EVRA transdermal patch

Each 20 cm² transdermal patch contains 6 mg norelgestromin (NGMN) and 600 micrograms ethinyl estradiol (EE).

Each transdermal patch releases an average of 203 micrograms of NGMN and 33.9 micrograms of EE per 24 hours. Medicinal product exposure is more appropriately characterized by the pharmacokinetic profile (see section 5.2).

For a full list of excipients, see section 6.1.

Transdermal patch.

EVRA is a thin, matrix-type transdermal patch consisting of three layers.

The outside of the backing layer is beige and heat-stamped “EVRA”.

Female contraception

EVRA is intended for women of fertile age. The safety and efficacy has been established in women aged 18 to 45 years.

Posology

To achieve maximum contraceptive effectiveness, patients must be advised to use EVRA exactly as directed. For initiation instructions see 'How to start EVRA' below.

Only one patch is to be worn at a time.

Each used patch is removed and immediately replaced with a new one on the same day of the week (Change Day) on Day 8 and Day 15 of the cycle. Patch changes may occur at any time on the scheduled Change Day. The fourth week is patch-free starting on Day 22.

A new contraceptive cycle begins on the next day following patch-free week; the next EVRA patch should be applied even if there has been no bleeding or if bleeding has not yet stopped.

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 user may not be protected against pregnancy. A non-hormonal contraceptive must then 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 intercourse has occurred during such an extended patch-free interval, the possibility of fertilisation should be considered.

Method of administration

EVRA should be applied to clean, dry, hairless, intact healthy skin on the buttock, abdomen, upper outer arm or upper torso, in a place where it will not be rubbed by tight clothing. EVRA should not be placed on the breasts or on skin that is red, irritated or cut. Each consecutive patch should be applied to a different place on the skin to help avoid potential irritation, although they may be kept within the same anatomic site.

The patch should be pressed down firmly until the edges stick well.

To prevent interference with the adhesive properties of the patch, no make-up, creams, lotions, powders or other topical products should be applied to the skin area where the patch is placed or where it will be applied shortly.

It is recommended that users visually check their patch daily to ensure continued proper adhesion.

Used patches should be discarded carefully in accordance with the instructions given in section 6.6.

How to start EVRA

When there has been no hormonal contraceptive use in the preceding cycle

Contraception with EVRA begins on the first day of menses. A single patch is applied and worn for one full week (7 days). The day the first patch is applied (Day 1/Start Day) determines the subsequent Change Days. The patch Change Day will be on this day every week (cycle Days 8, 15, 22 and Day 1 of the next cycle) The fourth week is patch-free starting on Day 22.

If Cycle 1 therapy starts after first day of the menstrual cycle, a non-hormonal contraceptive should be used concurrently for the first 7 consecutive days of the first treatment cycle only.

When switching from an oral combined 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 the start of treatment with EVRA. If therapy starts after the first day of withdrawal bleeding, a non-hormonal contraceptive must be used concurrently for 7 days.

If more than 7 days elapse after taking the last active oral contraceptive tablet, the woman may have ovulated and should, therefore, be advised to consult a physician before initiating treatment with EVRA. If intercourse has occurred during such an extended pill-free interval, the possibility of pregnancy should be considered.

When changing from a progestogen-only-method

The woman may switch any day from the minipill (from an implant on the day of its removal, from an injectable when the next injection would be due), but a back-up barrier method of birth control must be used during the first 7 days.

Following 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.

Following delivery

Users who choose not to breast-feed should start contraceptive therapy with EVRA no sooner than 4 weeks after child-birth. When starting later, the woman should be advised to additionally use a barrier method for the first 7 days. However, if intercourse has already occurred, pregnancy should be excluded before the actual start of EVRA or the woman has to wait for her first menstrual period.

For breast-feeding women, see section 4.6.

What to do if the patch comes off or partly detaches

If the EVRA patch partly or completely detaches and remains detached, insufficient medicinal product delivery occurs.

If EVRA remains even partly detached:

- for less than one day (up to 24 hours): it should be re-applied to the same place or replaced with a new EVRA patch immediately. No additional contraceptive is needed. The next EVRA patch should be applied on the usual “Change Day”.

