Leaflet EVRA 203mcg / 24h+33.9mcg / 24h transdermal patch

EVRA 203 micrograms/24 hours + 33.9 micrograms/24 hours transdermal patch

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

Each transdermal patch releases an average of 203 micrograms of NGMN and 33.9 micrograms of EEper 24 hours. Medicinal product exposure is more appropriately characterised by the pharmacokineticprofile (see section 5.2).

For the full list of excipients, see section 6.1.

Transdermal patch.

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 womenaged 18 to 45 years.

The decision to prescribe EVRA should take into consideration the individual woman’s current riskfactors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with EVRAcompares with other CHCs (see sections 4.3 and 4.4).

To achieve maximum contraceptive effectiveness, patients must be advised to use EVRA exactly asdirected. For initiation instructions see ‘How to start EVRA’ below.

Only one transdermal patch is to be worn at a time.

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

A new contraceptive cycle begins on the next day following transdermal patch-free week; the next

EVRA transdermal patch should be applied even if there has been no withdrawal bleeding or ifwithdrawal bleeding has not yet stopped.

Under no circumstances should there be more than a 7-day transdermal patch-free interval betweendosing cycles. If there are more than 7 transdermal patch-free days, the user may not be protectedagainst pregnancy. A non-hormonal contraceptive must then be used concurrently for 7 days. The riskof ovulation increases with each day beyond the recommended contraceptive-free period. Ifintercourse has occurred during such an extended transdermal patch-free interval, the possibility ofpregnancy should be considered.

Body weight equal or greater than 90 kg

Contraceptive efficacy may be decreased in women weighing equal or greater than 90 kg.

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

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

Post-menopausal women

EVRA is not indicated for post-menopausal women and is not intended for use as hormonalreplacement therapy.

Safety and efficacy have not been established in adolescents under 18 years of age. There is norelevant use of EVRA in children and pre-menarchal adolescents.

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

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

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

It is recommended that users visually check their transdermal patch daily to ensure continued properadhesion.

The EVRA transdermal patch should not be cut, damaged or altered in any way as this maycompromise contraceptive effectiveness.

Used transdermal patches should be discarded carefully in accordance with the instructions given insection 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 transdermal patch is applied andworn for one full week (7 days). The day the first transdermal patch is applied (Day 1/Start Day)determines the subsequent Change Days. The transdermal patch Change Day will be on this day everyweek (cycle Days 8, 15, 22 and Day 1 of the next cycle). The fourth week is transdermal patch-freestarting on Day 22.

If Cycle 1 therapy starts after first day of the menstrual cycle, a non-hormonal contraceptive should beused 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 withdrawalbleeding within 5 days of the last active (hormone containing) tablet, pregnancy must be ruled outprior to the start of treatment with EVRA. If therapy starts after the first day of withdrawal bleeding, anon-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 haveovulated 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 ofpregnancy should be considered.

When changing from a progestogen-only-method

The woman may switch any day from the progestogen-only pill (from an implant on the day of itsremoval, from an injectable when the next injection would be due), but a back-up barrier method ofbirth 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 startedimmediately. An additional method of contraception is not needed if EVRA is started immediately. Beadvised 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 startedeither on Day 21 post-abortion or on the first day of the first spontaneous menstruation, whichevercomes 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 than4 weeks after child-birth. When starting later, the woman should be advised to additionally use abarrier method for the first 7 days. However, if intercourse has already occurred, pregnancy should beexcluded 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 transdermal patch comes off or partly detaches

If the EVRA transdermal patch partly or completely detaches and remains detached, insufficientmedicinal 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 witha new EVRA transdermal patch immediately. No additional contraceptive is needed. The next

EVRA transdermal 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 transdermal patchhas lifted or become detached: the user may not be protected from pregnancy: The user shouldstop the current contraceptive cycle and start a new cycle immediately by applying a new

EVRA transdermal patch. There is now a new “Day 1” and a new “Change Day”. Anon-hormonal contraceptive must be used concurrently for the first 7 days of the new cycleonly.

