide, meprobamate,

temazepam)

INTERACTIONS WITH THIS MEDICATION

IMPORTANT: PLEASE READ

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pain medication (meperidine,

morphine, acetaminophen)

antidepressants (e.g., clomipramine)

some nutritional supplements (e.g., vitamin B

vitamin C, folic acid)

antacids (use 2 hours before or after taking TRI-

JORDYNA

grapefruit juice.

TRI-JORDYNA

may also interfere with the working

of other drugs.

Please inform your doctor and pharmacist if you are

taking or have recently taken any other drugs or 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 TRI-

JORDYNA

. They can tell you if you need to use an

additional method of contraception and if so, for how

long.

This is not a complete list of possible drug interactions

with

TRI-JORDYNA™ . Talk to your doctor for more

information about drug interactions.

HOW TO TAKE TRI-JORDYNA

21 or TRI-

JORDYNA ™ 28:

1.

READ THESE DIRECTIONS

before you start taking your pills, and

any time you are not sure what to do.

2.

LOOK AT YOUR PILL PACK to see if it has 21

or 28 pills:

21-PILL PACK: 21 active pills (with hormones)

taken daily for three weeks, and then no pills

taken for one week

28-PILL PACK: 21 active pills (with

hormones) taken daily for three weeks, and then

seven "reminder" pills (no hormones) taken

daily for one week.

ALSO CHECK: the pill pack for instructions on:

1) where to start, and, 2) direction to take pills.

21-Day Package

28-Day Package

3.

You may wish to use a second method of birth control

(e.g. 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.

5.

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.

6.

MISSING PILLS ALSO 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.

7.

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.

PROPER USE OF THIS MEDICATION

IMPORTANT: PLEASE READ

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8.

ALWAYS BE SURE YOU HAVE READY:

ANOTHER KIND OF BIRTH

CONTROL (such as latex or

polyurethane condoms and spermicidal

foam or gel) to use as a back-up in case

you miss pills; and

AN EXTRA, FULL PACK OF PILLS.

9.

IF YOU EXPERIENCE VOMITING OR

DIARRHEA, OR IF YOU TAKE CERTAIN

MEDICINES, such as antibiotics, your pills

may not work as well. Use a back-up method,

such as latex or polyurethane condoms and

spermicidal foam or gel, until you can check

with your doctor or clinic.

10.

IF YOU FORGET MORE THAN ONE PILL

TWO MONTHS IN A ROW, talk to your

doctor or clinic about how to make pill-taking

easier or about using another method of birth

control.

11.

THERE IS NO NEED TO STOP TAKING

BIRTH CONTROL PILLS FOR A REST

PERIOD.

12.

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 is the best day

for you to start taking your first pack of pills. Your

pills may be either a 21-day or a 28-day type.

DIRECTIONS FOR 21-DAY AND 28-DAY PILL

PACKS

THE FIRST DAY OF YOUR MENSTRUAL

PERIOD (BLEEDING) IS DAY 1 OF YOUR

CYCLE. The pills may be started up to Day 6 of

your cycle. Your starting day will be chosen in

discussion with your doctor. You will always begin

taking your pill on this day of the week. 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.

IF YOU ARE USING

A: 21-DAY Pill Pack:

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.

Take one pill at approximately the same time every day

for 21 days. THEN DO NOT TAKE A PILL FOR

SEVEN DAYS. Start a new pack on the eighth day.

You will probably have a period during the seven days

off the pill. (This bleeding may be lighter and shorter

than your usual period.)

28-DAY Pill Pack:

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

contain hormones and seven pills that contain no

hormones.

Take one pill at approximately the same time every day

for 28 days. Begin a new pack the next day, NOT

MISSING ANY DAYS ON THE PILLS. Your

period should occur during the last seven days of

using that pill pack.

INSTRUCTIONS FOR USING YOUR PACKAGE

FOR BOTH 21-DAY AND 28-DAY PACKS.

FOLLOW THESE INSTRUCTIONS CAREFULLY:

The pill package indicates Sunday as the day you start

your pills. If you are starting the pills on any other day

but Sunday, peel the appropriate day label from the

enclosed stickers and place the label over the pre-printed

days of the week.

For Day 1 start: Label the pill package by selecting

the day label that starts with Day 1 of your menstrual

period (the first day of menstruation is Day 1). For

example, if your first day of menstruation is Tuesday,

attach the day label that begins with TUE over the pre-

printed days of the week.

OR

For Day 5 start: Label the pill package by selecting the

day label that starts with the day that is 5 days after your

period begins. (Count 5 days including the first day of

menstruation.) For example, if your first day of

menstruation is Saturday, place the day label that starts

with WED over the pre-printed days of the week.

OR

For Sunday start: No day label is required. The package

is printed for a Sunday start. (The first Sunday after your

period begins, or, if your period starts on Sunday, start

that same day.)

Ensure the day label lines up with the pills..

Having the package labelled with the days of the

IMPORTANT: PLEASE READ

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week will help remind you to take your pill

every day.

To begin taking your pills, start with the pill

inside the circle (beside the word START).

