Ortho 1/35 Tablets (21 Day) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ORTHO^® 1/35 Tablets are indicated for conception control.

CONTRAINDICATIONS

• History of or actual thrombophlebitis or thromboembolic disorders.
• Known thrombophilic conditions.
• History of or actual cerebrovascular disorders including transient ischemic attack.
• History of or actual myocardial infarction or coronary arterial disease including angina pectoris.
• Active liver disease or history of or actual benign or malignant liver tumours.
• Known or suspected carcinoma of the breast.
• Carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia.
• Undiagnosed abnormal vaginal bleeding.
• Steroid-dependent jaundice, cholestatic jaundice or history of jaundice in pregnancy.
• 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.
• Current or history of migraine with focal aura.
• Valvular heart disease with complications.
• History of or actual pancreatitis if associated with severe hypertriglyceridemia.

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

  • severe hypertension (persistent values of ≥160 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.
• Use with Hepatitis C virus (HCV) combination drug regimen paritaprevir, ritonavir, ombitasvir, with or without dasabuvir (see WARNINGS AND PRECAUTIONS).

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 combination hormonal contraceptives is associated with increased risks of several serious conditions including myocardial infarction, thromboembolism, stroke, hepatic neoplasia and gallbladder disease, although the risk of serious morbidity and mortality is small in healthy women without underlying risk factors. The risk of morbidity and mortality increases significantly if associated with the presence of other risk factors such as hypertension, hyperlipidemias, obesity and diabetes. Other examples of medical conditions which have been associated with adverse circulatory events e.g., systemic lupus erythematosus⁽¹⁾, hemolytic uremic syndrome^(2-4), chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis)⁽⁵⁾, sickle cell disease⁽⁶⁾, 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: porphyria⁽⁹⁾, systemic lupus erythematosus⁽¹⁰⁾, hemolytic uremic syndrome⁽¹¹⁾, Sydenham’s chorea^(12,13), herpes gestationis^(14,15) and otosclerosis-related hearing loss⁽¹⁶⁾.

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

Carcinogenesis and Mutagenesis

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 papillomavirus (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. See Product Monograph Part II: TOXICOLOGY for discussion on animal data.

Cardiovascular

Predisposing Factors for Coronary Artery Disease

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Combination oral contraceptives (COC) increase this risk, particularly in women over 35 years of age, and with the number of cigarettes smoked. Convincing data are available to support an upper age limit of 35 years for oral contraceptive use by women who smoke. For this reason, COCs, including ORTHO^® 1/35 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 persistent and significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary and an alternative 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 CONTRAINDICATIONS). Elevations of plasma triglycerides may lead to pancreatitis and other complications.

Gastrointestinal

Published epidemiological studies suggest a possible association of COC 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

ORTHO^® 1/35 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 and without dasabuvir to obtain further information about restarting ORTHO^® 1/35.

Immune

Angioedema

Exogenous estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema^(24-26).

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 Lesions

There have been clinical case reports of retinal thrombosis associated with the use of oral contraceptives. Oral contraceptives should be discontinued if there is unexplained 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.

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.

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.

Renal

Fluid Retention

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

Sexual Function/Reproduction

Return to Fertility

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

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.

Reduced Efficacy

The efficacy of COCs may be reduced in the event of missed tablets, vomiting, diarrhea or concomitant medication (see DRUG INTERACTIONS).

Skin

Chloasma may occasionally occur with use of COCs, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while taking COCs. Chloasma is often not fully reversible.

Special Populations

Pregnant Women

ORTHO^® 1/35 is contraindicated during pregnancy. If pregnancy occurs during treatment with ORTHO^® 1/35, further pill use should be stopped. However, if conception accidentally occurs while taking the pill, there is no conclusive evidence that the estrogen and progestin contained in the oral contraceptive will damage the developing child.

Nursing Women

In breast-feeding women, the use of oral contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. Published studies of related progestins have indicated that during lactation, small amounts of the daily maternal dose of the progestin⁽²⁷⁾ and 0.02% of the daily maternal dose of ethinyl estradiol⁽²⁸⁾ could be transferred to the newborn via milk. Adverse effects on the child have been reported, including jaundice and breast enlargement⁽²⁹⁾. The nursing mother should be advised not to use oral contraceptives but to use other forms of contraception until she has completely weaned her child.