A transdermal patch should not be re-applied if it is no longer sticky; a new transdermal patch shouldbe applied immediately. Supplemental adhesives or bandages should not be used to hold the EVRAtransdermal patch in place.

If subsequent EVRA transdermal patch change days are delayed

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

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

If during the 7 days preceding the first skipped day of transdermal patch application, thetransdermal 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. Theuser should stop the current contraceptive cycle and start a new four-week cycle immediately byputting on a new EVRA transdermal 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 daysof the new cycle.

At the end of the cycle (Week Four/Day 22)

- If the EVRA transdermal patch is not removed at the beginning of Week 4 (Day 22), it shouldbe removed as soon as possible. The next cycle should begin on the usual “Change Day”, whichis 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 transdermalpatch at the beginning of Week 4 (Day 22) thus not observing the transdermal patch-free interval.

Breakthrough bleeding or spotting may occur. After 6 consecutive weeks of transdermal patch wear,there should be a transdermal 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 transdermal patch on the correct day. During the transdermal patch-free week a new Change

Day may be selected by applying the first EVRA transdermal patch of the next cycle on the firstoccurrence of the desired day. In no case should there be more than 7 consecutive transdermalpatch-free days. The shorter the transdermal patch-free interval, the higher the risk that the user doesnot have a withdrawal bleed and may experience breakthrough bleeding and spotting during thesubsequent treatment cycle.

In case of minor skin irritation

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

Combined hormonal contraceptives (CHCs) should not be used in the following conditions. If one ofthese disorders occurs during the use of EVRA, EVRA must be discontinued immediately.

* Presence or risk of venous thromboembolism (VTE)

* Venous thromboembolism - current VTE (on anticoagulants) or history of (e.g. deepvenous thrombosis [DVT] or pulmonary embolism [PE]);

* Known hereditary or acquired predisposition for venous thromboembolism, such as

APC-resistance, (including Factor V Leiden), antithrombin-III-deficiency, protein Cdeficiency, protein S deficiency;

* Major surgery with prolonged immobilisation (see section 4.4);

* A high risk of venous thromboembolism due to the presence of multiple risk factors (seesection 4.4);

* Presence or risk of arterial thromboembolism (ATE)

* Arterial thromboembolism - current arterial thromboembolism, history of arterialthromboembolism (e.g. myocardial infarction) or prodromal condition (e.g. anginapectoris);

* Cerebrovascular disease - current stroke, history of stroke or prodromal condition(e.g. transient ischaemic attack, TIA);

* Known hereditary or acquired predisposition for arterial thromboembolism, such ashyperhomocysteinaemia and antiphospholipid-antibodies (anticardiolipin-antibodies,lupus anticoagulant);

* History of migraine with focal neurological symptoms;

* A high risk of arterial thromboembolism due to multiple risk factors (see section 4.4) orto the presence of one serious risk factor such as:

- diabetes mellitus with vascular symptoms

- severe hypertension

- severe dyslipoproteinaemia

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1

* Known or suspected carcinoma of the breast

* Carcinoma of the endometrium or other known or suspected oestrogen-dependent neoplasia

* Abnormal liver function related to acute or chronic hepatocellular disease

* Hepatic adenomas or carcinomas

* Undiagnosed abnormal genital bleeding

* Concomitant use with the medicinal products containing ombitasvir/paritaprevir/ritonavir anddasabuvir, medicinal products containing glecaprevir/pibrentasvir orsofosbuvir/velpatasvir/voxilaprevir (see section 4.5).

Warnings

If any of the conditions/risk factors mentioned below is present, the suitability of EVRA should bediscussed with the woman.

In the event of aggravation, or first appearance of any of the conditions or risk factors, the womanshould be advised to contact her doctor to determine whether the use of EVRA should bediscontinued.

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

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

Risk of venous thromboembolism (VTE)

The use of any combined hormonal contraceptive (CHC) increases the risk of venousthromboembolism (VTE) compared with no use. Products that contain levonorgestrel,norgestimate or norethisterone are associated with the lowest risk of VTE. Other products suchas EVRA may have up to twice this level of risk. The decision to use any product other than onewith the lowest VTE risk should be taken only after a discussion with the woman to ensure sheunderstands the risk of VTE with EVRA, how her current risk factors influence this risk, andthat her VTE risk is highest in the first ever year of use. There is also some evidence that the riskis increased when a CHC is re-started after a break in use of 4 weeks or more.