- for more than one day (24 hours or more) or if the user is not aware when the patch has lifted or become detached: the user may not be protected from pregnancy: The user should stop the current contraceptive cycle and start a new cycle immediately by applying a new EVRA patch. There is now a new “Day 1” and a new “Change Day”. A non-hormonal contraceptive must be used concurrently for the first 7 days of the new cycle only.

A patch should not be reapplied if it is no longer sticky; a new patch should be applied immediately. Supplemental adhesives or bandages should not be used to hold the EVRA patch in place.

If subsequent EVRA patch change days are delayed

At the start of any patch cycle (Week One/Day 1):

The user may not be protected from pregnancy. The user should apply the first patch of the new cycle as soon as remembered. There is now a new patch “Change Day” and a new “Day 1”. A non-hormonal contraceptive must be used concurrently for the first 7 days of the new cycle. If intercourse has occurred during such an extended patch-free interval, the possibility of fertilisation should be considered.

In the middle of the cycle (Week Two/Day 8 or Week Three/Day 15):

- for one or two days (up to 48 hours): The user should apply a new EVRA patch immediately. The next EVRA patch should be applied on the usual “Change Day”. If during the 7 days preceding the first skipped day of patch application, the patch was worn correctly, no additional contraceptive use is required.

- for more than two days (48 hours or more): The user may not be protected from pregnancy. The user should stop the current contraceptive cycle and start a new four-week cycle immediately by putting on a new EVRA patch. There is now a new “Day 1” and a new “Change Day”. A non-hormonal contraceptive must be used concurrently for the first 7 consecutive days of the new cycle.

- at the end of the cycle (Week Four/Day 22): If the EVRA patch is not removed at the beginning of Week 4 (Day 22), it should be removed as soon as possible. The next cycle should begin on the usual “Change Day”, which is the day after Day 28. No additional contraceptive use is required.

Change Day adjustment

In order to postpone a menstrual period for one cycle, the woman must apply another patch at the beginning of Week 4 (Day 22) thus not observing the patch free interval. Breakthrough bleeding or spotting may occur. After 6 consecutive weeks of patch wear, there should be a patch free interval of 7 days. Following this, the regular application of EVRA is resumed.

If the user wishes to move the Change Day the current cycle should be completed, removing the third EVRA patch on the correct day. During the patch-free week a new Change Day may be selected by applying the first EVRA patch of the next cycle 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 that the user does not have a withdrawal bleed and may experience breakthrough bleeding and spotting during the subsequent treatment cycle.

In case of minor 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.

Special populations

Body weight equal or greater than 90 kg: contraceptive efficacy may be decreased in women weighing equal or greater than 90 kg.

Renal impairment: EVRA has not been studied in women with renal impairment. No dose adjustment is necessary but as there is a suggestion in the literature that the unbound fraction of ethinyl estradiol is higher, EVRA should be used with supervision in this population.

Hepatic impairment: EVRA has not been studied in women with hepatic impairment. EVRA is contraindicated in women with hepatic impairment (see section 4.3).

Post-menopausal women: EVRA is not intended for use as hormonal replacement therapy.

Children and adolescents: EVRA is not recommended for use in children and adolescents under age 18 due to insufficient data on safety and efficacy.

EVRA should not be used in the presence of one of the following disorders. If one of these disorders occurs during the use of EVRA, EVRA must be discontinued immediately.

- Hypersensitivity to the active substances or to any of the excipients

- Presence or history of venous thrombosis, with or without the involvement of pulmonary embolism

- Presence or history of arterial thrombosis (e.g., cerebrovascular accident, myocardial infarction, retinal thrombosis) or prodrome of a thrombosis (e.g., angina pectoris or transient ischaemic attack)

- Migraine with focal aura

- The presence of serious or multiple risk factor(s) for the occurrence of arterial thrombosis:

- Severe hypertension (Persistent blood pressure values of 160 mm Hg systolic or 100 mm Hg diastolic)

- Diabetes Mellitus with vascular involvement

- Hereditary dyslipoproteinemia

- Possible hereditary predisposition for venous or arterial thrombosis, such as activated protein C (APC-) resistance, antithrombin-III deficiency, protein C deficiency, protein S deficiency, hyperhomocysteinemia, and antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant)

- Known or suspected carcinoma of the breast

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

- Abnormal liver function related to acute or chronic hepatocellular disease

- Hepatic adenomas or carcinomas

- Undiagnosed abnormal genital bleeding

There is no clinical evidence indicating that a transdermal patch is, in any aspect, safer than combined oral contraceptives.

