Evra -(6/0.75) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

The EVRA (norelgestromin and ethinyl estradiol) transdermal system is indicated for the prevention of pregnancy.

The pharmacokinetic profile for the EVRA transdermal system is different from that of an oral contraceptive. The clinical relevance of the differences in PK profiles between transdermal and oral delivery is not known. (See WARNINGS AND PRECAUTIONS

• General, Transdermal versus Oral Contraceptives and ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics, Transdermal versus Oral Contraceptives.)

CONTRAINDICATIONS

The EVRA (norelgestromin and ethinyl estradiol) transdermal system should not be used in women with:

• a history of or actual thrombophlebitis or thromboembolic disorders;
• a history of or actual cerebrovascular disorders;
• a history of or actual myocardial infarction or coronary artery disease;
• valvular heart disease with complications;
• active liver disease, or history of or actual benign or malignant liver tumours;
• known or suspected carcinoma of the breast;
• carcinoma of the endometrium or other known or suspected estrogen-dependent neoplasia;
• undiagnosed abnormal vaginal bleeding;
• steroid-dependent jaundice, cholestatic jaundice, history of jaundice of pregnancy;
• any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision, or defect in visual fields;
• known or suspected pregnancy;
• current or history of migraine with focal aura;

• presence of severe or multiple risk factor(s) for arterial or venous thrombosis such as:

  • severe hypertension (persistent values of ≥160 /100 mm Hg)
  • 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, hyperhomocysteinaemia (e.g. due to MTHFR C677T, A1298 mutations), prothrombin mutation G20210A, and antiphospholipid-antibodies (anticardiolipin antibodies, lupus anticoagulant)
  • severe dyslipoproteinemia
  • heavy smoking (>15 cigarettes per day) and over age 35
  • diabetes mellitus with vascular involvement

• major surgery associated with an increased risk of post-operative

  thromboembolism

• prolonged immobilization
• hypersensitivity to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

The risk of venous thromboembolism (VTE) in users of the ORTHO EVRA patch (the formulation of EVRA marketed in the United States) compared to users of oral contraceptives containing norgestimate and 35µg of EE was assessed in two epidemiological studies with a nested case-control design conducted in women aged 15 to 44 years. One of these studies found an increased risk of VTE for current users of ORTHO EVRA compared to current users of the oral contraceptives [odds ratio 2.42 (95% CI 1.07 – 5.46)]⁴⁴ The other study did not find an increase in risk of VTE for current users of ORTHO EVRA [odds ratio 0.9 (95% CI 0.5 – 1.6)].¹⁵

Prescribers are advised to carefully assess a patient’s baseline and cumulative risk of thromboembolism before prescribing hormonal contraceptives, including EVRA . Obesity (BMI ≥30 kg/m²) has been identified as a risk factor for venous thromboembolism.^1,10,38,42 Particular caution should be exercised when prescribing hormonal contraceptives, including EVRA, to women who are obese (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS – General, Cardiovascular, Endocrine and Metabolism, Hematologic and ADVERSE REACTIONS).

Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels. This risk increases with age and becomes significant in hormonal contraceptive users older than 35 years of age. Women should be counselled not to smoke (see Cardiovascular section below).

Hormonal contraceptives DO NOT PROTECT against sexually transmitted diseases including HIV/AIDS. For protection against STDs, it is advisable to use latex condoms IN COMBINATION WITH hormonal contraceptives.

General

Transdermal versus Oral Contraceptives

Prescribers should be aware of the differences in pharmacokinetic (PK) profiles of transdermal and oral combined hormonal contraceptives and should exercise caution when making a direct comparison between these parameters. In general, transdermal patches are designed to maintain steady delivery of EE and NGMN over a seven-day period while oral contraceptives are administered on a daily basis and produce daily peaks and troughs. Inter-subject variability (%CV) for PK parameters following delivery from the patch is higher relative to the variability determined from the oral contraceptive. The clinical relevance of the differences in PK profiles between transdermal and oral delivery is not known. (See ACTION AND CLINICAL PHARMACOLOGY – Pharmacokinetics, Transdermal versus Oral Contraceptives.)

Sex Hormone Binding Globulin (SHBG)

Published reports have indicated that the mean percent change in concentration of SHBG, a marker of systemic estrogenic activity, is higher following the application of a combined transdermal patch releasing ethinyl estradiol 20 µg and norelgestromin 150 µg per 24 hours than following administration of a daily oral contraceptive. The clinical significance of this finding is not known.^23,49

Discontinue Medication at the Earliest Manifestation of:

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 vascular thrombosis, such as 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 hormonal contraceptives when surgery is contemplated, see Peri-operative Considerations below;

C. Visual defects—partial or complete;

D. Papilledema or ophthalmic (retinal) vascular lesions;

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

Risk of Unintentional Increase in Drug Exposure

(See Drug-Lifestyle Interactions, PHARMACOKINETICS-Absorption).

Patients with Fever: Serum estradiol concentrations could theoretically increase in patients with fever. Any clinical consequences due to any increase in temperature are unknown at this time.

External Heat Sources: Due to a theoretical risk of increased exposure to ethinyl estradiol, all patients should be advised to avoid exposing the EVRA application site to direct external heat sources, such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths, intensive sunbathing, etc.

The following information is provided from studies of combination oral contraceptives. The use of the EVRA (norelgestromin and ethinyl estradiol) transdermal system is expected to be associated with similar risks.

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 or 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. The excess risk of venous thromboembolism (VTE) is highest during the first year a woman ever uses a combined hormonal contraceptive.

The information contained in this section is principally based on studies carried out in women who used combination oral contraceptives with higher formulations of estrogens and progestins than those in common use today. The effect of long-term use of combination hormonal contraceptives with lower doses of both estrogen and progestin administered orally or transdermally 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 hormonal contraceptives (more than eight years) and starters at early age. In a few women, the use of hormonal 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 using hormonal contraceptives should be instructed in breast self-examination. Their healthcare providers should be notified whenever any mass is detected. A yearly clinical breast examination is recommended because, if a breast cancer should develop, drugs that contain estrogen may cause a rapid progression.

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 – Mutagenicity and Carcinogenicity for discussion on animal data.

Cardiovascular

See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS – Boxed Warning, General, Hematologic and ADVERSE DRUG REACTIONS. In the post-market period there have been cases of myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism associated with use of EVRA, with some cases resulting in fatality.

Prescribers are advised to carefully assess a patient’s baseline and cumulative risk of thromboembolism and discuss the risk of thromboembolism with all patients before prescribing EVRA.

Predisposing Factors for Coronary Artery Disease

Cigarette smoking increases the risk of serious cardiovascular side effects and mortality. Hormonal contraceptives increase this risk, especially with increasing age. Convincing data are available to support an upper age limit of 35 years for hormonal contraceptive use by women who smoke.

Other women who are independently at high risk for cardiovascular disease include those who suffer from or have a family history of diabetes, hypertension or an abnormal lipid profile. Whether hormonal contraceptives accentuate this risk is unclear.

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

Hypertension

Patients with essential hypertension whose blood pressure is well controlled may be given hormonal contraceptives but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.

In three clinical trials of EVRA (n = 1530, 819 and 748, respectively), mean changes from baseline in systolic and diastolic blood pressure were less than 1 mm Hg.

Endocrine and Metabolism

Obesity

Obesity (BMI ≥30 kg/m²) is generally considered a risk factor for venous thromboembolism. ^1,10,38,42

There have been a number of post-market cases of thromboembolism reported in overweight (BMI ≥ 25kg/m²) and obese (BMI≥30kg/m²) women using EVRA. Particular caution should be exercised when prescribing hormonal contraceptives, including EVRA, to women who are obese. (See also WARNINGS AND PRECAUTIONS-Boxed Warning, Hematologic.)”

Body Weight ≥90 kg

Analyses of Phase III data suggest that the EVRA (norelgestromin and ethinyl estradiol) transdermal system may be less effective in women with body weight ≥90 kg (198 lbs.) than in women with lower body weights. Below 90 kg, there was no apparent association between body weight and pregnancy rate. (See Product Monograph Part II: CLINICAL TRIALS.)

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.

Diabetes

Current low-dose hormonal 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 hormonal 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 hormonal contraceptives.

In a 6-cycle clinical trial with EVRA, there were no clinically significant changes in fasting blood glucose from baseline to end of treatment.

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 hormonal contraceptive use.

Hematologic

See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS- Boxed Warning, General, Cardiovascular, Peri-operative Considerations and ADVERSE REACTIONS.

In the clinical trials (n = 3330 subjects with 1704 women years of exposure), two cases of non-fatal pulmonary embolism were reported with use of EVRA, one of which was postoperative.

In the post-market period there have been cases of myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism associated with use of EVRA, with some cases resulting in fatality.

Prescribers are advised to carefully assess a patient’s baseline and cumulative risk of thromboembolism and discuss the risk of thromboembolism with all patients before prescribing EVRA.