In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE overthe period of one year. However, in any individual woman the risk may be far higher, depending onher underlying risk factors (see below).

It is estimated that out of 10,000 women who use a low dose CHC that contains levonorgestrel, about61 will develop a VTE in one year. Studies have suggested that the incidence of VTE in women whoused EVRA is up to 2-fold higher than in users of CHCs that contain levonorgestrel. This correspondsto between about 6 and 12 VTEs in a year out of 10,000 women who use EVRA.

In both cases, the number of VTEs per year is fewer than the number expected in women duringpregnancy or in the postpartum period.

VTE may be fatal in 1-2% of cases.

Number of VTE events per 10,000 women in one year

Number of

VTE events

Non-CHC user (2 events) Levonorgestrel-containing CHC (5-7 Norelgestromin-containing CHC (6-12events) events)

Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels,e.g. hepatic, mesenteric, renal or retinal veins and arteries.

Risk factors for VTE

The risk for venous thromboembolic complications in CHC users may increase substantially in awoman with additional risk factors, particularly if there are multiple risk factors (see table).

EVRA is contraindicated if a woman has multiple risk factors that put her at high risk of venousthrombosis (see section 4.3). If a woman has more than one risk factor, it is possible that the increasein risk is greater than the sum of the individual factors - in this case her total risk of VTE should beconsidered. If the balance of benefits and risks is considered to be negative a CHC should not beprescribed (see section 4.3).

Table: Risk factors for VTE

Risk factor Comment

Obesity (body mass index over Risk increases substantially as BMI rises.30 kg/m²) Particularly important to consider if other risk factorsalso present.

1 Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containinglevonorgestrel versus non-use of approximately 2.3 to 3.6

Prolonged immobilisation, major In these situations it is advisable to discontinue the usesurgery, any surgery to the legs or pelvis, of the patch (in the case of elective surgery at least fourneurosurgery, or major trauma weeks in advance) and not resume until two weeks aftercomplete remobilisation. Another method of

Note: temporary immobilisation contraception should be used to avoid unintentionalincluding air travel > 4 hours can also be pregnancy.a risk factor for VTE, particularly in Antithrombotic treatment should be considered if EVRAwomen with other risk factors has not been discontinued in advance.

Positive family history (venous If a hereditary predisposition is suspected, the womanthromboembolism ever in a sibling or should be referred to a specialist for advice beforeparent at relatively early age) deciding about any CHC use.

Other medical conditions associated with Cancer, systemic lupus erythematosus, haemolytic

VTE uraemic syndrome, chronic inflammatory bowel disease(Crohn's disease or ulcerative colitis) and sickle celldisease.

Increasing age Particularly above 35 years.

There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in theonset or progression of venous thrombosis.

The increased risk of thromboembolism in pregnancy, and particularly the 6 week period of thepuerperium, must be considered (for information on 'Pregnancy and lactation' see section 4.6).

In the event of symptoms women should be advised to seek urgent medical attention and to inform thehealthcare professional that she is taking a CHC.

Symptoms of deep vein thrombosis (DVT) can include:

- unilateral swelling of the leg and/or foot or along a vein in the leg;

- pain or tenderness in the leg which may be felt only when standing or walking;

- increased warmth in the affected leg; red or discoloured skin on the leg.

Symptoms of pulmonary embolism (PE) can include:

- sudden onset of unexplained shortness of breath or rapid breathing;

- sudden coughing which may associated with haemoptysis;

- sharp chest pain;

- severe light headedness or dizziness;

- rapid or irregular heartbeat.

Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might bemisinterpreted as more common or less severe events (e.g. respiratory tract infections).

Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration ofan extremity.

If the occlusion occurs in the eye symptoms can range from painless blurring of vision which canprogress to loss of vision. Sometimes loss of vision can occur almost immediately.