EVRA is not indicated during pregnancy (see section 4.6).

If any of the conditions/risk factors mentioned below is present, the benefits of the use of EVRA should be weighed against the possible risks for each individual woman and discussed with the woman before she decides to start using EVRA. In the event of aggravation, exacerbation or first appearance of any of these conditions or risk factors, the woman should be emphatically told to contact her physician who will decide on whether its use should be discontinued.

Thromboembolic and other vascular disorders

The use of any combined hormonal contraceptive, including EVRA, carries an increased risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism) compared to no use. Epidemiological studies have shown that the incidence of venous thromboembolism (VTE) in women with no other risk factors for VTE who use low dose oestrogen (<50 micrograms ethinyl estradiol) combined contraceptives ranges from about 20 to 40 cases per 100,000 women-years, but this risk estimate varies according to the type of progestagen. This compares with 5 to 10 cases per 100,000 women-years for non-users and 60 cases per 100,000 pregnancies. VTE is fatal in 1%-2% of cases.

Data from a retrospective cohort study in women aged 15 to 44 years have suggested that the incidence of VTE in women who used EVRA is increased in comparison with users of a levonorgestrel-containing OC (so-called “second generation” OC).

The incidence was 1.4 fold (95% CI 0.9-2.3) increased in women with or without other risk factors for VTE and 1.5 fold (95% CI 0.8-2.7) increased in women with no other risk factors for VTE.

Epidemiological studies have also associated the use of combined oral contraceptives (COCs) with an increased risk for arterial (myocardial infarction, transient ischaemic attack, stroke) thromboembolism.

Extremely rarely, thrombosis has been reported to occur in other blood vessels e.g., hepatic, mesenteric, renal, cerebral or retinal veins and arteries, in COC users. There is no consensus as to whether the occurrence of these events is associated with the use of COCs.

Symptoms of venous or arterial thrombosis can include:

- Unilateral leg pain, and/or swelling

- Sudden severe pain in the chest with possible radiation to the left arm

- Sudden breathlessness, sudden onset of coughing without a clear cause

- Any unusual, severe, prolonged headache

- Sudden partial or complete loss of vision

- Diplopia

- Slurred speech or aphasia

- Vertigo; collapse with or without focal seizure

- Weakness or very marked numbness suddenly affecting one side or one part of the body

- Motor disturbances

- 'Acute' abdominal pain

The risk of venous thromboembolism in combined contraceptives users increases with:

- Increasing age

- A positive family history (i.e. venous thromboembolism ever in a sibling or parent at relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use

- Prolonged immobilisation, major surgery to the legs, or major trauma. In these situations it is advisable to discontinue use (in the case of elective surgery at least 4 weeks in advance) and not to resume until two weeks after complete remobilisation

- Obesity (body mass index over 30 kg/m²)

- Possibly also with superficial thrombophlebitis and varicose veins. There is no consensus about the possible role of these conditions in the aetiology of venous thrombosis.

The risk of arterial thromboembolic complications in combined contraceptives users increases with:

- Increasing age;

- Smoking (with heavier smoking and increasing age the risk further increases, especially in women over 35 years of age);

- Dyslipoproteiniaemia;

- Obesity (body mass index over 30 kg/m²);

- Hypertension;

- Valvular heart disease;

- Atrial fibrillation;

- A positive family history (arterial thrombosis ever in a sibling or parent at a relatively early age). If a hereditary predisposition is suspected, the woman should be referred to a specialist for advice before deciding about any hormonal contraceptive use.

Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C (APC) resistance, hyper homocysteinaemia, antithrombin-III deficiency, protein C deficiency, protein S deficiency, antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant).

Other medical conditions, which have been associated with adverse circulatory events, included diabetes mellitus, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis).

The increased risk for thromboembolism in the puerperium must be considered (see section 4.6).

An increase in frequency or severity of headache (which may be prodromal of a cerebrovascular event) may be a reason for immediate discontinuation of combination contraceptives.

Women using combined contraceptives should be emphatically advised to contact their physician in case of possible symptoms of thrombosis. In case of suspected or confirmed thrombosis, hormonal contraceptive use should be discontinued. Adequate contraception should be initiated because of the teratogenicity of anti-coagulant therapy (coumarins).