Post-partum period

There have been post-market cases of thromboembolism reported in women using EVRA up to two months post-partum. Since the immediate postpartum period is associated with an increased risk of thromboembolism, hormonal contraceptives should be started no earlier than four weeks after delivery in women who elect not to breast-feed. If possible,

women should be encouraged to use a non-hormonal form of contraception in the three months following delivery. Women who elect to use EVRA in the immediate post-partum period should be carefully monitored for signs and symptoms of thromboembolism.

Post-abortion/post-miscarriage

After an abortion or miscarriage 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.)

Obesity

Obesity (BMI≥30kg/m²⁾ is generally considered a risk factor for venous thromboembolism.^1,10,38,42

There have been a number of post-market cases of thromboembolism reported in overweight (BMI ≥ 25kg/m²) and obese (BMI≥30kg/m²) women using EVRA. Particular caution should be exercised when prescribing hormonal contraceptives, including EVRA, to women who are obese (See also WARNINGS AND PRECAUTIONS-Boxed Warning, Endocrine and Metabolism.)

Other risk factors for venous thromboembolism

Other generalized risk factors for venous thromboembolism include but are not limited to a personal history, a family history (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition) and systemic lupus erythematosus. The risk of VTE also increases with age and smoking. The risk of VTE may be temporarily increased with prolonged immobilization, major surgery or trauma. Also, patients with varicose veins and leg cast should be closely supervised.

If a hereditary or acquired predisposition to venous thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any hormonal contraception use.

Hepatic/Biliary/Pancreatic

Jaundice

Patients who have had jaundice should be given hormonal contraceptives only with great care and under close observation. Oral contraceptive-related cholestasis has been described in women with a history of pregnancy-related cholestasis. Women with a history of cholestasis may have the condition recur with subsequent hormonal contraceptive use.

The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved.

If a patient develops jaundice that proves to be cholestatic in type, the use of hormonal contraceptives should not be resumed. In patients taking hormonal contraceptives,

changes in the composition of the bile may occur and an increased incidence of gallstones has been reported.

Hepatic nodules

Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of hormonal 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.

Gallbladder disease

Users of 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.

Neurologic

Migraine and Headache

The onset or exacerbation of migraine or the development of headaches with a new pattern that is recurrent, persistent or severe requires discontinuation of hormonal contraceptives and evaluation of the cause. Women with migraine headache who take hormonal contraceptives may be at increased risk of stroke (see

CONTRAINDICATIONS).

Epilepsy/seizures

There have been very rare cases of seizure/convulsion reported in patients using EVRA (see Post-market Adverse Drug Reactions). Patients with epilepsy or other seizure disorders who are being treated with anticonvulsants should be monitored closely while using hormonal contraceptives. In some patients being treated with anticonvulsants, a method of contraception other than hormonal contraceptives may be recommended (see DRUG INTERACTIONS: Drug-Drug Interactions). If a woman experiences new onset or exacerbation of seizures while using EVRA, the use of EVRA should be re-evaluated.

Ophthalmologic

Ocular Disease

Patients who are pregnant or are taking oral contraceptives may experience corneal edema. This may cause visual disturbances and changes in contact lens tolerance in rigid contact lens users; soft contact lenses do not usually cause disturbances. If visual changes or alterations in lens tolerance 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 using hormonal 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 hormonal 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 hormonal 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. There may be some delay in the patient becoming pregnant following discontinuation of the contraceptive patch, particularly if the patient had irregular menstrual cycles before using the contraceptive patch.

Amenorrhea

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

Women with 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.

Special Populations

Pregnant Women

Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy.

Hormonal contraceptives should not be taken by pregnant women. However, if conception accidentally occurs while hormonal contraceptives are being used, there is no conclusive evidence that the hormones contained in the contraceptive will harm the developing child. The majority of recent studies also do not indicate a teratogenic effect, particularly insofar as cardiac anomalies and limb reduction defects are concerned, when taken inadvertently during early pregnancy.³⁴

Nursing Women

In breast-feeding women, the use of hormonal contraceptives results in the hormonal components being excreted in breast milk and may reduce its quantity and quality. If the use of oral contraceptives is initiated after the establishment of lactation, there does not appear to be any effect on the quantity and quality of the milk.

A few adverse effects on the child have been reported, including jaundice and breast enlargement.⁷ The nursing mother should be advised not to use combination hormonal contraceptives, but to use other forms of contraception until she has completely weaned her child.

Pediatrics (<18 years of age)

The safety and efficacy of EVRA have not been established in women younger than 18 years of age. Use of this product before menarche is not indicated.

Geriatrics

EVRA is not indicated for use in post-menopausal women.

Renal Impairment

EVRA has not been studied in women with renal impairment. There is a suggestion in the literature that the unbound fraction of ethinyl estradiol is higher.²⁶ EVRA should be used with supervision in this population.

Hepatic Impairment

EVRA is contraindicated in this population (see CONTRAINDICATIONS).

Monitoring and Laboratory Tests

Physical Examination and Follow-up

Before hormonal contraceptives are used, a thorough history and physical examination should be performed, including a blood pressure determination. Breasts, liver, extremities and pelvic organs should be examined. A Papanicolaou smear should be taken if the patient has been sexually active.

The first follow-up visit should be three months after the initiation of hormonal contraceptive therapy. Thereafter, examinations should be performed at least once a

year, or more frequently if indicated. Women with a strong family history of breast cancer or who have breast nodules should be monitored with particular care. At each visit, examination should include those procedures that were done at the initial visit, as outlined above or as per the recommendations of the Canadian Task Force on the Periodic Health Examination.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Listed below are adverse events that have been associated with the use of combination hormonal contraceptives. These are also likely to apply to combination transdermal hormonal contraceptives such as EVRA.

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

• Thrombophlebitis and venous thrombosis with or without embolism
• Arterial thromboembolism
• Pulmonary embolism
• Mesenteric thrombosis
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumours
• Neuro-ocular lesions (e.g. Retinal thrombosis)
• Congenital anomalies

The following adverse reactions have also been reported in patients receiving hormonal contraceptives:

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea during and after treatment
• Temporary infertility after discontinuation of treatment
• Edema
• Chloasma or melasma that may persist
• Breast changes (tenderness, enlargement, secretion)
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
• Administration-site reaction (transdermal, sub-dermal or intramuscular administration only)
• Premenstrual-like syndrome
• Cataracts
• Optic neuritis
• Retinal thrombosis
• Chorea
• Changes in appetite
• Cystitis-like syndrome
• Rhinitis
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Raynaud’s phenomenon
• Auditory disturbances
• Pancreatitis
• Dysmenorrhea
• Increase in size of uterine leiomyomata
• Endocervical hyperplasia
• Change in libido

•

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.

Two adequate and well-controlled trials demonstrated that the incidence of breakthrough bleeding and spotting with EVRA is statistically and clinically comparable to that seen with CYCLEN* (norgestimate/ethinyl estradiol) and TRIPHASIL^®

(levonorgestrel/ethinyl estradiol) tablets.

Presented in the following table are the most common treatment-emergent adverse events reported with the use of EVRA in three clinical studies (n=3330), two comparing EVRA to an oral contraceptive, and a third evaluating EVRA alone, occurring in ≥1% of subjects. Treatment-emergent adverse events are all adverse events reported in three clinical studies in subjects receiving EVRA regardless of whether they were deemed by the Investigator to be causally related to EVRA use.

Table 1.1 Incidence (% of patients) of Treatment-Emergent Adverse Events in Three Studies

Less common Clinical Trial Treatment-Emergent Adverse Events occurring in <1% of Subjects

Blood and lymphatic system disorders: anemia, granulocytopenia, leucopenia, leukocytosis, lymphadenopathy, monocytosis, platelets abnormal, thrombocytopenia

Cardiac disorders: angina pectoris, bradycardia, edema dependent, hypertension, hypotension, palpitation, tachycardia

Ear and labyrinth disorders: ear disorder nos, earache, tinnitus, vestibular disorder

Endocrine disorders: goitre, hyperprolactinaemia, hypothyroidism

Eye disorders: conjunctival discolouration, conjunctivitis, corneal ulceration, exophthalmos, eye abnormality, eye pain, eyelid retraction, myopia, retinal detachment, vision abnormal, xerophthalmia

Gastrointestinal disorders: abdomen enlarged, colitis, constipation, enanthema, enteritis, gastritis, gastro-intestinal disorder nos, gastroesophageal reflux, gingival bleeding, gingivitis, glossitis, hemorrhoids, mouth dry, periodontal destruction, rectal disorder, saliva increased, stomatitis ulcerative, taste perversion, tenesmus, tooth caries, tooth disorder

General disorders and administration site conditions: asthenia, chest pain, application site cellulitis, face edema, hot flushes, edema, edema generalized, edema peripheral, pain, rigors, syncope, thirst, tolerance decreased

Hepatobiliary disorders: cholesystitis, cholelithiasis, hepatic function abnormal

Immune system disorders: allergic reaction, vasculitis allergic

Infections and infestations: abscess, herpes simplex, herpes zoster, infection, infection bacterial, infection fungal, infection viral

Investigations: globulins increased, SGOT increased, SGPT increased, weight decrease