Pediatrics

The safety and efficacy of ORTHO^® 1/35 have been established in women of reproductive age. Use of this product before menarche is not indicated.

Geriatrics

ORTHO^® 1/35 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 should be evaluated if a first-degree family member has suffered from thromboembolic disease or event (e.g., deep vein thrombosis, stroke, myocardial infarction) at a young age. Breasts, liver, extremities and pelvic organs should be examined and a Papanicolaou (PAP) smear should be taken if the patient has been sexually active.

The first follow-up visit should be done three months after oral contraceptives are prescribed. Thereafter, examinations should be performed at least once a year, or more frequently if indicated. At each annual visit, the examination should include those procedures that were done at the initial visit as outlined above or per recommendations of the Canadian Task Force on the Periodic Health Examination.

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:

Post-Market Adverse Drug Reactions

Adverse drug reactions first identified during post-marketing experience with ORTHO^® have been listed.

DRUG INTERACTIONS

Overview

The concurrent administration of oral contraceptives with other drugs may result in an altered response to either agent (see Tables 1 and 2). Reduced effectiveness of the oral contraceptive, should it occur, is more likely with the low-dose formulations.

It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, 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⁽³⁰⁾.

TABLE 1: 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 2: 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 coadministration 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-Food Interactions

Interactions with food have not been established.

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.

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 pills 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

The use of ORTHO^® 1/35 for contraception should be started no earlier than 4 weeks postpartum in women who elect not to breast-feed. When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered (See WARNINGS AND PRECAUTIONS, Hematologic). The possibility of ovulation and conception prior to initiation of medication should be considered.

Use after abortion or miscarriage

After an abortion or miscarriage that occurs prior to 20 weeks gestation, ORTHO^® 1/35 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, ORTHO^® 1/35 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.⁽²⁰⁾ Gastric lavage may be utilized if considered necessary. 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 ORTHO^® 1/35 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.

STORAGE AND STABILITY

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Form

ORTHO^® 1/35 Tablets are available in:

21-Day DISCREET Package that contains:

• 21 PEACH tablets each containing 1.0 mg norethindrone and 0.035 mg ethinyl estradiol

28-Day DISCREET Package that contains:

• 21 PEACH tablets each containing 1.0 mg norethindrone and 0.035 mg ethinyl estradiol
• 7 GREEN tablets with inert ingredients.

Composition

Each ORTHO^® 1/35 tablet (peach, unscored with "C135" engraved on each side) contains 1.0 mg norethindrone plus 0.035 mg ethinyl estradiol.

Each peach tablet contains lactose, magnesium stearate, Red Ferric Oxide and Yellow Ferric Oxide, and starch as non-medicinal ingredients.

In the 28-day regimen the green tablets, engraved on each side with "C-C", contain inert ingredients, namely D&C Yellow #10 Lake, FD&C Blue #2 Lake, lactose, magnesium stearate, microcrystalline cellulose, and starch.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Norethindrone:

Chemical Name: 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one

Structural Formula:

Molecular Weight: 298.42 Molecular Formula: C₂₀H₂₆O₂

Description:

Norethindrone is a white to creamy-white, odourless, crystalline powder with a melting range of 202^oC – 208^oC. It is practically insoluble in water, soluble in chloroform and in dioxan, sparingly soluble in alcohol, and slightly soluble in ether.

Ethinyl Estradiol:

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

Structural Formula:

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 ^{(21,31,37,38)}

Extensive clinical experience with formulations containing norethindrone alone or in combination with mestranol, as well as 0.05 mg of ethinyl estradiol in combination with various progestogens other than norethindrone, has been documented in the literature.^(32-34) Such formulations have been extremely effective in controlling conception, the combined products being more successful than the progestogen alone products.