Tumours

An increased risk of cervical cancer in long-term users of COCs has been reported in some epidemiological studies, but there continues to be controversy about the extent to which this finding is attributable to the compounding effects of sexual behaviour and other factors such as human papilloma virus (HPV).

A meta-analysis of 54 epidemiological studies reported that there is a slightly increased risk (RR = 1.24) of having breast cancer diagnosed in women who are currently using COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. Therefore a hepatic tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women using EVRA.

Other conditions

- Contraceptive efficacy may be reduced in women weighing equal or greater than 90 kg (see sections 4.2 and 5.1).

- Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using combination hormonal contraceptives.

- Although small increases of blood pressure have been reported in many women using hormonal contraceptives, clinically relevant increases are rare. A definitive relationship between hormonal contraceptive use and clinical hypertension has not been established. If, during the use of a combination hormonal contraceptive in pre-existing hypertension, constantly elevated blood pressure values or a significant increase in blood pressure do not respond adequately to antihypertensive treatment, the combination hormonal contraceptive must be withdrawn. Combination hormonal contraceptive use may be resumed if normotensive values can be achieved with antihypertensive therapy.

- The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: Jaundice and/or pruritus related to cholestasis; gallstones; porphyria; systemic erythematosus; haemolytic ureamic syndrome; Sydenham's chorea; herpes gestationis; otosclerosis-related hearing loss.

- Acute or chronic disturbances of liver function may necessitate the discontinuation of combination hormonal contraceptives until markers of liver function return to normal. Recurrence of cholestatic-related pruritus, which occurred during a previous pregnancy or previous use of sex steroids necessitates the discontinuation of combination hormonal contraceptives.

- Although combined hormonal contraceptives may have an effect on peripheral insulin resistance and glucose tolerance there is no evidence for a need to alter the therapeutic regimen in diabetes during use of combined hormonal contraception. However, diabetic women should be carefully observed, particularly in the early stage of EVRA use.

- Worsening of endogenous depression, of epilepsy, of Crohn's disease and of ulcerative colitis has been reported during COC use.

- Chloasma may occasionally occur with the use of hormonal contraception, especially in users with a history of chloasma gravidarum. Users with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation while using EVRA. Chloasma is often not fully reversible.

Medical examination/consultation

Prior to the initiation or reinstitution of EVRA a complete medical history (including family history) should be taken and pregnancy should be ruled out. Blood pressure should be measured and a physical examination should be performed guided by the contraindications (see section 4.3) and warnings (see section 4.4). The woman should also be instructed to carefully read the package leaflet and to adhere to the advice given.

The frequency and nature of subsequent examinations should be based on established guidelines and be adapted to the individual woman on the basis of clinical impression.

Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmissible diseases.

Bleeding irregularities

With all combination hormonal contraceptives, irregular blood loss (spotting or breakthrough bleeding) can occur, especially during the initial months of usage. For this reason, a medical opinion on irregular blood loss will only be useful after an adjustment period of approximately three cycles. If breakthrough bleeding persists, or breakthrough bleeding occurs after previously regular cycles, while EVRA has been used according the recommended regimen, a cause other than EVRA should be considered. Non-hormonal causes should be considered and, if necessary, adequate diagnostic measures taken to rule out organic disease or pregnancy. This may include curettage. In some women withdrawal bleeding may not occur during this patch free period. If EVRA has been taken according to the directions described in section 4.2, it is unlikely that the woman is pregnant. However, if EVRA has not been taken according to these directions prior to the first missed withdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before EVRA use is continued.

Some users may experience amenorrhoea or oligomenorrhoea after discontinuing hormonal contraception, especially when such a condition was pre-existent.

Herbal preparations containing St John's Wort (Hypericum perforatum) should not be used while taking EVRA (see section 4.5)

Note: The prescribing information of concomitant medications should be consulted to identify potential interactions.

• Influence of other medicinal products on EVRA

Interactions between oral contraceptives and other medicinal products may lead to breakthrough bleeding and/or contraceptive failure. The following interactions have been reported in the literature.

Hepatic metabolism

Interactions can occur with drugs that induce hepatic enzymes which can result in increased clearance of sex hormones (e.g. phenytoin, barbiturates, primidone, carbamazepine, rifampicin, bosentan and HIV-medication (e.g. ritonavir, nevirapine) and possibly also oxcarbazepine, topiramate, felbamate, griseofulvin and products containing the herbal remedy St. John's Wort (hypericum perforatum)). Maximal enzyme induction is generally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation of drug therapy.