Metabolism and nutrition disorders: alcohol intolerance, anorexia, appetite increase, dehydration, diabetes mellitus, fat disorder, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hypoglycaemia, oedema legs, obesity

Musculoskeletal and connective tissue disorders: arthralgia, arthritis, arthrosis, bursitis, cramps legs, leg pain, muscle weakness, myositis, osteoma, skeletal pain, tendonitis, torticollis

Neoplasms benign, malignant and unspecified: breast neoplasm benign female, cervical uterine polyp, cervix carcinoma in situ, lipoma, melanoma malignant, neoplasm nos, neuroma, ovarian cyst, phaeochromocytoma, skin neoplasm malignant, thyroid cyst, uterine fibroid

Nervous System disorders: convulsions, coordination abnormal, dysphonia, hemiplegia, hypertonia, hypoesthesia, hypotonia, meningitis, migraine aggravated, neuralgia, paraesthesia, stupor, tremor, vertigo

Psychiatric disorders: amnesia, anxiety, apathy, crying abnormal, depersonalization, depression aggravated, dyspareunia, insomnia, libido increased, nervousness, paroniria, psychosis manic-depressive, sleep disorder, somnolence, suicide attempt

Renal and urinary disorders: dysuria, micturition frequency, pyelonephritis, renal calculus, renal pain, strangury, urethral disorder, urinary incontinence, urine abnormal

Reproductive system and breast disorders: breast atrophy, cervical dysplasia, cervicitis, cervix lesion, endometriosis, genital ulceration, lactation nonpuerperal, mastitis, ovarian disorder, pelvic inflammation, perineal pain female, uterine disorder nos, uterine spasm, vaginal hemorrhage, vulva disorder, withdrawal bleeding

Respiratory, thoracic and mediastinal disorders: asthma, bronchospasm, dyspnoea, laryngitis, pleurisy, pneumonia, stridor

Skin and subcutaneous tissue disorders: alopecia, bullous eruption, chloasma, dermatitis, dermatitis contact, eczema, folliculitis, furunculosis, hypertrichosis, melanosis, nail disorder, paronychia, photosensitivity allergic reaction, photosensitivity reaction, pigmentation abnormal, psoriasis, purpura, rash erythematous, rash maculo-papular, seborrhoea, skin cold clammy, skin depigmentation, skin discolouration, skin disorder, skin dry, sweat gland disorder, sweating increased, urticaria, vasculitis allergic, verruca

Social Circumstance: drug abuse

Vascular disorders: aneurysm, epistaxis, flushing, hematoma, peripheral ischaemia, phlebitis, pulmonary embolism, purpura allergic, thrombophlebitis, thrombophlebitis superficial, vascular disorder, thrombosis arterial leg, vasculitis, vein disorder, vein distended, vein pain, vein varicose

Post-Market Adverse Drug Reactions

In addition to the adverse events observed in clinical trials listed above, the following other serious and unexpected adverse events have been reported in users of EVRA in the post-marketing period. These adverse events are compiled from spontaneous reports and are listed regardless of frequency and whether or not a causal relationship with EVRA has been established:

Blood and lymphatic system disorders: hemolytic uremic syndrome, idiopathic thrombocytopenic purpura, iron deficiency anemia

Cardiac disorders: acute coronary syndrome, arrhythmia, atrial tachycardia, cardiac failure, coronary artery atherosclerosis, coronary artery dissection (with fatal outcome), intracardiac thrombus, myocardial infarction, myocarditis (with fatal outcome), pericardial effusion, sinus tachycardia, supraventricular tachycardia

Congenital, familial and genetic disorders: atrial septal defect, cleft lip, cleft palate, congenital musculoskeletal anomaly, dermoid cyst of ovary, Fallot’s tetralogy, limb malformation, skull malformation, ventricular septal defect

Ear and labyrinth disorders: motion sickness, otosclerosis

Endocrine disorders: thyroid disorder

Eye disorders: amaurosis fugax, blindness, blindness transient, blindness unilateral, cataract, contact lens intolerance, corneal neovascularisation, diplopia, dry eye, eye disorder, eye irritation, eye haemorrhage, eye swelling, iritis, mydriasis, ocular discomfort, ocular hyperaemia, ocular icterus, optic nerve disorder, papilloedema, photophobia, retinal vascular thrombosis, vision blurred, visual acuity reduced, visual disturbance

Gastrointestinal disorders: abdominal discomfort, abdominal distension, ascites, colitis ulcerative, edema mouth, gastric disorder gastrointestinal edema, gastrointestinal hemorrhage, gastrointestinal pain, gastrooesophageal reflux disease, hypoaesthesia oral, intestinal ischemia, intestinal obstruction, irritable bowel syndrome, oral mucosal blistering, pancreatic disorder, pancreatitis, rectal hemorrhage, stomach discomfort, umbilical hernia

General disorders and administration site conditions: abasia, application site burn, application site dermatitis, application site discolouration, application site erythema, application site irritation, application site pain, application site photosensitivity reaction, application site pruritus, application site swelling, application site urticaria, chest discomfort, chills, cyst rupture, death, difficulty in walking, disease progression, drug ineffective, drug interaction, drug withdrawal syndrome, dysplasia, feeling abnormal, feeling cold, feeling hot and cold, feeling jittery, feeling of body temperature change, gait disturbance, hernia, hunger, irritability, local swelling, swelling, temperature intolerance, therapeutic response delayed

Hepatobiliary disorders: cholestasis, gallbladder disorder, hepatic cirrhosis, hepatic failure, hepatic pain, hepatitis, hepatocellular damage, hepatomegaly, jaundice, liver disorder, portal vein thrombosis

Immune system disorders: anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, autoimmune disorder, food allergy, hypersensitivity, sarcoidosis

Infections and infestations: alpha haemolytic streptococcal infection, appendicitis, breast abscess, cavernous sinus thrombosis, cellulitis, ear infection, encephalitis viral (with fatal outcome), Escherichia urinary tract infection, gastroenteritis viral, gastrointestinal infection, infectious mononucleosis, influenza, joint abscess, nasopharyngitis, osteomyelitis, pelvic inflammatory disease, pneumonia, respiratory tract infection, septic embolus, septic shock, skin infection, staphylococcal infection,

streptococcal infection, tonsillitis, vaginal candidiasis, vaginal infection, vaginitis bacterial, vulvovaginal mycotic infection

Injury, poisoning and procedural complications: brachial plexus injury, closed head injury, collapse of lung, concussion, contusion, drug administration error, drug exposure during pregnancy, drug exposure via breast milk, fall, inappropriate schedule of drug administration, incision site complication, intentional misuse, joint sprain, limb injury, medication error, overdose, road traffic accident, stress fracture, wrist fracture

Investigations: alanine aminotransferase increased, anti-thyroid antibody positive, aspartate aminotransferase increased, blood cholesterol increased, blood creatine phosphokinase increased, blood glucose increased, blood lactate dehydrogenase increased, blood pressure increased, blood test abnormal, blood triglycerides increased, cardiac enzymes increased, electrocardiogram abnormal, electrocardiogram T wave abnormal, fetal heart rate decreased, hemoglobin abnormal, haemoglobin decreased, heart rate decreased, heart rate increased, heart rate irregular, hepatic enzyme increased, intraocular pressure increased, liver function test abnormal, red blood cell sedimentation rate increased, smear cervix abnormal, thyroid function test abnormal

Metabolism and nutrition disorders: anorexia, decreased appetite, diabetes mellitus non-insulin-dependent, fluid retention, food intolerance, gestational diabetes, hypokalemia, iron deficiency

Musculoskeletal and connective tissue disorders: bone pain, flank pain, groin pain, joint effusion, joint swelling, muscle spasms, muscle tightness, muscle twitching, pain in extremity, rhabdomyolysis, rotator cuff syndrome, sensation of heaviness, shoulder pain

Neoplasms benign, malignant and unspecified: benign hydatidiform mole, brain neoplasm, cervix carcinoma, colon cancer Stage II, colon neoplasm, fibroadenoma of breast, fibromatosis, focal nodular hyperplasia, gastrointestinal carcinoma, hepatic neoplasm, neoplasm malignant, ovarian cancer, peritoneal neoplasm, renal neoplasm, teratoma benign, thyroid gland cancer

Nervous system disorders: amnesia, basilar artery thrombosis, benign intracranial hypertension, burning sensation, carotid artery stenosis, cerebral artery occlusion, cerebral hemorrhage, cerebral infarction, cerebral thrombosis, cerebral venous thrombosis (with fatal outcome), cerebrovascular accident (with fatal outcome), coma, depressed level of consciousness, dysarthria, dysgeusia, dyskinesia, encephalitis, facial palsy, facial paresis, formication, grand mal convulsion, hemiparesis, hemorrhagic stroke, intracranial aneurysm, intracranial venous sinus thrombosis, ischemic stroke, lethargy, loss of consciousness, mental impairment, migraine with aura, monoparesis, multiple sclerosis, multiple sclerosis relapse, nervous system disorder, optic neuritis, petit mal epilepsy, polyneuropathy, sinus headache, somnolence, speech disorder, subarachnoid haemorrhage, superior sagittal sinus thrombosis, syncope, thrombotic stroke, transient ischemic attack, transverse sinus thrombosis, tunnel vision, visual field defect