Risk of arterial thromboembolism (ATE)

Epidemiological studies have associated the use of CHCs with an increased risk for arterialthromboembolism (myocardial infarction) or for cerebrovascular accident (e.g. transient ischaemicattack, stroke). Arterial thromboembolic events may be fatal.

Risk factors for ATE

The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC usersincreases in women with risk factors (see table). EVRA is contraindicated if a woman has one seriousor multiple risk factors for ATE that puts her at high risk of arterial thrombosis (see section 4.3). If awoman has more than one risk factor, it is possible that the increase in risk is greater than the sum ofthe individual factors - in this case her total risk should be considered. If the balance of benefits andrisks is considered to be negative a CHC should not be prescribed (see section 4.3).

Table: Risk factors for ATE

Risk factor Comment

Increasing age Particularly above 35 years

Smoking Women should be advised not to smoke if theywish to use a CHC. Women over 35 whocontinue to smoke should be strongly advised touse a different method of contraception.

Obesity (body mass index over 30 kg/m2) Risk increases substantially as BMI rises.

Particularly important in women with additionalrisk factors.

Positive family history (arterial If a hereditary predisposition is suspected, thethromboembolism ever in a sibling or parent at woman should be referred to a specialist forrelatively early age e.g. below 50) advice before deciding about any CHC use.

Migraine An increase in frequency or severity of migraineduring CHC use (which may be prodromal of acerebrovascular event) may be a reason forimmediate discontinuation.

Other medical conditions associated with Diabetes mellitus, hyperhomocysteinaemia,adverse vascular events valvular heart disease and atrial fibrillation,dyslipoproteinaemia, systemic lupuserythematosus.

In the event of symptoms women should be advised to seek urgent medical attention and to inform thehealthcare professional that she is taking a CHC.

Symptoms of a cerebrovascular accident can include:

- sudden numbness or weakness of the face, arm or leg, especially on one side of the body;

- sudden trouble walking, dizziness, loss of balance or coordination;

- sudden confusion, trouble speaking or understanding;

- sudden trouble seeing in one or both eyes;

- sudden, severe or prolonged headache with no known cause;

- loss of consciousness or fainting with or without seizure.

Temporary symptoms suggest the event is a transient ischaemic attack (TIA).

Symptoms of myocardial infarction (MI) can include:

- pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, orbelow the breastbone;

- discomfort radiating to the back, jaw, throat, arm, stomach;

- feeling of being full, having indigestion or choking;

- sweating, nausea, vomiting or dizziness;

- extreme weakness, anxiety, or shortness of breath;

- rapid or irregular heartbeats.

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

Tumours

An increased risk of cervical cancer in long-term users of COCs has been reported in someepidemiological studies, but there continues to be controversy about the extent to which this finding isattributable to the confounding effects of sexual behaviour and other factors such as human papillomavirus (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 excessrisk gradually disappears during the course of the 10 years after cessation of COC use. Because breastcancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in currentand recent COC users is small in relation to the overall risk of breast cancer. The breast cancersdiagnosed 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 COCusers, 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 reportedin users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominalhaemorrhages. Therefore a hepatic tumour should be considered in the differential diagnosis whensevere upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur inwomen using EVRA.

Psychiatric Disorders

Depressed mood and depression are well-known undesirable effects of hormonal contraceptive use(see section 4.8). Depression can be serious and is a well-known risk factor for suicidal behaviour andsuicide. Women should be advised to contact their physician in case of mood changes and depressivesymptoms, including shortly after initiating the treatment.

Other conditions

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

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

- Although small increases of blood pressure have been reported in many women using hormonalcontraceptives, clinically relevant increases are rare. A definitive relationship between hormonalcontraceptive use and clinical hypertension has not been established. If, during the use ofcombined hormonal contraceptives in pre-existing hypertension, constantly elevated bloodpressure values or a significant increase in blood pressure do not respond adequately toantihypertensive treatment, the combined hormonal contraceptive must be withdrawn.