This pill should correspond to the day of the

week that you are taking your first pill. To

remove the pill, push through the back of the

package.

On the following day, take the next pill in

the same row, always proceeding from left

to right (→). Each row will always begin on

the same day of the week.

WHAT TO DO DURING THE MONTH

1.

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.

2.

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. Available information from cases of

accidental ingestion of oral contraceptives by children

indicates no serious effects.

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 PILL

MISS ONE PILL

Take it as soon as you

remember and take the next

pill at the usual time. This

means that you might take

two pills in one day.

Take it as soon as you

remember, and take the next

pill at the usual time. This

means that you might take

two pills in one day.

MISS TWO PILLS IN A

ROW

MISS TWO 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 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 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.

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 method of

birth control if you have

sex in the seven days

after you miss the pills.

Third Week

Safely dispose of the rest

of the pill pack and start

a new pack that same

day.

Use a back-up 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 PILLS IN A

ROW

MISS THREE OR MORE

PILLS IN A ROW

If you think you have taken too much TRI-JORDYNA™ ,

contact your healthcare professional, hospital emergency

department or regional Poison Control Centre immediately,

even if there are no symptoms.

IMPORTANT: PLEASE READ

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Any Time in the Cycle

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 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.

Any Time in the Cycle

Safely dispose of the rest

of the pill pack and start

a new pack that same

day.

Use a back-up 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

"reminder" pills (without hormones) 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 CLINIC about ways to make pill-

taking easier or about using another method of birth

control.

NON-CONTRACEPTIVE 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

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.

Some users of birth control pills have unpleasant side effects.

These side effects are temporary and are not hazardous to

health.

There may be tenderness of the breasts, nausea and vomiting.

Some users will experience weight gain or loss. Many of

these side effects occurred with high-dose combination birth

control pills. These side effects are less common with the

low-dose pills prescribed today.

Unexpected vaginal bleeding or spotting and changes in the

usual menstrual period also may occur. These side effects

usually disappear after the first few cycles. They are NOT

an indication to stop taking birth control pills. Unless more

significant complications occur, a decision to stop using the

pill or to change the brand of pill should be made only after

three consecutive months of use.

Occasionally, users develop high blood pressure that may

require stopping the use of birth control pills.

The following additional symptoms have been reported in

women taking hormonal contraceptives in general:

difficulty wearing contact lenses

vaginal irritation or infections

change in skin pigmentation (can be permanent)

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Pr

TRI-JORDYNA

(Norgestimate and Ethinyl Estradiol Tablets USP)

Page 62 of 63

IMPORTANT: PLEASE READ

urinary tract infections or inflammation

upper respiratory tract infections (colds, bronchitis,

runny or stuffy nose, sore throat, etc.)

severe headaches

insomnia

amenorrhea (lack of a period or breakthrough bleeding)

flu-like symptoms

allergy, fatigue, fever, rash

diarrhea, flatulence

blood clots in a vein – this can lead to blocked blood

vessels in the liver, which cause an enlarged liver, pain

and swelling from build-up of fluid around the gut

(Budd-Chiari syndrome)

A woman's menstrual period may be delayed after

stopping birth control pills. There is no evidence that the

use of the pill leads to a decrease in fertility. As

mentioned, it is wise to delay starting a pregnancy for one

menstrual period after stopping birth control pills.

This is not a complete list of side effects. For any

unexpected effects while taking

TRI-JORDYNA

,

contact your doctor or pharmacist.

Store in original packaging, between 15°C – 30°C. Keep

out of the sight and reach of children.

HOW TO STORE IT

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/effect

Talk with your

doctor or

pharmacist

Stop taking

drug and

seek

immediate

medical

help

Only if

severe

In all

cases

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)

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/effect

Talk with

your doctor or

pharmacist

Stop

taking

drug and

seek

immediate

medical

help

Only if

severe

In all

cases

common

Abdominal

pain, nausea or

vomiting or

lump in the

abdomen

Breast lump

Crushing chest

pain or

heaviness

Pain or swelling

in the leg

Persistent sad

mood

Sharp pain in

the chest,

coughing blood,

or sudden

shortness of

breath

Sudden partial

or complete loss

of vision or

double vision

Pr

TRI-JORDYNA

(Norgestimate and Ethinyl Estradiol Tablets USP)

Page 63 of 63

IMPORTANT: PLEASE READ

MORE INFORMATION

If you want more information about TRI-JORDYNA™:

Talk to your healthcare professional

Find the full Product Monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada website

(https://www.canada.ca/en/health-canada.html); or by

contacting the manufacturer, Glenmark

Pharmaceuticals Canada Inc., at: 1-844-801-7468.

This leaflet was prepared by

Glenmark Pharmaceuticals

Canada Inc.

1600 Steeles Ave. West,

Suite 407

Concord, ON

L4K 4M2

Date of Revision: October 4, 2019

Reporting Side Effects

You can report any suspected side effects associated

with the use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction

Reporting (https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html ) for

information on how to report online, by mail or by

fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical

advice.

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