Pregnancy, puerperium and perinatal conditions: abnormal product of conception, abortion, abortion incomplete, abortion missed, abortion spontaneous, abortion threatened, antepartum hemorrhage, blighted ovum, ectopic pregnancy, fetal disorder, fetal growth retardation, intra-uterine death, oligohydramnios, placenta previa, placental insufficiency, postpartum haemorrhage, preeclampsia, pregnancy, pregnancy-induced hypertension, premature labour, premature separation of placenta, ruptured ectopic pregnancy, twin pregnancy, unintended pregnancy

Psychiatric disorders: abnormal behaviour, acute psychosis, affect lability, aggression, anger, attention deficit/hyperactivity disorder, bipolar disorder, completed suicide, confusional state, decreased interest, depressed mood, expressive language disorder, hallucination (auditory, visual), homicidal ideation, mood altered, mood swings, nightmare, panic attack, personality change, stress, suicidal ideation

Renal and urinary disorders: chromaturia, renal disorder, renal failure, renal failure acute, urethral cyst

Reproductive system and breast disorders: adenomyosis, amenorrhea, breast discharge, breast disorder, breast dysplasia, breast mass, breast swelling, breast tenderness, galactorrhea, genital discharge, genital rash, hypertrophy breast, hypomenorrhea, infertility, menometrorrhagia, oligomenorrhea, ovulation pain, pelvic discomfort, pelvic pain, polymenorrhea, premenstrual syndrome, reproductive tract disorder, uterine cyst, uterine hemorrhage, vaginal disorder, vaginal lesion, withdrawal bleeding irregular

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dyspnea, lung consolidation, neonatal respiratory distress syndrome, pharyngeal edema, pharyngolaryngeal pain, pharynx discomfort, pulmonary alveolar hemorrhage (with fatal outcome), pulmonary congestion, pulmonary edema (with fatal outcome), pulmonary alveolar hemorrhage, pulmonary congestion, pulmonary embolism (with fatal outcome), pulmonary hypertension, pulmonary infarction, pulmonary thrombosis, respiratory disorder, respiratory failure, sinus disorder, sleep apnea syndrome, tonsillar disorder

Skin and subcutaneous tissue disorders: angioneurotic edema, dermatitis allergic, erythema nodusum, hyperhidrosis, night sweats, pigmentation disorder, pruritus generalized, pyoderma gangrenosum, rash generalized, rash papular, rash pruritic, seborrheic dermatitis, skin irritation, skin reaction, swelling face, urticaria generalized, yellow skin

Surgical and medical procedures: abortion induced, appendectomy, dental operation, foot operation, gallbladder operation, hospitalization, hysterectomy, lipectomy, plastic surgery, renal stone removal, salpingo-oophorectomy, surgery, sympathectomy

Vascular disorders: angiopathy, arterial thrombosis, cavernous sinus thrombosis, circulatory collapse, deep vein thrombosis (with fatal outcome), diastolic hypertension, embolism, hemorrhage, iliac artery thrombosis, jugular vein thrombosis, malignant

hypertension, orthostatic hypotension, pallor, Raynaud’s phenomenon, thrombosis (with fatal outcome), vasculitis necrotizing (with fatal outcome), venous thrombosis, venous thrombosis limb

DRUG INTERACTIONS

Overview

The metabolism of hormonal contraceptives may be influenced by various drugs. Of potential clinical importance are drugs that cause the induction of enzymes that are responsible for the degradation of estrogens and progestins, and drugs that interrupt enterohepatic recirculation of estrogen (e.g. certain antibiotics).

The proposed mechanism of interaction of antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible interactions with the concomitant use of oral contraceptives and ampicillin or tetracycline.

The major target for enzyme inducers is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4). Reduced contraceptive efficacy has been documented with concomitant use of hormonal contraceptives and rifampicin. Literature reports that hormonal contraceptives interact with topiramate, barbiturates, phenylbutazone, griseofulvin, phenytoin sodium and carbamazepine. Interactions with medicines that increase clearance of sex hormones may result in breakthrough bleeding and pregnancy. The efficacy of EVRA in women who are receiving long-term treatment with a hepatic enzyme-inducing agent has not been established.

Some protease inhibitors and some antiretroviral agents have been found to either increase (e.g. indinavir) or decrease (e.g. ritonavir) circulating levels of combination hormonal contraceptives.

Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, the clinical consequence of such an interaction on the levels of other concomitant medications is likely to be insignificant. Under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (K_i).

Physicians are advised to refer to the prescribing information of those specific agents for recommendations regarding management of concomitant therapy.

The concurrent administration of oral contraceptives with other drugs may result in an altered response to either agent (Tables 1.2 and 1.3). Similar drug interactions are likely with the transdermal system. It is important to ascertain all drugs that a patient is taking, both prescription and non-prescription, before hormonal contraceptives are prescribed.

Refer to Oral Contraceptives 1994 (Chapter 8), Health Canada, for possible drug interactions with hormonal contraceptives.

Table 1.2: Drugs that May Decrease the Efficacy of Oral Contraceptives

*See Drug-Drug Interactions for information specific to EVRA.

Table 1.3: Modification of Other Drug Action by Oral Contraceptives

Table 1.3: Modification of Other Drug Action by Oral Contraceptives (cont’d)

Drug-Drug Interactions

In a pharmacokinetic drug interaction study, oral administration of tetracycline HCl, 500 mg q.i.d. for 3 days prior to and 7 days during wear of EVRA did not significantly affect the pharmacokinetics of norelgestromin or EE.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

A possible interaction has been suggested with hormonal contraceptives and the herbal supplement St. John’s Wort based on some reports of oral contraceptive users experiencing breakthrough bleeding shortly after starting St. John’s Wort. Pregnancies

have been reported by users of combined hormonal contraceptives who also used some form of St. John’s Wort.

Drug-Laboratory Test Interactions

Laboratory Test Interactions

Certain endocrine and liver function tests and blood components may be affected by hormonal contraceptives:

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

Thyroid Function Tests

Protein-Bound Iodine (PBI) Increased

Total serum thyroxine (T₄) Increased

Thyroid Stimulating Hormone (TSH) Unchanged

Free T₃ resin uptake Decreased, reflecting the elevated TBG Free T₄ concentration Unchanged

Miscellaneous Tests

Other binding proteins May be elevated in serum

Sex Hormone Binding Globulins Increased and resulted in elevated levels of total circulating endogenous sex steroids and corticoids; however, free or biologically active levels either decrease or remain unchanged

High-Density Lipoprotein (HDL-C) May increase

Total Cholesterol (Total-C) May increase

Low-Density Lipoprotein (LDL-C) May increase

Triglycerides May increase

LDL-C/HDL-C ratio May remain unchanged

Glucose tolerance May be decreased

Serum folate levels May be depressed by hormonal contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing hormonal contraceptives.

Insulin response Mild to moderate increase c-Peptide response Mild to moderate increase

Tissue Specimens

Pathologists should be advised of hormonal contraceptive use when specimens from surgical procedures and/or Pap smears are submitted for examination.

Drug-Lifestyle Interactions

When use of EVRA was studied under conditions encountered in a health club (sauna, whirlpool and treadmill), there were slight increases in both steady state concentration (C^SS) and area under the curve (AUC) of ethinyl estradiol; however, the C^SS values following these treatments were within the reference range. The clinical significance of this finding is not known. Due to a theoretical risk of increased exposure to ethinyl estradiol, all patients should be advised to avoid exposing the EVRA application site to direct external heat sources, such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths, intensive sunbathing, etc. (See WARNINGS AND PRECAUTIONS –General and

PHARMACOKINETICS- Absorption.)

NON-CONTRACEPTIVE BENEFITS OF HORMONAL CONTRACEPTIVES

Several health advantages other than contraception have been reported.

1. 1. Combination hormonal contraceptives reduce the incidence of cancer of the endometrium and ovaries.
2. 2. Hormonal contraceptives reduce the likelihood of developing benign breast disease and, as a result, decrease the incidence of breast biopsies.
3. 3. Hormonal contraceptives reduce the likelihood of development of functional ovarian cysts.
4. 4. Users of hormonal contraceptives have less menstrual blood loss and have more regular cycles, thereby reducing the chance of developing iron-deficiency anemia.
5. 5. The use of hormonal contraceptives may decrease the severity of dysmenorrhea and premenstrual syndrome, and may improve acne vulgaris, hirsutism, and other androgen-mediated disorders.
6. 6. Hormonal contraceptives decrease the incidence of acute pelvic inflammatory disease and, thereby, reduce as well the incidence of ectopic pregnancy.
7. 7. Hormonal contraceptives have potential beneficial effects on endometriosis.

DOSAGE AND ADMINISTRATION

Dosing Considerations

To achieve maximum contraceptive effectiveness, the EVRA (norelgestromin and ethinyl estradiol) transdermal system must be used exactly as directed. Complete instructions to facilitate patient counselling on proper system usage may be found in Product Monograph Part III: CONSUMER INFORMATION.