Combined hormonal contraceptive use may be resumed if normotensive values can be achievedwith 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/orpruritus related to cholestasis; gallbladder disease including cholecystitis and cholelithiasis;porphyria; systemic lupus 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 combinedhormonal contraceptives until markers of liver function return to normal. Recurrence ofcholestatic-related pruritus, which occurred during a previous pregnancy or previous use of sexsteroids necessitates the discontinuation of combined hormonal contraceptives.

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

- Worsening of endogenous depression, of epilepsy, of Crohn’s disease and of ulcerative colitishas been reported during COC use.

- Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquiredangioedema.

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

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 physicalexamination should be performed guided by the contra-indications (see section 4.3) and warnings (seesection 4.4). It is important to draw a woman’s attention to the information on venous and arterialthrombosis, including the risk of EVRA compared with other CHCs, the symptoms of VTE and ATE,the known risk factors and what to do in the event of a suspected thrombosis.

The woman should also be instructed to carefully read the user leaflet and to adhere to the advicegiven. The frequency and nature of examinations should be based on established practice guidelinesand be adapted to the individual woman.

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

Bleeding irregularities

With all combined 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 irregularblood loss will only be useful after an adjustment period of approximately three cycles. Ifbreakthrough bleeding persists, or breakthrough bleeding occurs after previously regular cycles, while

EVRA has been used according to the recommended regimen, a cause other than EVRA should beconsidered. Non-hormonal causes should be considered and, if necessary, adequate diagnosticmeasures taken to rule out organic disease or pregnancy. This may include curettage. In some womenwithdrawal bleeding may not occur during this transdermal patch free period. If EVRA has been takenaccording 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 missedwithdrawal bleed or if two withdrawal bleeds are missed, pregnancy must be ruled out before EVRAuse is continued.

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

Note: The prescribing information of concomitant medicinal products should be consulted to identifypotential interactions.

During clinical trials with patients treated for hepatitis C virus infections (HCV) with medicinalproducts containing ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin,transaminase (ALT) elevations higher than 5 times the upper limit of normal (ULN) occurredsignificantly more frequently in women using ethinyl estradiol-containing medications such ascombined hormonal contraceptives (CHCs). Additionally, also in patients treated withglecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed inwomen using ethinyl estradiol-containing medications such as CHCs (see section 4.3).

Therefore, EVRA-users must switch to an alternative method of contraception (e.g., progestagen-onlycontraception or non-hormonal methods) prior to starting therapy with these combination drugregimens. EVRA can be restarted 2 weeks following completion of treatment with these combinationdrug regimens.

Effects of other medicinal products on EVRA

Interactions can occur with drugs that induce microsomal enzymes which can result in increasedclearance of sex hormones and which may lead to breakthrough bleeding and/or contraceptive failure.

The following interactions have been reported in the literature.

Substances increasing the clearance of CHCs (diminished efficacy of CHCs by enzyme-induction),e.g.:

Barbiturates, bosentan, carbamazepine, phenytoin, primidone, rifampicin, modafinil, and HIVmedications ritonavir, nevirapine and efavirenz; and possibly also felbamate, griseofulvin,oxcarbazepine, topiramate and products containing the herbal remedy St. John's Wort (hypericumperforatum).

Enzyme induction may be observed after a few days of treatment. Maximal enzyme induction isgenerally seen in about 10 days but may then be sustained for at least 4 weeks after the cessation ofmedicinal product therapy.

Short-term

A woman on short-term treatment with medicinal products that induce hepatic drug metabolisingenzymes or individual active substances that induce these enzymes should temporarily use a barriermethod in addition to EVRA, i.e. during the time of concomitant medicinal product administration andfor 28 days after their discontinuation.

If concomitant medicinal product administration extends beyond the end of the three-week patchperiod, the next transdermal patch should be applied without the usual transdermal patch-free interval.

Long-term

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

Substances with variable effects on the clearance of CHCs

When co-administered with CHCs, many combinations of HIV protease inhibitors and non-nucleosidereverse transcriptase inhibitors, including combinations with HCV inhibitors can increase or decreaseplasma concentrations of estrogen or progestins. The net effect of these changes may be clinicallyrelevant in some cases.