CLINICAL EVALUATION OF NORETHINDRONE (1.0 mg)

AND ETHINYL ESTRADIOL (0.035 mg) FORMULATION

The contraceptive efficacy and side effect pattern of tablets containing 1.0 mg norethindrone and 0.035 mg ethinyl estradiol have been evaluated in an open study, conducted by a combined total of 17 investigators for the United States, Canada, Mexico, and Puerto Rico. This recently terminated study involved 940 patients who completed a total of 14,366 cycles of use with a pregnancy rate of 0.17 per hundred women-years.

Contraceptive Efficacy

In this study only two unplanned pregnancies were reported by patients while on therapy. In both cases tablets had not been taken according to the recommended regimen and these pregnancies were considered patient failures.

(a) PEARL INDEX⁽³⁵⁾

Pregnancy rate = 0.17/100 women-years.

(b) LIFE TABLE METHOD OF ANALYSIS⁽³⁶⁾

Cycles of Number of Cumulative Pregnancy Rate

Use Patients per 100 women

6 697 0.00

12 449 0.00

18 314 0.27

24 247 0.27

30 144 0.27

36 107 1.20

42 58 1.20

48 10 1.20

51 1 1.20

• (c) MENSTRUAL IRREGULARITIES

  Overall Cycle Incidence Overall Patient Incidence

  No. of % of No. of % of Patient

  Effect Cycles Cycles Patients Enrollment

  (a) Intermenstrual 697 4.9 357 38.0

  Spotting

  (b) Intermenstrual 686 4.8 344 36.6

  Breakthrough

  Bleeding (BTB)

  (c) Amenorrhea 111 0.8 83 8.8

• (d) MISCELLANEOUS EFFECTS

  Overall Cycle Incidence Overall Patient Incidence

  No. of % of No. of % of Patient

  Effect Cycles Cycles Patients Enrollment

  (a) Nausea 256 1.8 146 15.5

  (b) Vomiting 91 0.6 40 4.3

  (c) Other 1 0.01 1 0.1

  Gastro-

  intestinal

  (d) Total G.I. 348 2.4 170 18.1

  Disturbances

  (e) Headache 175 1.2 75 7.9

  (including

  migraine)

  Although somewhat higher in the first cycle, the incidence of menstrual and gastrointestinal disturbances decreased in subsequent therapy cycles. Unlike intermenstrual spotting and breakthrough bleeding, where the highest incidence occurred in the first cycle, the frequency of amenorrhea had no definitive pattern, except to say that the incidence was evenly distributed throughout all cycles of therapy. Other incidents reported on therapy were of a mild nature, low frequency or considered unrelated to therapy.

(e) INTERMENSTRUAL SPOTTING

Cycles of Number of Number of Cycles % of Cycles

Use Patients with Incidence

in Cycle

____________________________________________________________________

1 940 116 12.3

2 865 95 11.0

3 811 68 8.4

4 759 32 4.2

5 729 46 6.3

6 697 40 5.7

(f) INTERMENSTRUAL BREAKTHROUGH BLEEDING (BTB)

Cycles of Number of Number of Cycles % of Cycles

Use Patients with Incidence

in Cycle

____________________________________________________________________

1 940 118 12.6

2 865 76 8.8

3 811 57 7.0

4 759 49 6.5

5 729 34 4.7

6 697 34 4.9

(g) GASTROINTESTINAL DISTURBANCES (GID)

Cycles Number of Number of Cycles with Incidence % of of Use Patients Nausea Vomiting Other Total Cycles in Cycle GID

____________________________________________________________________________

1 940 90 15 105 11.2

2 865 50 12 62 7.2

3 811 33 6 1 40 4.9

4 759 17 2 19 2.5

5 729 12 4 16 2.2

6 697 8 1 9 1.3

Tolerance

(a) THERAPY DISCONTINUATION

A perspective on patient tolerance to effects reported during the course of administration of tablets containing 1.0 mg norethindrone and 0.035 mg ethinyl estradiol can be obtained from an examination of the incidence of "drop-out" from the study for the undesirable effects reported above.