Recommended Dose and Dosage Adjustment

Transdermal Contraceptive System Overview

This system uses a 28-day, four-week cycle. A new patch is applied each week for three weeks – 21 total days. Week Four is patch-free. Withdrawal bleeding is expected during this time.

This means that every new patch will be applied on the same day of the week. This day is known as the “Patch Change Day.” For example, if the first patch is applied on a Monday, all subsequent patches should be applied on a Monday. Only one patch should be worn at a time.

The patch should not be cut, damaged or altered in any way. If the patch is cut, damaged or altered in size, contraceptive efficacy may be impaired.

On the day after Week Four ends, a new four-week cycle is started by applying a new patch. Under no circumstances should there be more than a 7-day patch-free interval between dosing cycles.

Clinical trials demonstrated that subjects randomized to EVRA were able to adhere to the weekly dosing regimen better than with daily dosing of oral contraceptives (see Product Monograph Part II: CLINICAL TRIALS).

Administration

1

If the patient is starting EVRA for the first time, she should wait until the day she begins her menstrual period. Either a First Day start or Sunday start may be utilized (see below). The day she applies her first patch will be Day 1. Her “Patch Change Day” will be on this day every week.

Patch adhesion was assessed indirectly by replacement rates for complete and partial patch detachment. Experience with more than 70,000 EVRA patches worn for contraception for 6-13 cycles showed that 4.7% of patches were replaced because they either fell off (1.8%) or were partly detached (2.9%). Similarly, in a small study of patch wear under conditions of physical exertion and variable temperature and humidity, less than 2% of patches were replaced for complete or partial detachment.

If the EVRA patch becomes partially or completely detached and remains detached, insufficient drug delivery occurs.

If the patch remains even partly detached

• for less than one day (up to 24 hours), try to reapply it to the same place or replace with a new patch immediately. No back-up contraception is needed. The woman’s “Patch Change Day” will remain the same.
• for more than one day (> 24 hours) OR if the patient is not sure how long the patch has been detached, she may not be protected from pregnancy. She should stop the current contraceptive cycle and start a new cycle immediately by putting on a new patch. There is now a new “Day 1” and a new “Patch Change Day.” Back-up contraception must be used for the first week of the new cycle only.

A patch should not be re-applied if it is no longer sticky, if it has become stuck to itself or another surface, if it has other material stuck to it or if it has become loose or fallen off before. If a patch cannot be re-attached, a new patch should be applied immediately. Supplemental adhesives or wraps should not be used to hold the EVRA patch in place.

If the patient forgets to change her patch

• at the start of any patch cycle (Week One/Day 1): She may not be protected from pregnancy. She should apply the first patch of her new cycle as soon as she remembers. There is now a new “Patch Change Day” and a new “Day 1.” The patient must use back-up contraception for the first week of her new cycle.

• in the middle of the patch cycle (Week Two/Day 8 or Week Three/Day 15):

  • for one or two days (up to 48 hours), she should apply a new patch immediately.

    The next patch should be applied on the usual “Patch Change Day.” No back-up contraception is needed.

  • for more than two days (> 48 hours), she may not be protected from pregnancy. She should stop the current contraceptive cycle and start a new four-week cycle immediately by putting on a new patch. There is now a new “Patch Change Day” and a new “Day 1”. The patient must use back-up contraception for one week.

• at the end of the patch cycle (Week Four/Day 22):

  if the patient forgets to remove her patch, she should take it off as soon as she remembers. The next cycle should be started on the usual “Patch Change Day,” which is the day after Day 28. No back-up contraception is needed.

Under no circumstances should there be more than a 7-day patch-free interval between dosing cycles. If there are more than 7 patch-free days, the patient may not be protected from pregnancy and back-up contraception must be used concurrently for 7 days. As with combined oral contraceptives, the risk of ovulation increases with each day beyond the recommended contraceptive-free period. If coital exposure has occurred during the patch-free interval, the possibility of fertilization should be considered.

Change Day Adjustment

If the patient wishes to move her “Patch Change Day” she should complete her current cycle, removing the third EVRA patch on the correct day. During the patch-free week, a new “Patch Change Day” may be selected by applying a new EVRA patch on the first occurrence of the desired day. In no case should there be more than 7 consecutive patch-free days.

The shorter the patch-free interval, the higher the risk of breakthrough bleeding and spotting replacing the expected withdrawal bleeding. This practice is for a one-time only change and should not be used as a standard dosing regimen, as there are no long term safety data available on the continuous use of EVRA.

Switching from an Oral Contraceptive

Treatment with EVRA should begin on the first day of withdrawal bleeding. If there is no withdrawal bleeding within 5 days of the last active (hormone-containing) tablet, pregnancy must be ruled out prior to start of treatment with EVRA. If therapy starts after the first day of withdrawal bleeding, a non-hormonal contraceptive should be used concurrently for 7 days. If more than 7 days elapse after taking the last active oral contraceptive tablet, the patient may have ovulated. The patient should be instructed to consult her physician before initiating treatment with EVRA.

Use after Childbirth

Women who elect not to breast-feed should start contraceptive therapy with EVRA no sooner than 4 weeks after childbirth (see WARNINGS AND PRECAUTIONS - Hematologic).

Use after Abortion or Miscarriage

After an abortion or miscarriage that occurs before 20 weeks gestation, EVRA may be started immediately. An additional method of contraception is not needed if EVRA is started immediately. Be advised that ovulation may occur within 10 days of an abortion or miscarriage.

After an abortion or miscarriage that occurs at or after 20 weeks gestation, EVRA 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.

In Case of Vomiting or Diarrhea

Unlike oral contraceptives, dose delivery by transdermal application should be unaffected by vomiting. Dose delivery is also expected to be unaffected by diarrhea.

In Case of Skin Irritation

If patch use results in uncomfortable irritation, a new patch may be applied to a new location until the next Change Day. Only one patch should be worn at a time.

Additional Instructions for All Dosing Regimens

Breakthrough bleeding, spotting, and amenorrhea are frequent reasons for patients discontinuing hormonal contraceptives.

Breakthrough Bleeding or Spotting

In the event of breakthrough bleeding or spotting (bleeding that occurs during EVRA usage), treatment should be continued. This type of bleeding usually disappears after the first few cycles. Non-functional causes should be considered, however, and in cases of undiagnosed persistent or recurrent abnormal bleeding from the vagina, adequate diagnostic measures are indicated to rule out pregnancy or malignancy. If pathology has been excluded, time or a change to another formulation may solve the problem. Changing to a hormonal contraceptive with a higher estrogen content, while potentially useful in minimizing menstrual irregularity, should be done only if necessary since this may increase the risk of thromboembolic disease.

Amenorrhea

Use of hormonal contraceptives in the event of a missed menstrual period:

1. 1. If the woman has not adhered to the prescribed schedule, the possibility of pregnancy should be ruled out at the time of the first missed period.
2. 2. If EVRA has been used correctly, the absence of withdrawal bleeding (bleeding that should occur during the patch-free week) is not necessarily an indication of pregnancy. If the woman has adhered to the prescribed regimen and misses one period, she should continue using her contraceptive patches on the next scheduled Change Day. If the woman has adhered to the prescribed regimen and misses two consecutive periods, pregnancy should be ruled out before continuing hormonal contraceptive use.

OVERDOSAGE

Serious ill effects have not been reported following accidental ingestion of large doses of hormonal contraceptives. Overdosage may cause nausea and vomiting. Withdrawal bleeding may occur in females. In case of suspected overdose, all transdermal contraceptive systems should be removed and symptomatic treatment given.

ACTION AND CLINICAL PHARMACOLOGY

The EVRA (norelgestromin and ethinyl estradiol) transdermal system, with a contact surface area of 20 cm², is a thin, matrix-type transdermal system consisting of three layers. Each transdermal system contains 6.0 mg norelgestromin and 0.60 mg ethinyl estradiol (EE). Systemic exposures (as measured by area under the curve [AUC] and steady state concentration [C_ss]) of NGMN and EE during use of EVRA are comparable to those produced by an oral contraceptive containing norgestimate 250 µg / EE 35 µg, and peak concentrations (Cmax) are lower than those produced by this oral contraceptive.

Each EVRA transdermal system consists of three layers.

1. 1. The backing layer is composed of a beige flexible film consisting of a low-density pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment.
2. 2. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and lauryl lactate as inactive components. The active components in this layer are the hormones, norelgestromin and EE.
3. 3.

   The third layer is the release liner, which is a transparent polyethylene terephthalate

   (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer. The release liner protects the adhesive layer during storage and is removed just prior to application.

The outside of the backing layer is heat-stamped “EVRA™ 150/20”.

Pharmacodynamics

Norelgestromin is the active progestin largely responsible for the progestational activity that occurs in women following application of EVRA. Norelgestromin is also the primary active metabolite produced following oral administration of norgestimate (NGM), the progestin component of the oral contraceptive products CYCLEN* (norgestimate/ethinyl estradiol) and TRI-CYCLEN* (norgestimate/ethinyl estradiol).

Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).