Therefore, the prescribing information of concomitant HIV medications should be consulted toidentify potential interactions and any related recommendations. In case of any doubt, an additionalbarrier contraceptive method should be used by women on protease inhibitor or non-nucleosidereverse transcriptase inhibitor therapy.

Inhibition of ethinyl estradiol metabolism

Etoricoxib has been shown to increase plasma levels of ethinyl estradiol (50 to 60%) when takenconcomitantly with an oral triphasic hormonal contraceptive. It is thought that etoricoxib increasesethinyl estradiol levels because it inhibits sulfotransferase activity thereby inhibiting ethinyl estradiolmetabolism.

Effect of EVRA on other medicinal products

Hormonal contraceptives may affect the metabolism of certain other active substances. Accordingly,plasma and tissue concentrations may increase (e.g. ciclosporin). Dosage adjustment of theconcomitant medicinal product may be necessary.

Lamotrigine: Combined hormonal contraceptives have been shown to significantly decrease plasmaconcentrations of lamotrigine when coadministered likely due to induction of lamotrigineglucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may benecessary.

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

EVRA is not indicated during pregnancy.

Epidemiological studies indicate no increased risk of birth defects in children born to women whoused combined oral contraceptives prior to pregnancy. The majority of recent studies also do notindicate a teratogenic effect when combined oral contraceptives are used inadvertently during earlypregnancy.

Limited data on the outcomes of exposed pregnancies in women using EVRA do not allow forconclusions about its safety during pregnancy.

Animal studies have shown undesirable effects during pregnancy and lactation (see section 5.3). Basedon these animal data, undesirable effects due to hormonal action of the active compounds cannot beexcluded. However, general experience with combined oral contraceptives during pregnancy did notprovide evidence for an actual undesirable effect in humans.

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

The increased risk of VTE during the postpartum period should be considered when re-starting EVRA(see sections 4.2 and 4.4).

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

Women may experience a delay in conception following discontinuation of EVRA.

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

The most commonly reported adverse reactions in clinical trials were headache, nausea, and breasttenderness, occurring in approximately 21.0%, 16.6%, and 15.9% of patients, respectively. Adversereactions that may occur at the beginning of treatment but usually diminish after the first three cyclesinclude spotting, breast tenderness and nausea.

An increased risk of arterial and venous thrombotic and thrombo-embolic events, includingmyocardial infarction, stroke, transient ischemic attacks, venous thrombosis and pulmonary embolismhas been observed in women using CHCs, which are discussed in more detail in section 4.4.

Safety was evaluated in 3 322 sexually active women who participated in three Phase III clinical trials,which were designed to evaluate contraceptive efficacy. These subjects received six or 13 cycles ofcontraception (EVRA or oral contraceptive comparator), took at least one dose of study medicinalproduct and provided safety data. Table 1 below reflects the adverse reactions reported in clinical trialsand from post-marketing experience. Frequency MedDRA convention: 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); veryrare (< 1/10 000); not known (cannot be estimated from the available data).

Table 1: Frequency of adverse reactions

System Organ Class Adverse reaction

Frequency

Infections and infestationscommon (Vulvo) vaginal fungal infection

Vaginal candidiasisrare Rash pustular*

Application site pustules

Neoplasms benign, malignant and unspecified (incl cysts and polyps)rare Hepatic neoplasm*†

Breast cancer*†

Cervix carcinoma*†

Hepatic adenoma*†

Uterine leiomyoma

Fibroadenoma of breast

Immune system disordersuncommon Hypersensitivityrare Anaphylactic reaction*not known Exacerbation of symptoms of hereditary and acquiredangioedema*

Metabolism and nutrition disordersuncommon Hypercholesterolaemia

Fluid retention

Increased appetiterare Hyperglycaemia*

Insulin resistance*

Psychiatric disorderscommon Mood, affect and anxiety disordersuncommon Insomnia

Libido decreasedrare Anger*

Frustration*

Libido increased

Nervous system disordersvery common Headachecommon Migraine

Dizzinessrare Cerebrovascular accident**†

Cerebral haemorrhage*†

Abnormal taste*

Eye disordersrare Contact lens intolerance*

Cardiac disordersrare Arterial thromboembolism(Acute) myocardial infarction*†

Vascular disordersuncommon Hypertensionrare Hypertensive crisis*

Arterial thrombosis**†

Venous thrombosis**†

Thrombosis*†

Respiratory, thoracic and mediastinal disordersrare Pulmonary (artery) thrombosis*†