Patient Incidence of Patient Drop-out Incidence

Effect __ due to Effect _______

No. of % of Patient No. of % of Patient

Effect Patients Enrollment Patients Enrollment

(a) Intermenstrual 357 38.0 17 1.8

Spotting

(b) Intermenstrual 344 36.6 48 5.1

Breakthrough

Bleeding (BTB)

(c) Amenorrhea 83 8.8 37 3.9

(d) Headache 75 7.9 20 2.1

(including

migraine)

(e) Total Gastro- 170 18.1 17 1.8

intestinal

Disturbances (GID)

(b) LABORATORY TESTS

Patients were selected at random from two investigational groups for ophthalmologic examinations and from two investigational groups for laboratory testing (CBC, urinalysis, SMA-12, PBI, and T₃ determinations). No abnormal results were reported for these tests.

(c) ENDOMETRIAL BIOPSY

A clinical study of endometrial biopsies in patients administered tablets containing 1.0 mg norethindrone and 0.035 mg ethinyl estradiol was conducted in Mexico by a single investigator. Endometrial biopsies were performed pretherapy and again after approximately six months on therapy. The biopsies of the twenty-three patients who completed the study did not show any changes of pathological significance. Five women experienced breakthrough bleeding and seven experienced spotting during therapy. Other clinical data were unremarkable. Two patients withdrew from the study, one for non-medical reasons and one for breakthrough bleeding. In the majority of women, changes consistent with the administration of an oral contraceptive, specifically a suppressed endometrium with small and inactive glands, were observed upon completion of the study at cycle 6.

DETAILED PHARMACOLOGY

Both norethindrone (NET) and ethinyl estradiol (EE) have been subjected to extensive biological examination over the past two decades.^(21-27) Norethindrone, using the Clauberg assay with rabbits, has been variously estimated to possess an oral progestational activity at least 10 times that of injected progesterone.⁽²⁷⁾ Only slight estrogenic activity along with some androgenic activity (9% that of methyl testosterone) has been evident. Ethinyl estradiol has been demonstrated to be slightly more active than 17 β-estradiol using the vaginal cornification test in rats.⁽²⁵⁾

Norethindrone/ethinyl estradiol, in the ratio of 1.0/0.035, fed to female rats for 22 days at a daily dose of 0.15 mg/kg was effective in reducing the littering activity during a period of fifteen days cohabitation with fertile males. Subsequent to the dosing period, these females regained their fertility.

Estrogenic, progestational, and antigonadotrophic characteristics are revealed for the endocrine profile of this combination. In female rats a uterotrophic effect is clearly demonstrated for a range of 0.1-0.4 μg, total oral dose. In rabbits a McPhail index of 2.6 is recorded at a total oral dose of 0.8 mg of this progestogen/estrogen combination. At a total dose of 450 μg (based on EE content), compensatory ovarian hypertrophy is completely inhibited in hemicastrated female rats.

TOXICOLOGY

Toxicology studies have evaluated norethindrone alone, as well as in combination with mestranol in the mouse, rat, rabbit, dog, and monkey. ^(21,28-30) Ethinyl estradiol has also been evaluated both alone and in combination with synthetic steroidal progestogens in the mouse, rat, rabbit, dog, and monkey. ^(21,28-30) Compound-related gross and microscopic lesions have been minimal and show the typical pathological changes known to occur with the administration of progestogen and estrogen.

Acute Toxicity Studies

The acute oral toxicity of norethindrone in combination with ethinyl estradiol (1.0/0.035) was assessed in male and female hooded Long-Evans derived rats and Swiss Webster mice. This combination at an oral dose level of 4 g/kg produced no deaths in either species. Animals were observed for 28 days post-administration.

In addition, the acute oral toxicity of ethinyl estradiol alone has been assessed in male and female Swiss Webster mice, male and female Long-Evans rats, and female Beagle dogs.