Receptor and human sex hormone-binding globulin (SHBG) binding studies, as well as studies in animals and humans, have shown that both norgestimate and norelgestromin exhibit high progestational activity with minimal intrinsic androgenicity. Transdermally-administered norelgestromin, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in SHBG, resulting in lower levels of free testosterone in serum compared to baseline.

Pharmacokinetics

Absorption: Following application of EVRA, both norelgestromin and EE rapidly appear in the serum, reach a plateau by approximately 48 hours, and are maintained at an approximate steady-state throughout the wear period. C^SS concentrations for norelgestromin and EE during one week of patch wear are approximately 0.8 ng/mL and 50 pg/mL, respectively, and are generally consistent from all studies and application sites. These C^SS concentrations are well within the reference ranges for norelgestromin (0.6 to 1.2 ng/mL) and EE (25 to 75 pg/mL) established based upon the C_ave concentrations in 90% of the individual subjects taking CYCLEN*. This was computed from AUC_0-t/t for these analytes from steady-state data following administration of the NGM/EE oral contraceptives.

The absorption of norelgestromin and EE following application of EVRA to the abdomen, buttock, upper outer arm and upper torso (excluding breast) was evaluated in a crossover design study. The results of this study indicated that C^SS and AUC for the buttock, upper arm and torso for each analyte were equivalent. While C^SS values for the abdomen were within reference ranges for EE 35 µg/NGM 250 µg oral contraceptive users, strict bioequivalence requirements for AUC were not met in this study for the abdomen. However, in a separate parallel-group multiple-application pharmacokinetic study, C^SS and AUC for the buttock and abdomen were not statistically different. In a dose-ranging study, EVRA caused effective ovulation suppression when applied to the abdomen. Therefore, all four sites are therapeutically equivalent.

The absorption of norelgestromin and EE following application of EVRA was studied under conditions encountered in a health club (sauna, whirlpool and treadmill) and in a

cold-water bath. The results indicated that for norelgestromin there were no significant treatment effects on C^SS or AUC when compared to normal wear. For EE, slight increases were observed due to sauna, whirlpool and treadmill; however, the C^SS values following these treatments were within the reference range. There was no significant effect of cold water on these parameters. Serum estradiol concentrations could theoretically increase in patients with fever. Any clinical consequences due to an increase in temperature are unknown at this time. Due to a theoretical risk of increased exposure to ethinyl estradiol, all patients should be advised to avoid exposing the EVRA application site to direct external heat sources, such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths, intensive sunbathing, etc. See WARNINGS AND PRECAUTIONS – General and Drug-Lifestyle Interactions.

In multiple dose studies, C^SS and AUC for norelgestromin and EE were found to increase slightly over time when compared to Week 1 of Cycle 1. In a three-cycle study, these pharmacokinetic parameters reached steady-state conditions during all three weeks of Cycle 3 (see Table 1.4, Figures 1.1 and 1.2).

Table 1.4: Mean (SD) Pharmacokinetic Parameters of Norelgestromin and EE Following Three Consecutive Cycles of EVRA Wear on the Buttock

Analyte Parameter

Cycle 1

Week 1 Cycle 3

Week 1 Cycle 3

Week 2 Cycle 3

Week 3

Norelgestromin C^{ss a} 0.70 (0.28) 0.70 (0.29) 0.80 (0.23) 0.70 (0.32)

AUC_0-168^b 107 (44.2) 105 (45.5) 132 (57.1) 120 (52.8)

t_½^c nc nc nc 32.1 (12.9)

EE C^{ss d} 46.4 (17.9) 47.6 (17.3) 59.0 (25.1) 49.6 (27.0)

AUC _0-168^e 6796 (2673) 7160 (2893) 10054 (4205) 8840 (5176)

t_½^c nc nc nc 21.0 (9.07)

^a ng/mL ^b ng·h/mL ^c h ^d pg/mL ^e pg·h/mL nc = not calculated

Figure 1.1: Mean Norelgestromin (NGMN) Serum Concentrations (ng/mL) in Healthy Female

Volunteers Following Application of EVRA on the Buttock for Three Consecutive Cycles (Dotted horizontal lines indicate the reference range. Dotted vertical arrow indicates time of patch removal.)

Time, hours 0 48 96 144 192 240

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

Figure 1.2: Mean Ethinyl Estradiol (EE) Serum Concentrations (pg/mL) in Healthy Female

Volunteers Following Application of EVRA on the Buttock for Three Consecutive Cycles (Dotted horizontal lines indicate the reference range. Dotted vertical arrow indicates time of patch removal.)

Time, hours 0 48 96 144 192 240

0

25

50

75

100

Results from a study of consecutive EVRA wear for 7 days and 10 days indicated that target C^ss of norelgestromin and EE were maintained during a 3-day extended wear of EVRA. These findings suggest that clinical efficacy would be maintained even if a scheduled change is missed for as long as 2 full days (see Figures 1.3 and 1.4).

Figure 1.3: Mean Norelgestromin (NGMN) Serum Concentrations (ng/mL) Following

Application of EVRA to the Abdomen for 7 Days and 10 Days (Dotted horizontal lines indicate the reference range. Solid vertical arrows indicate actual time of patch removal. Dotted vertical arrow indicates theoretical time of patch removal under normal use.)

Time, hours 0 48 96 144 192 240 288 336 384 432 480

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Figure 1.4: Mean Ethinyl Estradiol (EE) Serum Concentrations (pg/mL) Following Application of EVRA to Abdomen for 7 Days and 10 Days (Dotted horizontal lines indicate reference range. Solid vertical arrows indicate actual time of patch removal. Dotted vertical arrow indicates theoretical time of patch removal under normal use.)

Time, hours 0 48 96 144 192 240 288 336 384 432 480

0

25

50

75

100

Distribution: Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinyl estradiol is extensively bound to serum albumin.

Metabolism: Since EVRA is applied transdermally, first-pass metabolism (via the gastrointestinal tract and/or liver) of norelgestromin and ethinyl estradiol that would be expected with oral administration is avoided. Hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is highly bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolized to various hydroxylated products and their glucuronide and sulfate conjugates.

Excretion: Following removal of transdermal systems, the elimination kinetics of norelgestromin and ethinyl estradiol were consistent for all studies with half-life values of approximately 28 hours and 17 hours, respectively. The metabolites of norelgestromin and ethinyl estradiol are eliminated by renal and fecal pathways.

Transdermal versus Oral Contraceptives

The pharmacokinetic profiles of transdermal and oral combined hormonal contraceptives are different and caution should be exercised when making a direct comparison of these PK parameters.

The EVRA transdermal patch was designed to deliver EE and NGMN over a seven-day period while oral contraceptives (containing NGM 250 µg / EE 35 µg) are administered on a daily basis. Figures 1.5 and 1.6 present mean pharmacokinetic (PK) profiles for EE and NGMN following administration of an oral contraceptive (containing NGM 250 µg / EE 35 µg) compared to the 7-day transdermal EVRA patch (containing NGMN 6.0 mg / EE 0.60 mg) in 54 healthy female volunteers.

Figure 1.5: Mean Serum Concentration-Time Profiles of NGMN Following Once-Daily

Administration of an Oral Contraceptive for 7 days or Application of EVRA to the Buttock in Healthy Female Volunteers

Time (h) 0 24 48 72 96 120 144 168

0.0

0.5

1.0

1.5

2.0

2.5

EVRA - Application to the Buttock

Oral Contraceptive (NGM 250 µg/EE 35 µg)

Oral Contraceptive (NGM 250 mg/EE 35 mg) - Simulated Data for Days 2-6

Figure 1.6: Mean Serum Concentration-Time Profiles of EE Following Once-Daily Administration of an Oral Contraceptive for 7 days or Application of EVRA to the Buttock in Healthy Female Volunteers

Time (h) 0 24 48 72 96 120 144 168

0

20

40

60

80

100

120

140

160

EVRA - Application to the Buttock

Oral Contraceptive (NGM 250 µg/EE 35 µg)

Oral Contraceptive (NGM 250 mg/EE 35 mg) - Simulated Data for Days 2-6

Table 1.5 provides the mean (%CV) for NGMN and EE pharmacokinetic (PK) parameters.

Table 1.5: Mean (%CV) NGMN and EE Steady State Pharmacokinetic Parameters Following

Application of EVRA and Once-daily Administration of an Oral Contraceptive (containing NGM 250 µg / EE 35 µg) in Healthy Female Volunteers

Parameter EVRA^d ORAL CONTRACEPTIVE^e

NGMN^a

C_max (ng/mL)

AUC_0-168 (ng_•h/mL)

C_ss (ng/mL)

0.934 (37.7) 118 (36.9) 0.768 (34.0)

1.95 (21.3) 108 (21.5)^b 0.663 (25.1)^c

EE

C_max (pg/mL)

AUC_0-168 (pg_•h/mL)

C_ss (ng/mL)

58.5 (38.1) 7289 (35.8) 49.9 (34.8)

118 (28.7) 7226 (28.3)^b 45.2 (27.8)^c

^aNGM is rapidly metabolized to NGMN following oral administration ^bAverage weekly exposure, calculated as AUC₂₄ × 7

cCavg

^dDays 1-7

^eWeek 1

In general, C_max values were 2-fold higher for NGMN and EE in subjects administered the oral contraceptive compared to EVRA, while overall exposure (AUC and C_ss) was comparable in subjects treated with EVRA. Inter-subject variability (%CV) for the PK parameters following delivery from EVRA was higher relative to the variability determined from the oral contraceptive. The mean pharmacokinetic profiles are different between the two products and caution should be exercised when making a direct comparison of these PK parameters.

