Cyclen Tablets (28 Day) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

CYCLEN^® Tablets are indicated for conception control.

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.

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 circulatory events are systemic lupus erythematosus¹, hemolytic uremic syndrome^2-4, chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis)⁵, sickle cell disease⁶, valvular heart disease and atrial fibrillation^7,8.

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: porphyria9, systemic lupus erythematosus10, hemolytic uremic syndrome¹¹, Sydenham’s chorea^12,13, herpes gestationis^14,15 and otosclerosis-related hearing loss¹⁶.

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.

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 CYCLEN^®, should not be used by women who are over 35 years of age and smoke.

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

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

Hypertension

Patients with essential hypertension whose blood pressure (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.

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 µg 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. ²³

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/m²), a personal history, a positive family history (the occurrence of VTE/ATE in a direct relative at a relatively early age may indicate genetic predisposition) and systemic lupus erythematosus. If a hereditary or acquired predisposition for venous or arterial thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use. The risk of VTE/ATE may be temporarily increased with prolonged immobilization, major surgery, or trauma. In these situations, it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume COC use until 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).

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

CYCLEN^® 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 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 restarting CYCLEN^®.

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 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.

Special Populations

Pregnant Women:

CYCLEN^® is contraindicated during pregnancy. If pregnancy occurs during treatment with CYCLEN^®, 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 CYCLEN^® 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 CYCLEN^® tablets have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatrics (> 65 years of age):

CYCLEN^® is 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 also 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.

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:

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 CYCLEN^® was evaluated in 1,891 healthy women of child-bearing potential who participated in 5 clinical trials and received at least 1 dose of CYCLEN^® for contraception. Two trials were randomized, active-controlled trials and 3 were uncontrolled, open-label trials. In 3 trials, subjects were followed for up to 24 cycles and in the other 2 trials, subjects were followed for up to 12 cycles. The most frequent Adverse Drug Reactions (ADRs) reported in >5% of subjects were headache, vaginal infection, genital discharge and breast pain. ADRs reported by ≥1% of CYCLEN^®-treated subjects in these trials are shown in Table 1.

Additional ADRs reported by <1% of CYCLEN^®-treated subjects (N=1,891) in the above clinical dataset are shown in Table 2.

In the above trials with CYCLEN^®, details for specific ADRs, namely nausea, vomiting, gastrointestinal disorder (reported as nausea or vomiting), dysmenorrhea, metrorrhagia, abnormal withdrawal bleeding and amenorrhea, were solicited or determined from bleeding pattern or cycle characteristics data on a by-treatment cycle (i.e., “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. In addition to the 5 clinical trials whose data were used in Tables 1 and 2, an uncontrolled, 6 – cycle trial was included in the by-cycle ADR analysis (Table 3). This trial was not included in Tables 1 and 2, as it did not report overall incidences for ADR data.

¹Number of subjects with available data for cycle 1.

²Based on data from 1 trial.

³Reported as nausea or vomiting.

⁴Based on data from 3 trials.

⁵Based on data from 4 trials.

⁶Based 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.

¹ 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.

Drug-Drug Interactions

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

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.

Table 6: Modification of Other Drug Action by Oral Contraceptives

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

Several of the anti-HIV protease inhibitors (e.g., ritonavir) and non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) have been studied with 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

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 (T₄) Increased

Thyroid Stimulating Hormone (TSH) Unchanged

T₃ 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.

1. 1. Combination oral contraceptives reduce the incidence of cancer of the endometrium and ovaries.
2. 2. Oral contraceptives reduce the likelihood of developing benign breast disease and, as a result, decrease the incidence of breast biopsies.
3. 3. Oral contraceptives reduce the likelihood of development of functional ovarian cysts.
4. 4. Pill users have less menstrual blood loss and have more regular cycles, thereby reducing the chance of developing iron-deficiency anemia.
5. 5. 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.
6. 6. Oral contraceptives decrease the incidence of acute pelvic inflammatory disease and, thereby, reduce as well the incidence of ectopic pregnancy.
7. 7. Oral contraceptives have potential beneficial effects on endometriosis.

DOSAGE AND ADMINISTRATION

INFORMATION TO PATIENTS ON HOW TO TAKE THE BIRTH CONTROL PILL

1. 1.

   READ THESE DIRECTIONS

   • before you start taking your pills, and
   • any time you are not sure what to do.
2. 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 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 DISCREET Package	28-Day DISCREET Package

1. 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.
2. 4. When receiving any medical treatment, be sure to tell your doctor that you are using birth control pills.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 11. 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

1. 1. 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.
2. 2.

   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 DISCREET PACKAGE FOR BOTH 21-DAY AND 28-DAY PACKS.