Pulmonary embolism†

Gastrointestinal disordersvery common Nauseacommon Abdominal pain

Abdominal distensionrare Colitis*

Hepatobiliary disordersrare Cholecystitis

Cholelithiasis†

Hepatic lesion*

Jaundice cholestatic*†

Cholestasis*†

Skin and subcutaneous tissue disorderscommon Acne

Pruritus

Skin reaction

Skin irritationuncommon Alopecia

Dermatitis allergic

Eczema

Photosensitivity reaction

Dermatitis contact

Urticaria

Erythemarare Angioedema*

Erythema (multiforme, nodosum)*

Chloasma†

Exfoliative rash*

Pruritus generalised

Rash (erythematous, pruritic)

Seborrheic dermatitis*

Musculoskeletal and connective tissue disorderscommon Muscle spasms

Reproductive system and breast disordersvery common Breast tendernesscommon Dysmenorrhoea

Vaginal bleeding and menstrual disorders**†

Uterine spasm

Breast disorders

Vaginal dischargeuncommon Galactorrhoea

Premenstrual syndrome

Vulvovaginal drynessrare Cervical dysplasia*

Suppressed lactation*

Genital discharge

General disorders and administration site conditionscommon Malaise

Application site reactions (erythema, irritation, pruritus, rash)uncommon Generalised oedema

Oedema peripheral

Application site reactions**rare Face oedema*

Pitting oedema*

Swelling

Application site reactions* (e.g., abscess, erosion)

Localised oedema*

Investigationscommon Weight increaseduncommon Blood pressure increased

Lipid disorders**rare Blood glucose decreased*†

Blood glucose abnormal*†

* Post-marketing reports.

** Includes adverse reactions reported in clinical trials and post-marketing reports.† See section 4.4.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Serious ill effects have not been reported following accidental ingestion of large doses of oralcontraceptives. Overdose may cause nausea or vomiting. Vaginal bleeding may occur in somefemales. In cases of suspected overdose, all transdermal contraceptive systems should be removed andsymptomatic treatment given.

Pharmacotherapeutic group: Sex hormones and modulators of the genital system, progestogens andestrogens, fixed combination; ATC-code: G03AA13.

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

Pearl Indices (see table):

Study CONT-002 CONT-003 CONT-003 CONT-004 CONT-004 All EVRA

Group EVRA EVRA COC* EVRA COC** Subjects# of cycles 10 743 5 831 4 592 5 095 4 005 21 669

Overall 0.73 0.89 0.57 1.28 2.27 0.90

Pearl Index (0.15; 1.31) (0.02; 1.76) (0.0; 1.35) (0.16; 2.39) (0.59; 3.96) (0.44; 1.35)(95% CI)

Method 0.61 0.67 0.28 1.02 1.30 0.72

Failure (0.0; 1.14) (0.0; 1.42) (0.0; 0.84) (0.02; 2.02) (0.03; 2.57) (0.31; 1.13)

Pearl Index(95% CI)

* DSG 150 mcg + 20 mcg EE

** 50 mcg LNG + 30 mcg for days 1 - 6, 75 mcg LNG + 40 mcg EE for days 7 - 11, 125 mcg LNG + 30 mcg EE for 12- 21 days

Exploratory analyses were performed to determine whether in the Phase III studies (n=3 319) thepopulation characteristics of age, race and weight were associated with pregnancy. The analysesindicated no association of age and race with pregnancy. With respect to weight, 5 of the15 pregnancies reported with EVRA were among women with baseline body weight equal or greaterthan 90 kg, which constituted < 3% of the study population. Below 90 kg there was no associationbetween body weight and pregnancy. Although only 10-20% of the variability in pharmacokinetic datacan be explained by weight (see section 5.2), the greater proportions of pregnancies among women ator 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 andovarian cancer is reduced. Whether this is also applies to the lower dosed combined hormonalcontraceptives remains to be confirmed.