The clinical relevance of the difference in PK profile and pharmacodynamic (PD) response between transdermal and oral delivery is not known. (See WARNINGS AND PRECAUTIONS – General).

Special Populations and Conditions

Effects of Age, Body Weight, Body Surface Area and Race

The effects of age, body weight, body surface area and race on the pharmacokinetics of norelgestromin and ethinyl estradiol were evaluated in 230 healthy women from nine pharmacokinetic studies of single 7-day applications of EVRA. For both norelgestromin and ethinyl estradiol, increasing age, body weight and body surface area each were associated with slight decreases in C^SS and AUC values. However, only a small fraction (10-20%) of the overall variability in the pharmacokinetics of norelgestromin and ethinyl estradiol following application of EVRA may be associated with any or all of the above demographic parameters. There was no significant effect of race with respect to Caucasians, Hispanics and Blacks.

Hepatic Insufficiency: No studies with EVRA have been conducted in women with hepatic impairment. EVRA is contraindicated in patients with hepatic dysfunction (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Renal Insufficiency: No studies with EVRA have been conducted in women with renal impairment.

STORAGE AND STABILITY

Store between 15ºC - 30ºC. Do not refrigerate or freeze. Store patches in their protective pouches inside the original box. Apply patch immediately upon removal from its packaging.

Keep new and used transdermal systems out of the reach of children and pets.

SPECIAL HANDLING INSTRUCTIONS

Disposal of EVRA

Used transdermal systems still contain some active hormones. Used transdermal systems should be carefully folded in half so the adhesive side sticks to itself, and disposed of in the garbage out of the reach of children and pets. Remaining active hormonal ingredients of the patch may have harmful effects if reaching the aquatic environment. Used or unused patches should not be flushed down the toilet or placed in liquid waste disposal systems.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Dosage Forms and Packaging

The EVRA (norelgestromin and ethinyl estradiol) transdermal system is available in cartons containing 3 systems each. Each system is sealed within a protective pouch and heat-stamped “EVRA™ 150/20.”

Composition

Backing Layer: low-density pigmented polyethylene outer layer and a polyester inner layer.

Middle Layer: Active components - 6.00 mg norelgestromin and 0.60 mg ethinyl estradiol. Inactive components - polyisobutylene/ polybutene adhesive, crospovidone, non-woven polyester fabric, lauryl lactate.

Release Liner: polyethylene terephthalate film with polydimethylsiloxane coating on one side.

The EVRA transdermal system does not contain any metal components.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: norelgestromin

Chemical name: (17α)-17-Hydroxy-13-ethyl-18,19-dinorpregn-4-en-20-yn-3- one-3-oxime18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl, 17-hydroxy, 3-oxime, (17α)

Molecular formula and molecular mass: C₂₁H₂₉NO₂

327.47

Structural formula:

CH₂

OH

HON

H H

H

H₃C

H

C CH

Physicochemical properties: norelgestromin is a white or off-white crystalline powder

Partition coefficient: 2.70

Solubility: Practically insoluble in water, freely soluble in ethanol and acetone, and sparingly soluble in methylene chloride.

Melting point: As 17d-NGM is a mixture of the syn- and anti-isomers, its melting point varies between 174°C and 185°C.

Proper name: ethinyl estradiol

INN: Ethinylestradiol

Ph. Eur.: Ethinylestradiol, Ethinylestradiolum

USP, USAN: Ethinyl Estradiol

BAN: Ethinyloestradiol

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

19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol (17)-αEthinyl-1,3,5(10)-estratrien-3,17-diol 19-Ethinyl-estra-1,3,5(10)-triene-3,17β-diol

Molecular formula and molecular mass: C₂₀H₂₄O₂

296.41

Structural formula:

Physicochemical properties: ethinyl estradiol is a white or slightly yellowish-white, crystalline powder

Partition coefficient: 1.69

Solubility: Practically insoluble in water, freely soluble in ethanol, acetone, dioxane, and diethyl ether.

Soluble in chloroform.

Melting point: 180°C to 186°C; EE forms a stable hemihydrate, characterized by a melting range of approximately 140°C to 150°C.

H

H

H

HO

CH₃

OH

C C H

CLINICAL TRIALS

Three Phase III contraceptive trials (CONT-002, CONT-003 and CONT-004) involving 4578 women for 31,026 cycles were conducted worldwide. Overall, 3319 women received EVRA. The overall Pearl Index for EVRA from these trials was 0.88. Analyses were performed to determine whether in the Phase III studies (n = 3319) the population characteristics of age, race and weight were associated with pregnancy. The analyses indicated no association of age and race with pregnancy. With respect to weight, 5 of the 15 pregnancies reported with EVRA were among women with a baseline body weight ≥ 90 kg (198 lbs.), which constituted < 3% of the study population. Below 90 kg, there was no apparent association between body weight and pregnancy rate. Although only 10 – 20% of the variability in pharmacokinetic data can be explained by weight (see ACTION AND CLINICAL PHARMACOLOGY - Special Populations), the greater proportion of pregnancies among women at or above 90 kg was statistically significant and suggests that EVRA may be less effective in these women (see WARNINGS AND PRECAUTIONS - Body Weight ≥ 90 kg).

In the North American comparative trial, 811 women received EVRA and 605 women received TRIPHASIL^® (levonorgestrel/ethinyl estradiol), an oral contraceptive containing a triphasic regimen. Phase 1 consisted of 50 µg levonorgestrel and 30 µg EE for 6 days, phase 2 consisted of 75 µg levonorgestrel and 40 µg of EE for 5 days and phase 3 consisted of 125 µg of levonorgestrel and 30 µg EE for 10 days. In this trial, the Pearl Index for EVRA was 1.24 and the Pearl Index for TRIPHASIL^® was 2.18.

Adherence to the EVRA dosing regimen was shown to be superior to that for oral contraceptives in two (CONT-001 and CONT-004) adequate and well-controlled comparative trials (89% vs. 79%, respectively).

Among more than 3000 women who used EVRA for up to 13 cycles, the mean change in body weight from baseline to the end of treatment was an increase less than 1 lb. In a 9-cycle, placebo-controlled trial there was no difference between EVRA and placebo in the mean change in body weight from baseline to the end of treatment.

The following table gives reported pregnancy rates for various forms of birth control, including no birth control. The reported rates represent the number of women out of 100 who would become pregnant in one year.

Reported Pregnancies per 100 Women per Year:

Combination pill less than 1 to 2

Intrauterine device (IUD) less than 1 to 6

Condom with spermicidal foam or

gel

1 to 6

Mini-pill 3 to 6

Condom 2 to 12

Diaphragm with spermicidal foam

or gel

3 to 18

Spermicide 3 to 21

Sponge with spermicide 3 to 28

Cervical cap with spermicide 5 to 18

Periodic abstinence (rhythm), all

types

2 to 20

No birth control 60 to 85

DETAILED PHARMACOLOGY

Nonclinical Pharmacology

Norelgestromin is the primary active metabolite produced following oral administration of norgestimate (NGM). Extensive in vivo and in vitro pharmacology studies have been conducted with oral norelgestromin, NGM and EE, alone or in combination. Tables 2.1 and 2.2 present results for norelgestromin (17d-NGM), and NGM and EE in combination.

Table 2.1: Pharmacological Effects of 17-Deacetylnorgestimate (17d-NGM)

Pharmacological Effects Test Methods Results

Progestational Activity Clauberg progestational assay: Measured ability to

stimulate the endometrium of immature estrogen-primed rabbits.

The response and potency of 17d-NGM was similar to that of norgestimate (NGM). 3-Keto-norgestimate and levonorgestrel were 3.39 and 4.92 times more potent than NGM, respectively.

Progestin receptor binding: Measured displacement of

³H-R50200 (a synthetic progestin ligand) from isolated progestin receptors of rabbit uteri. 0.01 or 0.1% bovine serum albumin (BSA) was added to the test solutions to prevent binding of test substances to glassware.

Test substance

17d-NGM^a

NGM

3-Keto-norgestimate^a

Levonorgestrel^a

Progesterone

IC50

2.82*

5.01*

0.83*

0.71*

-

(nM)

-

4.72**

-

0.84**

1.87**

*In presence of 0.1% BSA

**In presence of 0.01% BSA

Androgenic Measured stimulation of ventral prostate growth in

groups of castrated rats dosed orally and subcutaneously for 7 days.

Androgenic activity of 17d-NGM was not significantly different from that of NGM. 3-Keto-norgestimate and levonorgestrel were significantly more androgenic than NGM.