Mice:

An acute oral LD₅₀ study was performed with ethinyl estradiol in male and female mice. EE was suspended in 0.25% carboxymethylcellulose at a concentration of 166.67 mg/mL and used in a range-finding study at dosage levels of 5, 4, 3, 2, and 1 g/kg administered orally to one male and one female for each level. The dose volume was 0.03 mL/g of body weight. Observation of these mice for a period of 2 days revealed no mortality or other overt signs of toxicity. Subsequently, the highest dosage level of 5 g/kg, using the EE suspension of 166.67 mg/mL, was administered orally to ten male and ten female mice. The animals were observed immediately after dosing, at 1 and 4 hours, and daily thereafter for 14 days. An initial period of depression lasting approximately 2 hours was observed in male mice; no other overt signs of toxicity or mortality were noted in male or female mice during the 14-day observation period.

Necropsies performed at the end of the study revealed no gross pathological findings, with the exception of slightly enlarged uteri in the female mice.

Under the conditions of this study it was concluded that the oral LD₅₀ of ethinyl estradiol in mature HaM/1CR CD-1 male and female mice was greater than 5 g/kg.

Rats:

An acute oral LD₅₀ study was performed with ethinyl estradiol in Long-Evans derived male and female rats. Each animal was dosed by gavage with ethinyl estradiol suspended in 0.25% sodium carboxymethylcellulose. Doses of 3.2 g/kg, 4.0 g/kg, and 5.0 g/kg were administered. Each dose was given once to ten male and ten female rats. The animals were then observed immediately, at 1 and 4 hours after dosing, and daily for 14 days thereafter. All animals were examined macroscopically either upon death during the study, or at sacrifice after the 14-day observation period.

Depression, ataxia, and exophthalmos were the toxic signs exhibited, with severity and frequency of occurrence related to increase in dosage levels. Among the males, 10% of the mortality occurred at the 3.2 g/kg level, no deaths at the 4.0 g/kg level, and a 50% mortality at the 5.0 g/kg level. The females dosed at 3.2 g/kg exhibited 50% mortality and at 4.0 and 5.0 g/kg a 70% and 90% mortality, respectively.

There were no drug- or dose-related macroscopic changes seen at necropsy.

Under the conditions of this experiment the oral LD₅₀ value for ethinyl estradiol in Long-Evans derived young adult rats was 5.3 g/kg for males and 3.2 g/kg for females.

Dogs:

An acute oral toxicity study was conducted in female Beagle dogs with ethinyl estradiol alone to determine the maximum tolerated oral dose.

Animals were dosed by gavage with ethinyl estradiol suspended in 0.25% carboxymethyl-cellulose. Two dogs per dosage level were given 1.0, 2.5, or 5.0 g/kg and three dogs received the vehicle alone. The doses were divided into two or three portions and administered at two- to three-hour intervals. The dogs were observed immediately after dosing and 14 days thereafter. Body weights were recorded prior to dosing and at the end of the observation period. The animals were necropsied at the end of the study.

There were no deaths during the 14-day observation period of the animals dosed orally with ethinyl estradiol.

Under the conditions of this experiment, ethinyl estradiol administered orally to female Beagle dogs at dose levels of 1.0, 2.5, or 5.0 g/kg produced no significant adverse effects. The maximum tolerated oral dose of ethinyl estradiol in carboxymethylcellulose for the female Beagle dog was greater than 5.0 g/kg.

Chronic Toxicity Studies

Chronic toxicity studies of the combination of norethindrone - ethinyl estradiol have been conducted in male and female mice and rats.

Mice:

Young adult CFW mice (45 males and 45 females per dose group) were dosed with NET/EE (20/1) at 0.10 + 0.005, 0.60 + 0.030, and 2.00 + 0.100 mg/kg/day for 80 weeks. Administration of the drug was admixture in the diet, concentrations being adjusted throughout the test to conform with changing body weight and food intake.

Changes in physical condition, appearance, and behaviour were observed more frequently in the intermediate- and high-dose drug-treated groups. While food consumption changes were not dose-related, drug-treated groups experienced a dose-related decrease in body weight when compared to control animals.

Eighty-nine animals did not survive the dosing schedule (28 females, 61 males). In females, mortality was distributed equally among dose groups, whereas highest male mortality was observed in control and high-dose groups.