FOLLOW THESE INSTRUCTIONS CAREFULLY:

WHAT TO DO DURING THE MONTH

1. 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. 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.

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.

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

CYCLEN^® 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, CYCLEN^® may 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, CYCLEN^® 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.²⁸ Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in females. There are no antidotes and treatment should be symptomatic.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

The primary mechanism of action of CYCLEN^® Tablets 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.

Pharmacodynamics

CYCLEN^® elevated HDL levels across all studies. CYCLEN^® exhibited minimal androgenicity. Sex hormone binding globulin levels were increased and testosterone was not readily displaced from its binding sites by norgestimate.

Pharmacokinetics

Investigations of norgestimate alone and of CYCLEN^® Tablets (norgestimate and ethinyl estradiol) were carried out to study the pharmacokinetics of the drug in oral dosage forms.

Absorption: Orally administered norgestimate plus ethinyl estradiol in CYCLEN^® Tablets has been shown to be absorbed rapidly, with maximum blood levels being reached in 0.5 to 1.0 hour for the norgestimate and in 1.0 to 2.0 hours for the ethinyl estradiol (C_max, the plasma concentration ± S.D = 278 ± 140 pg/mL for norgestimate and 119 ± 50 pg/mL for ethinyl estradiol; AUC, the area under the plasma level vs time curve, ± S.D = 1,064 ± 425 hr•pg/mL for norgestimate and 984 hr•pg/mL for ethinyl estradiol).

Distribution: It has also 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.³²

Metabolism: The elimination of norgestimate (t_1/2 = 4.4 - 7.2 hours) has been shown to be unaffected by ethinyl estradiol. A major norgestimate serum metabolite, 17-deacetyl norgestimate (serum t_1/2 = 12 - 30 hours) appears rapidly in serum with concentrations greatly exceeding that of norgestimate. This metabolite is pharmacologically active with a pharmacologic profile similar to that of norgestimate.

Excretion: Norgestimate is extensively metabolized and eliminated by renal and fecal pathways (similar to other contraceptive steroids). Following administration of ¹⁴C-norgestimate, 47% (45 - 49%) and 37% (16 - 49%) of administered radioactivity was eliminated in urine and feces, respectively.^29-30

Special Populations and Conditions

Pediatrics

The safety and efficacy of CYCLEN^® has been established in women of reproductive age.

Use of this product before menarche is not indicated.

Geriatrics

CYCLEN^® is not indicated for use in postmenopausal women.

Hepatic Insufficiency

The effects of hepatic impairment on the pharmacokinetics of CYCLEN^® 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 CYCLEN^® have not been studied.

STORAGE AND STABILITY

Store in original packaging, between 15ΕC – 30ΕC. Leave contents in protective packaging until time of use. Keep out of the sight and reach of children.

DOSAGE FORMS, COMPOSITION AND PACKAGING

CYCLEN^® Tablets are available in:

21-Day DISCREET Package that contains:

• 21 BLUE tablets each containing 0.250 mg norgestimate and 0.035 mg ethinyl estradiol

28-Day DISCREET Package that contains:

• 21 BLUE tablets each containing 0.250 mg norgestimate and 0.035 mg ethinyl estradiol
• 7 GREEN tablets with inert ingredients

Each blue CYCLEN^® Tablet contains 0.250 mg norgestimate plus 0.035 mg ethinyl estradiol.

Each blue tablet also contains: FD & C Blue #2 Aluminum Lake, carnauba wax, croscarmellose sodium, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, purified water and titanium dioxide.

Each green tablet contains inert ingredients: FD & C Blue #2 Aluminum Lake, ferric oxide, lactose, magnesium stearate, polyethylene glycol, pregelatinized corn starch, purified water, polyvinyl alcohol, talc, and titanium dioxide.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

(i) DRUG SUBSTANCE

Norgestimate:

Chemical Name: (+)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one oxime acetate (ester)

Structural Formula:

HON H H O H H C CH CH₃ O CH₃

Molecular Weight: 369.51 Molecular Formula: C₂₃H₃₁NO₃

Description:

Norgestimate is a white to off-white fine granular powder. Melting and decomposition begin at 221^oC.

Solubility:

Solvent Solubility Criteria for USP

Distilled Water (DW) 0.076 μg/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 μg/mL Insoluble

Sesame Oil 1.4 mg/mL Slightly Soluble

Norgestimate has a partition co-efficient 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^o to +46^o (1% in chloroform at 25^oC at the sodium D line).

Ethinyl Estradiol:

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

Structural Formula:

HO CH₃ H H H CH C OH

Molecular Weight: 296.41 Molecular Formula: C₂₀H₂₄O₂

Description:

Ethinyl estradiol is a white to creamy white, odourless, crystalline powder with a melting range of 183^oC - 184^oC. It is insoluble in water and soluble in alcohol, chloroform, ether, vegetable oils and solutions of fixed alkali hydroxides.