Interference with Enterohepatic Circulation

Contraceptive failures have also been reported with antibiotics, such as penicillins and tetracyclines. The mechanism of this effect has not been elucidated. In a pharmacokinetic interaction study, oral administration of tetracycline hydrochloride, 500 mg four times daily for 3 days prior to and 7 days during wear of EVRA, did not significantly affect the pharmacokinetics of norelgestromin or EE.

Management

Women on short-term treatment with any of the above-mentioned classes of medicinal products or individual active substances (hepatic enzyme-inducing medicine) besides rifampicin should temporarily use a barrier method in addition to EVRA, i.e. during the time of concomitant medicinal product administration and for 7 days after their discontinuation.

For women on rifampicin a barrier method should be used in addition to EVRA during the time of rifampicin administration and for 28 days after its discontinuation.

In women on long-term treatment with hepatic enzyme-inducing active substances, another reliable, non-hormonal, method of contraception is recommended.

Women on treatment with antibiotics (besides rifampicin, see above) should use the barrier method until 7 days after discontinuation.

If concomitant medicinal product administration runs beyond the end of the one-week wear period, the next patch should be applied without the usual patch-free interval.

• Influence of EVRA on other medicinal products

Hormonal contraceptives may affect the metabolism of certain other active substances. Accordingly, plasma and tissue concentrations may either increase (e.g. ciclosporin) or decrease (e.g. lamotrigine).

• Laboratory tests

The use of contraceptive steroids may influence the results of certain laboratory tests, including biochemical parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g. corticosteroid-binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate metabolism and parameters of coagulation and fibrinolysis. Changes generally remain within the normal laboratory range.

EVRA is not indicated during pregnancy.

Epidemiological studies indicate no increased risk of birth defects in children born to women who used hormonal contraceptives prior to pregnancy. The majority of recent studies also do not indicate a teratogenic effect when hormonal contraceptives are used inadvertently during early pregnancy.

For EVRA there are no clinical data on exposed pregnancies, which allow conclusions about its safety during pregnancy.

Studies in animals have shown reproductive toxicity (see section 5.3). On the basis of available data, a potential risk of masculinisation as a consequence of an exaggerated hormonal action cannot be excluded.

If pregnancy occurs during use of EVRA, EVRA should be stopped immediately.

Lactation may be influenced by combination hormonal contraceptives as they may reduce the quantity and change the composition of breast milk. Therefore, the use of EVRA is not to be recommended until the breast-feeding mother has completely weaned her child.

EVRA has no or negligible influence on the ability to drive and use machines.

4.8.1 Clinical Trial Data

The most commonly reported adverse drug reactions (ADRs) in clinical trials were headache, nausea, and breast tenderness, occurring in approximately 21.0%, 16.6%, and 15.9% of patients, respectively.

Frequency estimate: very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare ( 1/10,000 to <1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

4.8.2 Postmarketing Data

Additional adverse drug reactions first identified during postmarketing experience with EVRA are listed below:

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

Pharmacotherapeutic group: Norelgestromin and estrogen; ATC-code: G03AA13.

EVRA acts through the mechanism of gonadotropin suppression by the estrogenic and progestational actions of ethinyl estradiol and norelgestromin. The primary mechanism of action is inhibition of the ovulation, but the alterations of the cervical mucus, and to the endometrium may also contribute to the efficacy of the product.

Pearl Indices (see table):

*: DSG 150 μg + 20 μg EE

**: 50 μg LNG + 30 μg for days 1 – 6, 75 μg LNG + 40 μg EE for days 7 – 11, 125 μg LNG + 30 μg EE for 12 – 21 days

Exploratory 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 baseline body weight equal or greater than 90 kg, which constituted < 3 % of the study population. Below 90 kg there was no association between body weight and pregnancy. Although only 10-20 % of the variability in pharmacokinetic data can be explained by weight (see Pharmacokinetic Properties, Special Populations), the greater proportions of pregnancies among women at or above 90 kg was statistically significant and indicates the EVRA is less effective in these women.

With the use of higher dosed COCs (50 microgram ethinyl estradiol) the risk of endometrial and ovarian cancer is reduced. Whether this is also applies to the lower dosed combined hormonal contraceptives remains to be confirmed.