At autopsy, uterine and testicular organ weight analysis revealed a decrease of organ weights in all drug-treated groups. Ovarian and adrenal weights in females and prostatic weights in males were decreased in the intermediate- and high-dose levels. Pituitary and adrenal weights were increased in male animals in drug-treated groups.

Histopathological examination of processed tissues revealed spontaneous non-neoplastic and neoplastic lesions. No non-neoplastic lesions were found that could be related to the drug combination, except in some changes observed in the gonads and secondary sex organs. The distribution of neoplastic lesions was similar to that reported by the British Committee.⁽²⁹⁾ Males and females in the high-dose drug-treated group exhibited urinary bladder transitional cell carcinoma.

From the results the "no-effect dose" in mice treated for 80 weeks is greater than 0.100 mg NET + 0.005 mg EE/kg/day, but less than 0.60 mg NET + 0.030 mg EE/kg/day.

Rats:

Young adult Blue Spruce Farms, Long-Evans derived, hooded rats (45 females, 45 males per dose group) were dosed with NET/EE (20/1) at 0.10 + 0.005, 0.60 + 0.030, and 2.00 + 0.100 mg/kg/day for 116 weeks. Administration of the drug was by addition to the diet, concentrations being adjusted throughout the test to conform to changing body weight and food consumption.

No unusual changes in gross clinical observations were found, and the expected dose-dependent depression in food consumption and growth occurred.

One hundred and fifty-three animals failed to survive the dosing schedule (63 females, 90 males). In the females, the highest mortality was observed in the high-dose and control groups. The highest mortality in the males was in the control, low-dose, and high-dose levels.

At autopsy, individual organ weight analysis revealed weight decrease in the ovaries in the intermediate- and high-dose groups, a decrease in brain and kidney weights in the high-dose level, and an increase of uterine weights in the intermediate- and high-dose levels. In the males at the high-dose levels, kidney, testicular, and prostatic weights were decreased. The liver weights were increased in the males at the intermediate- and high-dose levels.

No non-neoplastic histopathological lesions were found that could be referable to drug treatment. Certain of the non-neoplastic lesions could be grouped as aging changes, while the other spontaneous lesions of this type were equally distributed among the dose groups.

Pheochromocytoma of the adrenals and transitional cell carcinoma of the renal pelvis were more frequently observed in male control animals than in treatment groups. Treated female rats had a lower incidence of malignant pituitary tumours than the female controls. The incidence of adenocarcinoma of the mammary glands was comparable in controls and treatment groups. A high incidence of hepatoma was observed in both treated male and female rats, indicating a dose-related response.

The "no effect dose" in rats treated with NET/EE (20/1) for 116 weeks is less than 0.60 mg NET + 0.030 mg EE/kg/day. Also, the tumour incidence pattern in this species does not vary from that previously reported in the literature for similar hormonal combinations.⁽²⁸⁾

Lifetime Toxicity Studies

Lifetime studies of norethindrone and ethinyl estradiol administered orally in combination to female Beagle dogs and female Rhesus monkeys continue.⁽²¹⁾

Dogs:

A combination of norethindrone plus ethinyl estradiol (20 parts norethindrone to 1 part ethinyl estradiol) has been administered orally for a period of sixty-nine months to sixteen mature female Beagle dogs at a dosage level equivalent to twenty-five times the human dosage level (0.525 mg/kg/day of the combination). The regimen has been cyclic, three weeks of compound administration followed by one week of no administration.

An additional sixteen dogs comprise a control group receiving vehicle (0.5% methocel) only.

The general appearance and behaviour of the animals has been normal, with most dogs gaining or maintaining body weight during the course of the study. Alopecia has been observed for some control and all treated dogs since initiation of the study. A red vaginal discharge has been observed sporadically both among control and treated dogs.

After sixty-nine months of study, mammary nodules have been noted in one control and four treated dogs.

Ophthalmological examinations have revealed eye changes in six control and two treated animals, which are not considered to be compound related.

A moderate to marked elevation in erythrocyte sedimentation rate (ESR) has been noted in a small number of dogs from both treated and control groups. Mean values of this parameter did not differ significantly between control and treated groups.