CLINICAL TRIALS

Extensive studies of norgestimate plus ethinyl estradiol establishing the safety and efficacy of the combination in Phase III trials have been carried out in the United States, Canada, Mexico and Europe.

Clinical Evaluation of CYCLEN^® Tablets

The contraceptive efficacy and side effect pattern of CYCLEN^® Tablets have been evaluated in three major controlled and open Phase III studies conducted in the United States. These Phase III studies of CYCLEN^® Tablets involved 1,647 women who completed a total of 22,237 cycles of use; of these 927 (56.3%) completed 12 cycles and 424 (25.7%) completed 24 cycles of therapy.

In the two comparative Phase III studies combined, CYCLEN^® was taken by 736 subjects of whom 382 (51.9%) completed 12 cycles and 198 (26.9%) completed 24 cycles of therapy.

Contraceptive Efficacy

In the three studies combined, only 16 unplanned pregnancies were reported by patients while on therapy, giving a Pearl Index of 0.86 and a Life Table Rate of 0.94. In 8 cases, tablets had not been taken according to the recommended regimen and these pregnancies were considered patient failures. The resulting corrected Pearl Index (theoretical efficacy) is 0.43.

Miscellaneous Effects

For the controlled and open studies combined, the adverse experiences which occurred in 5% or more of the subjects taking CYCLEN^® were, in decreasing order of frequency: headache (31.2%), upper respiratory infection (17.7%), flu (8.3%), mastodynia (5.6%), and female genitalia pain (5.4%).

For the two comparative studies combined, the adverse experiences which occurred in 5% or more of the subjects taking CYCLEN^® were: headache (29.5%), upper respiratory infection (15.1%), flu (7.3%), and mastodynia (6.4%).

In the three Phase III studies, 17.9% of patients (294 of 1,647) discontinued CYCLEN^® for medical use-related reasons during the entire 24 cycles (cumulative gross probability of discontinuation of 0.2319, standard error = 0.0125).

Tolerance

A perspective on patient tolerance to effects reported during the course administration of CYCLEN^® Tablets can be obtained from an examination of the incidence of "drop-out" from the studies for the undesirable effects reported above.

ADVERSE EXPERIENCES CAUSING DISCONTINUATION

IN 2% OR MORE OF SUBJECTS

CYCLEN^® CYCLEN^®

Adverse Three Major Two Comparative

Experience Studies Combined Studies

Breakthrough bleeding 6.8% 6.8% or spotting

Headache 4.1% 3.8%

Nausea and/or vomiting 3.8% 4.3%

Mood alterations 3.2% 3.8%

Menstrual disturbances other than 2.9% 3.5% amenorrhea or breakthrough

bleeding/spotting

All other 5.6% 5.8%

Laboratory Tests

Changes observed in thyroid analytes were clinically insignificant and consistent with those expected for low-dose oral contraceptive use.

While the changes observed in lipid tests were small and remained within reference ranges of the United States population of reproductive-aged women, CYCLEN^® appeared to have minimal adverse impact on cholesterol, triglycerides, and LDL while being associated with a salutary positive impact on HDL.

The mean changes in fasting glucose are small and clinically insignificant for all studies, regimens, and cycles, although there are several statistically significant changes. The results of glucose tolerance testing for all the studies and regimens are clinically neutral and show minimal changes.

CYCLEN^® also exhibited minimal androgenicity. Sex hormone binding globulin levels were increased and testosterone was not readily displaced from its binding sites by norgestimate.

DETAILED PHARMACOLOGY

Pharmacodynamics

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.

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 monkey. 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 LD₅₀ 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 5 g/kg of the combination than in controls. Ethinyl estradiol alone had an oral LD₅₀ 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 5.0 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), given orally at 11.0, 2.75, 1.10, 0.55 mg/kg/day for 90 days, 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.

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 incidence of these changes was 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 plus 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 the 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 seven-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 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 seven-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 two-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 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 were seen. 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.³¹

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 ^a

One leiomyoma of vagina high ^a

One lobular carcinoma in situ of mammary gland high ^b

One papilloma of mammary gland high ^b

One adenoma of mammary gland high

One urinary bladder papilloma mid

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 have 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 F₀ 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 F₁ females but to a lesser degree than the F₀ generation. Trends toward decreased fertility, decreased implantation, F₂ 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

Rats

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 F₀ 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.

In the F₁ 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 F₂ generation development at any dose level.

Rabbits

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, 100% and 65.5%, observed in the high- and intermediate- dose groups, respectively. No drug-related teratogenic changes were observed in any of the fetuses examined.

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