Androgen receptor binding: Measured displacement of

radiolabeled 5α-dihydrotestosterone from isolated androgen receptors from rat ventral prostates. 0.1% BSA was added to the test solutions to prevent binding of test substances to glassware.

Test substance

17d-NGM^a

NGM

3-Keto-norgestimate^a

Levonorgestrel^a

Dihydrotestosterone

IC₅₀ (nM)

156

857

78

11

2.2

Number of rats ovulating/10 rats treated

Antiovulatory Examined oviducts for presence of ova of rats dosed

orally or subcutaneously with 17d-NGM or NGM. The rats were dosed on the mornings of metestrus, diestrus, and proestrus.

Oral

s.c.

mg/kg:

17d-NGM:

NGM:

17d-NGM:

NGM:

1010 0.062

-

-

8

10

0.126 0.2589 0.053 1.0

3

2

-

• ^a Metabolite of NGM

IC₅₀ = the concentration of test substance corresponding to 50% inhibition on the linear regression response curve; s.c. = subcutaneous

Table 2.2: Pharmacological Effects of Norgestimate/Ethinyl Estradiol (NGM/EE)

Pharmacological Effects Test Methods Results

Antiovulatory Activity

Examination of oviducts for ova EE alone had no inhibitory effect on the number of rats ovulating. NGM alone and

NGM/EE at 0.5 mg/kg totally inhibited ovulation. Doses of 0.25 mg/kg showed partial inhibition of ovulation.

Examination of oviducts for ova NGM alone at 250, 500, and 1000 µg/kg inhibited ovulation in 30, 60 and 100% of the rats, respectively. EE alone had no effect at 140 µg/kg. At some doses NGM/EE caused a greater inhibition of ovulation than NGM alone.

Examination of oviducts for ova. Vaginal cytology of

rats monitored.

NGM given alone inhibited ovulation in 20, 30, 60 and 100% of animals at 0.25, 0.5, 1.0 and 2.0 mg/kg, respectively. EE alone inhibited ovulation by 50% at 270 µg/kg, but had no effect at lower doses. NGM/EE was approximately 2.8 times more potent than NGM alone at dose levels of 30, 90, and 270 mg/kg EE.

Progestational Activity

Uterine contents of rats and guinea pigs examined for

number of implants following oral administration (10:1

NGM/EE ratio).

The NGM/EE combination caused implantation failure at 2.0 mg/kg in the rat and 0.1 mg/kg in the guinea pig. NGM alone at the equivalent dose had no effect, confirming that the antifertility effects were due to EE.

Clauberg progestational assay: measured ability to

stimulate the endometrium of immature rabbits (10:1

NGM/EE ratio).

Endometrial proliferation observed at a total dose as low as 0.2 mg NGM alone. When in combination with EE, NGM was less potent.

Other Clinical Experience

In a multi-centre dose selection study for EVRA, 615 subjects were randomized to receive either one of 3 patch sizes or CYCLEN* (norgestimate/ethinyl estradiol), an oral contraceptive comparator containing 250 µg NGM/ 35 µg EE, for 4 cycles. This study demonstrated that the 20 cm² patch (EVRA) inhibits ovulation to the same extent as CYCLEN* (norgestimate/ethinyl estradiol).

Pharmacokinetic studies with EVRA demonstrated consistent elimination kinetics for norelgestromin and EE with half-life values of approximately 28 hours and 17 hours, respectively. One clinical trial assessed the return of hypothalamic-pituitary-ovarian axis function post-therapy and found that FSH, LH, and estradiol mean values, though suppressed during therapy, returned to near baseline values during the 6 weeks post-therapy. Therefore, it is anticipated that following discontinuation of EVRA treatment, return to fertility will be rapid, approximately that seen with oral contraceptives.

TOXICOLOGY

The toxicology program for EVRA 17d-NGM/EE with 17d-NGM, NGM and EE alone or in combination includes acute toxicity, long-term toxicity, mutagenicity, reproductive and special toxicity studies. The majority of subchronic and chronic toxicity studies conducted in support of EVRA are conducted with oral formulations of NGM/EE or NGM alone. Since 17d-NGM is the primary metabolite of NGM in most laboratory animal species, the pharmacological activity of 17d-NGM is equivalent to NGM, and the metabolism, distribution, and excretion of 17d-NGM in women following dermal administration of 17d-NGM and oral administration of NGM are comparable. Studies have also been conducted for the patch excipient, dermal lauryl lactate (LL).

Acute Toxicology

Table 2.3: Summary of the Acute Toxicity Studies Conducted with NGM and EE Alone and in Combination.

Long-term Toxicology

Table 2.4: Summary of the Repeated-dose Toxicity Studies Conducted with 17d-NGM/EE, NGM and EE.

Table 2.4: Summary of the Repeated-dose Toxicity Studies Conducted with 17d-NGM/EE, NGM and EE (cont’d)

Table 2.4: Summary of the Repeated-dose Toxicity Studies Conducted with 17d-NGM/EE, NGM and EE (cont’d)

Special Toxicity Studies

Table 2.5: Summary of Special Toxicity Studies with 17d-NGM/EE

Mutagenicity

The mutagenic potentials of 17d-NGM, NGM, and NGM/EE have been extensively tested in bacterial and mammalian cell point mutation assays, chromosome aberration assay, in vivo sister chromatid exchange assay, and in vivo micronucleus assays. There were no indications of mutagenic activity in any of the assays with these compounds.

Carcinogenicity

An initial carcinogenicity study of NGM/EE (5:1 ratio) was conducted in rats at dosages of 0.15 to 3.0 mg/kg/day. A significant increase in the incidence of malignant mammary tumours, especially adenocarcinomas in the high-dose group, was observed. A second rat oral carcinogenicity study was conducted with lower dosages of NGM/EE (5:1 ratio) that ranged from 0.01875 to 0.15 mg/kg/day. In this study, the incidence of mammary tumours was comparable between the control and treated groups supporting a dose-response relationship.

In a 7-year dog study with NGM/EE, oral dosages of 0.003, 0.03, and 0.075 mg/kg/day (5:1 ratio) were given for 46 months followed by 0.0057, 0.057, and 0.1425 mg/kg/day (7:1 ratio) for the remaining half of the study. A cyclic dosing regimen was used. An increased incidence over controls in leiomyomas and leiomyosarcomas, tumours of smooth muscle origin, occurred in the high-dose group. Hepatic nodular hyperplasia also occurred in a few NGM/EE-dosed dogs.

A 10-year study of NGM/EE was conducted with rhesus monkeys. The monkeys were given oral dosages of 0.003, 0.03, and 0.15 mg/kg/day (5:1 ratio) for 4 years followed by 0.0057, 0.057, and 0.285 mg/kg/day (7:1 ratio) for the remaining 6 years of the study using a cyclic dosing regimen. Single occurrences of tumours were noted in the vagina and cervix of one high-dose monkey, the lobular and ductal mammary tissue of one high-dose monkey, and the urinary bladder of a mid-dose monkey. Other less noteworthy tumours occurred without predilection for treated groups.

Reproduction and Teratology

All studies conducted with NGM/EE use the oral formulation while the 17d-NGM study uses a subcutaneous route of administration.

Table 2.6: Summary of the Fertility and Reproductive Performance Studies Conducted with 17d-NGM and NGM/EE.

Excipient: Dermal LL

Dermal LL is > 70% lauryl lactate and < 30% lauryl alcohol and lauryl lactoyl lactate. Lauryl lactate (LL) with empirical formula C₁₅H₃₀O₃ is an ester of lauryl alcohol and the alpha-hydroxy acid, lactic acid.

Lauryl lactate was not toxic when given orally to five male and five female rats at a dose of 5 mL/kg. The animals were observed over a 14-day period for pharmacological and toxicological activity.

Lauryl lactate was found to have no apparent potential to cause significant eye irritation when a 10% w/w solution was tested with six New Zealand white rabbits. In studies with face cream formulations containing 5% lauryl lactate, minimal or mild irritation was observed. Minimal eye irritation was caused by 15% lauryl lactate in propylene glycol in rabbits. Ocular irritation determined in the Eytex in vitro assay was reported as being minimal (0.1% in eye cream formulations) to moderate (3.2% in a face cream).

The potential of lauryl lactate to cause dermal irritation was investigated in one study in which six New Zealand white rabbits were dosed with 0.5 mL of a 10% w/w solution in propylene glycol. It was found that at 10%, lauryl lactate caused minimal irritation. Primary dermal irritation studies in rabbits of two cosmetic products containing lauryl lactate applied on an occlusive patch had caused minimal (1% concentration) or mild (5% concentration) irritation.

A contact sensitization assay was conducted in female guinea pigs. The animals were induced with 2 doses of lauryl lactate and challenged with 5% or 25% lauryl lactate. Signs of mild irritation were only observed in the high-dose group. This study suggests that lauryl lactate has little potential to cause contact sensitization.

The mutagenic potential of lauryl lactate has been extensively tested in bacterial and mammalian cell point mutation assays, and an in vivo micronucleus assay. There were no indications of mutagenic activity in any of the assays with lauryl lactate.

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