Decreases in mean erythrocyte and hemoglobin values have been noted which are statistically significant for the treated groups.

Mean fibrinogen values have been significantly greater in treated than in control dogs. Values have been above normal in a small number of dogs from both the control and treated groups.

Platelet counts, prothrombin times, and partial thromboplastin time have been reported to be significantly greater in treated than in control animals, although all values have been within accepted normal ranges. There have been no other changes in hematologic or clinical chemistry parameters.

The surviving test population consists of twelve control and nine treated dogs.

The seven-year study continues.

Monkeys:

A combination of norethindrone plus ethinyl estradiol (20 parts norethindrone to 1 part ethinyl estradiol) has been administered orally for a period of sixty-nine months to sixteen mature female monkeys at a dosage level equivalent to fifty times the human dosage level (1.05 mg/kg/day of the combination). The regimen has been cyclic, three consecutive weeks of compound administration followed by one week of no administration. Two monkeys have been added to the study as replacements for monkeys that died or were sacrificed in extremis.

An additional sixteen monkeys comprise a control group receiving a food vehicle only on the same regimen as the treated monkeys.

Most monkeys have maintained or shown minimal changes in body weight over the duration of the study. However, treated monkeys have demonstrated significantly less weight gains than control monkeys when compared to mean baseline values.

Red vaginal discharge has occurred in all the treated monkeys during the compound withdrawal phase of each cycle since the sixty-sixth cycle. The occurrence has been sporadic in most control monkeys during both the vehicle and withdrawal phase of each cycle.

Alopecia has been observed with equal frequency in both control and treated monkeys. A white or gray mammary discharge has been observed more frequently in treated animals than in control animals.

No behavioural changes considered to be compound related have been observed in treated animals.

Indirect ophthalmological examinations have been unremarkable. However, the use of a fundus camera as a direct ophthalmoscope has revealed the presence of hypopigmented spots in the maculae of both control and treated monkeys. There are no clinically observable defects in the visual acuity of these monkeys. Although the etiology of these clinical findings still requires definition, no significant interpretative differences in the findings have been reported in the period that direct ophthalmological examinations have been employed.

Marginal fluctuations in erythrocyte counts, hemoglobin concentration, hematocrit, and total leucocyte counts have occurred in both control and treated groups.

A statistically significant increase in erythrocyte sedimentation rate has been observed in the treated group compared to controls.

With the exception of SGPT, clinical chemistry determinations have remained within normal limits. While the mean SGPT activity for the treated group remains high and was progressive from the 48-month period through the sixty-three-month period, this value has decreased over the subsequent two reporting periods.

An increase in protein bound iodine (PBI) concentration has been observed since the thirty-month period in three control and nine treated monkeys.

Other clinicopathologic parameters have remained unremarkable.

The surviving population consists of nine control monkeys and ten treated monkeys.

The ten-year study continues.

Lifetime studies of norethindrone alone administered orally to Beagle dogs and Rhesus monkeys were initiated.⁽²¹⁾ The seven-year safety study in female dogs is complete; the ten-year safety study in female monkeys continues.

Dogs:

Norethindrone was administered orally for a period of eighty-four months (seven years) to mature female Beagle dogs daily at dosage levels of 0.007, 0.07, and 0.175 mg/kg/day (1, 10, and 25 times the human dosage); an additional group of dogs was administered 0.25% agar and served as a control group. Each group was assigned sixteen test animals.

There were no remarkable changes in general behaviour, body weight, ophthalmologic or hematologic parameters.

Clinicopathologic changes which were considered to be drug related were increased fibrinogen, serum glutamic pyruvic transaminase, and blood glucose.

The histopathologic changes which represented the exaggerated pharmacologic effects of the drugs were cystic changes in the uterus and gallbladder and inhibition of ovulation. The presence of endometrial-like glands in the lamina propria of the vagina was of uncertain etiology.

This seven-year drug safety study revealed no significant adverse changes attributable to long-term use of this compound.

Monkeys:

Norethindrone has been administered orally for a period of one hundred and eleven months to mature female Rhesus monkeys daily at dosage levels of 0.007, 0.07, and 0.35 mg/kg/day. An additional group of monkeys has been administered vehicle only and serves as a control group. Each group has been assigned sixteen test animals.