Absorption

Following application of EVRA, norelgestromin and ethinyl estradiol levels in serum reach a plateau by approximately 48 hours. Steady state concentrations of norelgestromin and EE during one week of patch wear are approximately 0.8 ng/ml and 50 pg/ml, respectively. In multiple-dose studies, serum concentrations and AUC for norelgestromin and EE were found to increase only slightly over time when compared to week 1 cycle 1.

The absorption of norelgestromin and ethinyl estradiol following application of EVRA was studied under conditions encountered in a health club (sauna, whirlpool, treadmill and other aerobic exercise) 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 treadmill and other aerobic exercise; however, the C_ss values following these treatments were within the reference range. There was no significant effect of cool water on these parameters.

Results from an EVRA study of extended wear of single contraceptive patch for 7 days and 10 days indicated that target C_ss of norelgestromin and ethinyl estradiol were maintained during a 3-day period of extended wear of EVRA (10 days). These findings suggest that clinical efficacy would be maintained even if a scheduled change is missed for as long as 2 full days.

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.

Biotransformation

Hepatic metabolism of norelgestromin occurs and metabolites include norgestrel, which is largely bound to SHBG, and various hydroxylated and conjugated metabolites. Ethinyl estradiol is also metabolised to various hydroxylated products and their glucuronide and sulfate conjugates.

Elimination

Following removal of a patch, the mean elimination half-lives of norelgestromin and ethinyl estradiol were 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.

In a study comparing EVRA to an oral contraceptive containing norgestimate (parent drug of norelgestromin) 250 μg/ethinyl estradiol 35 μg, 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.

Effects of age, body weight, and body surface area

The effects of age, body weight, and body surface area 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 EE, 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 the norelgestromin and EE following application of EVRA may be associated with any or all of the above demographic parameters.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. With respect to the reproductive toxicity norelgestromin showed foetal toxicity in rabbits, but the safety margin for this effect was sufficiently high. Data on reproductive toxicity of the combination of norelgestromin with ethinyl estradiol are not available. Data for combination of norgestimate (precursor of norelgestromin) with ethinyl estradiol indicate for female animals a decrease in fertility and implantation efficiency (rat), an increase in foetal resorption (rat, rabbit) and, with high dosages, a decrease in viability and fertility of female offspring (rat). The relevance of these data for human exposure is unknown as these effects have been seen as related to well-known pharmacodynamic or species-specific actions.

Studies conducted to examine the dermal effect of EVRA indicate this system has no potential to produce sensitisation and results in only mild irritation when applied to rabbits skin.

Backing layer:

low-density pigmented polyethylene outer layer,

polyester inner layer.

Middle layer:

polyisobutylene/polybutene adhesive,

crospovidone,

non-woven polyester fabric,

lauryl lactate.

Third layer:

polyethylene terephthalate (PET) film,

polydimethylsiloxane coating.

To prevent interference with the adhesive properties of EVRA, no creams, lotions or powders should be applied to the skin area where the EVRA transdermal patch is to be applied.

2 years

Store in the original package in order to protect from light and moisture.

Do not refrigerate or freeze.

Primary packaging material

A sachet is composed of four layers: a low-density polyethylene film (innermost layer), an aluminium foil, a low-density polyethylene film, and an outer layer of bleached paper.

Secondary packaging material

Sachets are packaged in a cardboard carton.

Every carton has 3, 9 or 18 EVRA transdermal patches in individual foil-lined sachets.

Sachets are wrapped per three in a transparent perforated plastic film and packed in a cardboard carton.

Apply immediately upon removal from the protective sachet. After use the patch still contains substantial quantities of active ingredients. Remaining hormonal active ingredients of the patch may have harmful effects if reaching the aquatic environment. Therefore, the used patch should be discarded carefully. The disposal label from the outside of the sachet should be peeled open. The used patch should be placed within the open disposal label so that the sticky surface covers the shaded area on the sachet. The disposal label should then be closed sealing the used patch within. Any used or unused patches should be discarded according to local requirements or returned to the pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste disposal systems.

JANSSEN-CILAG INTERNATIONAL N.V.

Turnhoutseweg, 30

B-2340 Beerse

Belgium

EU/1/02/223/001

EU/1/02/223/002

EU/1/02/223/003

Date of first authorization: 22 August 2002.

Date of latest renewal: 22 August 2007.

22 December 2009

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/