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

The absorption of norelgestromin and ethinyl estradiol following application of EVRA was studiedunder 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 significanttreatment effects on Css or AUC when compared to normal wear. For EE, slight increases wereobserved due to treadmill and other aerobic exercise; however, the Css values following thesetreatments were within the reference range. There was no significant effect of cool water on theseparameters.

Results from an EVRA study of extended wear of single contraceptive transdermal patch for 7 daysand 10 days indicated that target Css of norelgestromin and ethinyl estradiol were maintained during a3-day period of extended wear of EVRA (10 days). These findings suggest that clinical efficacy wouldbe maintained even if a scheduled change is missed for as long as 2 full days.

Norelgestromin and norgestrel (a serum metabolite of norelgestromin) are highly bound (> 97%) toserum proteins. Norelgestromin is bound to albumin and not to SHBG (sex hormone bindingglobulin), while norgestrel is bound primarily to SHBG, which limits its biological activity. Ethinylestradiol is extensively bound to serum albumin.

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

Following removal of a transdermal patch, the mean elimination half-lives of norelgestromin andethinyl estradiol were approximately 28 hours and 17 hours, respectively. The metabolites ofnorelgestromin and ethinyl estradiol are eliminated by renal and faecal pathways.

Transdermal versus oral contraceptives

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

In a study comparing EVRA to an oral contraceptive containing norgestimate (parent drug ofnorelgestromin) 250 mcg/ethinyl estradiol 35 mcg, Cmax values were 2-fold higher for NGMN and EEin subjects administered the oral contraceptive compared to EVRA, while overall exposure (AUC and

Css) was comparable in subjects treated with EVRA. Inter-subject variability (%CV) for the PKparameters following delivery from EVRA was higher relative to the variability determined from theoral 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 andethinyl estradiol were evaluated in 230 healthy women from nine pharmacokinetic studies of single7-day applications of EVRA. For both norelgestromin and EE, increasing age, body weight and bodysurface area each were associated with slight decreases in Css and AUC values. However, only a smallfraction (10-20%) of the overall variability in the pharmacokinetics of the NGMN and EE followingapplication of EVRA may be associated with any or all of the above demographic parameters.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. With respect to thereproductive toxicity norelgestromin showed foetal toxicity in rabbits, but the safety margin for thiseffect was sufficiently high. Data on reproductive toxicity of the combination of norelgestromin withethinyl 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 andfertility of female offspring (rat). The relevance of these data for human exposure is unknown as theseeffects 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 toproduce sensitisation and results in only mild irritation when applied to rabbits skin.

Backing layerlow-density pigmented polyethylene outer layerpolyester inner layer.

Middle layerpolyisobutylene/polybutene adhesivecrospovidonenon-woven polyester fabriclauryl lactate.

Third layerpolyethylene terephthalate (PET) filmpolydimethylsiloxane coating.

Not applicable.

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 aluminiumfoil, 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 cardboardcarton.

Not all pack sizes may be marketed.

The patch should be applied immediately upon removal from the protective sachet.

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

After use the transdermal patch still contains substantial quantities of active ingredients. Remaininghormonal active ingredients of the transdermal patch may have harmful effects if reaching the aquaticenvironment. Therefore, the used transdermal patch should be discarded carefully. The disposal labelfrom the outside of the sachet should be peeled open. The used transdermal patch should be placedwithin the open disposal label so that the sticky surface covers the shaded area on the sachet. Thedisposal label should then be closed sealing the used transdermal patch within. Any unused medicinalproduct or waste material should be disposed of in accordance with local requirements. Usedtransdermal patches should not be flushed down the toilet nor placed in liquid waste disposal systems.

Gedeon Richter Plc.

Gyömrői út 19-21.1103 Budapest

Hungary

EU/1/02/223/001

EU/1/02/223/002

EU/1/02/223/003

Date of first authorisation: 22 August 2002.

Date of latest renewal: 15 June 2012.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.