Daily observations of general health revealed no evidence of overt effects of drug treatment or significant changes in behaviour. The mean body weight of control and treated groups showed comparable weight gains.

Red vaginal discharge was noted more frequently and for a longer period in the control and low dosage groups than in the intermediate and high dosage groups.

Monthly mammary examination of all monkeys revealed, as of the one hundred and seventh month, an intermediate dosage monkey with a palpable structure, designated as a nodule, in the region of the mammary gland. This mammary gland nodule remains unchanged as of the one hundred and eleventh month and no other mammary gland nodules or signs of secretory activity have been found.

Comparable hemograms were noted among the four test groups except for the following differences: mean percent segmented neutrophils for the high and intermediate dosage groups were significantly less than the low dosage group (p < 0.05); the mean for the low dosage group was also greater than the control group mean (p < 0.01).

The opposite trend was seen for mean percent lymphocytes, with the high dosage (p < 0.01) and intermediate dosage (p < 0.05) group means greater than the low dosage group; the low dosage group mean was also lower than the control group (p < 0.01). Mean percent basophils was significantly greater (p < 0.05) in the intermediate dosage group than in the control. These trends were also apparent in the absolute differential values.

No significant differences were noted in coagulation parameters with the following exceptions. The mean activated partial thromboplastin time (APTT) for the intermediate dosage group was less than the control group mean (p < 0.05), and the mean fibrinogen for the high dosage group was greater than the control (p < 0.01), intermediate and low dosage group means (p < 0.05). The difference between mean APTT values for the intermediate and control groups was random and therefore is not considered to be drug related. However, the differences in mean fibrinogen values among the dosage groups appear to be dose related.

The high dosage group mean for total protein was significantly less (p < 0.05) than that for the low dosage group mean.

The high dosage group T₃ uptake mean was significantly less than the control (p < 0.01), intermediate and low dosage group means (p < 0.05). The mean T₃ (RIA) value for the high dosage group was significantly greater (p < 0.05) than the low dosage group mean. The high dosage group was observed to have a mean T₄ significantly higher (p < 0.05) than the control group.

One low-dose monkey continues to show evidence of hemoconcentration as indicated by high hematocrit, hemoglobin, and red blood cell count. The total white blood cell count was normal, but there was a higher percent segmented neutrophil count with a corresponding lower lymphocyte count as compared to other animals in the study. The platelet count and sedimentation rate were normal, but the prothrombin time and activated partial thromboplastin time were prolonged. There was insufficient plasma to analyze fibrinogen. Cholesterol, BUN, and T₃ RIA were high normal and SGPT was borderline. Alkaline phosphatase for this animal was high. Direct ophthalmoscopic examination of monkey eyes has indicated the presence of hypopigmented foci in the macular region of the retina in some monkeys from all test groups including controls. In examinations to date, the incidence of this phenomenon has appeared to be greater in the dosed groups than in the control group.

The ten-year study continues.

REPRODUCTION STUDIES

A perinatal and postnatal study was conducted using Long-Evans derived hooded rats to determine the effects of norethindrone on late fetal development, maternal labour, delivery, lactation, and growth and reproductive performance of the offspring. At the high-dose level (0.35 mg/kg), there was a growth retardation in the F₂ generation. At the lower dose level (0.07 mg/kg), there was retardation in skeletal development in those stillborn fetuses that were cleared and stained. No other significant effects attributed to the compound were observed.⁽²¹⁾

TERATOLOGY

A study was done to determine the teratogenic effect of norethindrone on the embryo and developing fetus of the hooded female rat (Long-Evans derived). The potential of the drug to produce fetal resorption and fetal malformation was specifically investigated. At a dose level of 0.7 mg/kg (which is approximately 100 x the human dose), no significant effect on the fetus was seen.⁽³⁾

A similar study was conducted on New Zealand white rabbits. As with the rat study, no significant effect on the fetus was observed at a dose level of 0.7 mg/kg⁽²¹⁾.

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