ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
EVRA
transdermal patch
Each 20 cm
2
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.
2
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.
3
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.
4
-
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.
-
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)
-
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
5
-
Hypersensitivity to the active substances or to any of the excipients
-
Migraine with focal aura
-
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
-
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
6
-
Hereditary dyslipoproteinemia
-
Abnormal liver function related to acute or chronic hepatocellular disease
-
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:
-
Smoking (with heavier smoking and increasing age the risk further increases, especially in
women over 35 years of age);
-
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).
7
-
Vertigo; collapse with or without focal seizure
-
Increasing age;
-
Dyslipoproteiniaemia;
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.
8
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
9
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.
10
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).
System Organ
Class
Adverse Drug Reactions in Clinical Trials
Frequency
Very
common
Common
Uncommon
Rare
Very rare
Infections and
infestations
Fungal infection
(vaginal only),
Vaginal candidiasis,
Vulvovaginal mycotic
infection
Metabolism
and nutrition
disorders
Fluid retention,
Hypercholesterolemia
Psychiatric
disorders
Depression, Mood
altered, Mood swings
Affect lability,
Anxiety, Insomnia,
Libido decreased
Crying,
Libido
increased,
Tearfulness
Aggression
Nervous system
disorders
Headache Dizziness, Migraine
Respiratory,
thoracic and
mediastinal
disorders
Pulmonary
embolism
Gastrointestinal
disorders
Nausea
Abdominal distension,
Abdominal pain,
Abdominal pain
lower, Abdominal
pain upper, Vomiting,
Diarrhoea
Hepatobiliary
disorders
Cholecystitis
Skin and
subcutaneous
tissue disorders
Acne, Pruritus, Skin
irritation
Dermatitis contact,
Erythema
Chloasma
Musculoskeletal
and connective
tissue disorders
Muscle spasms
Reproductive
system and
breast
disorders
Breast
tenderness
Breast discomfort,
Breast enlargement,
Breast pain, Dysmen-
orrhoea, Menorrhagia,
Metrorrhagia, Uterine
spasm, Vaginal
discharge
Breast disorder, Breast
engorgement, Breast
swelling, Fibrocystic
breast disease,
Galactorrhoea,
Premenstrual
syndrome, Vaginal
haemorrhage,
Vulvovaginal dryness
Genital
discharge,
Menstrual
disorder,
Menstruation
irregular
Polymen-
orrhoea
General
disorders and
administration
site conditions
Application site
erythema, Application
site irritation,
Application site
pruritus, Application
Application site
dermatitis,
Application site
discolouration,
Application site
Application
site urticaria,
Swelling
Applica-
tion site
oedema
11
site rash, Application
site reaction, Fatigue,
Malaise
hypersensitivity,
Application site pain,
Application site
papules, Application
site vesicles,
Generalized oedema
Investigations
Weight increased
Blood pressure
increased, Blood
triglycerides increased
Blood
cholesterol
increased
4.8.2
Postmarketing Data
Additional adverse drug reactions first identified during postmarketing experience with EVRA are
listed below:
Infections and
infestations
Application site pustules, Rash pustular
Neoplasms benign,
malignant and
unspecified (Incl cysts
and polyps)
Breast cancer, Breast cancer stage IV, Cervix carcinoma,
Fibroadenoma of breast, Hepatic adenoma, Hepatic
neoplasm, Uterine leiomyoma
Immune system
disorders
Hypersensitivity
Metabolism and
nutrition disorders
Hyperglycaemia, Insulin resistance
Psychiatric disorders
Anger, Emotional disorder, Frustration
Nervous system
disorders
Basilar artery thrombosis, Brain stem infarction, Carotid
artery occlusion, Cerebral artery embolism, Cerebral artery
occlusion, Cerebral artery thrombosis, Cerebral
haemorrhage, Cerebral infarction, Cerebral thrombosis,
Cerebral venous thrombosis, Cerebrovascular accident,
Abnormal taste, Embolic stroke, Haemorrhage intracranial,
Haemorrhagic stroke, Intracranial venous sinus thrombosis,
Ischaemic cerebral infarction, Ischaemic stroke, Lacunar
infarction, Migraine with aura, Subarachnoid haemorrhage,
Superior sagittal sinus thrombosis, Thromboembolic stroke,
Thrombotic stroke, Transient ischaemic attack, Transverse
sinus thrombosis
Eye disorders
Contact lens intolerance
Cardiac disorders
Acute myocardial infarction, Myocardial infarction
Vascular disorders
Arterial thrombosis, Arterial thrombosis limb, Axillary vein
thrombosis, Budd-Chiari syndrome, Coronary artery
thrombosis, Deep vein thrombosis, Embolism, Hepatic vein
thrombosis, Hypertension, Hypertensive crisis, , Iliac artery
thrombosis, Intracardiac thrombus, Jugular vein thrombosis,
Mesenteric vein thrombosis, Pelvic venous thrombosis,
Peripheral embolism, Portal vein thrombosis, Renal
embolism, Renal vein thrombosis, Retinal artery occlusion,
Retinal vascular thrombosis, Retinal vein occlusion, Splenic
vein thrombosis, Superficial thrombophlebitis,
Thrombophlebitis, Thrombosis, Vena cava thrombosis,
12
Venous thrombosis, Venous thrombosis limb
Respiratory, thoracic
and mediastinal
disorders
Pulmonary artery thrombosis, Pulmonary thrombosis
Gastrointestinal
disorders
Colitis
Hepatobiliary
disorders
Cholelithiasis, Cholestasis, Hepatic lesion, Jaundice
cholestatic
Skin and
subcutaneous tissues
disorders
Alopecia, Angioedema, Dermatitis allergic, Eczema,
Erythema multiforme, Erythema nodosum, Exfoliative rash,
Photosensitivity reaction, Pruritus generalised, Rash, Rash
erythematous, Rash pruritic, Seborrhoeic dermatitis, Skin
reaction, Urticaria
Reproductive system
and breast disorders
Amenorrhoea, Breast mass, Cervical dysplasia,
Hypomenorrhoea, Menometrorrhagia, Oligomenorrhoea,
Suppressed lactation
General disorders and
administration site
conditions
Application site abscess, Application site anaesthesia,
Application site atrophy, Application site bleeding,
Application site bruising, Application site burn, Application
site discharge, Application site discomfort, Application site
dryness, Application site eczema, Application site erosion,
Application site excoriation, Application site exfoliation,
Application site induration, Application site infection,
Application site inflammation, Application site mass,
Application site nodule, Application site odour, Application
site paraesthesia, Application site photosensitivity reaction,
Application site scab, Application site scar, Application site
swelling, Application site ulcer, Application site warmth,
Face oedema, Irritability, Localised oedema, Oedema
peripheral, Pitting oedema
Investigations
Blood cholesterol abnormal, Blood glucose abnormal, Blood
glucose decreased, Low density lipoprotein increased
Injury, poisoning and
procedural
complications
Contact lens complication
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.
13
5.1
Pharmacodynamic properties
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):
Study
Group
CONT-002
EVRA
CONT-003
EVRA
CONT-003
COC*
CONT-004
EVRA
CONT-004
COC**
All EVRA
Subjects
# of cycles 10,743
5831
4592
5095
4005
21,669
Overall
Pearl Index
(95% CI)
0.73
(0.15,1.31)
0.89
(0.02,1.76)
0.57
(0,1.35)
1.28
(0.16,2.39)
2.27
(0.59,3.96)
0.90
(0.44,1.35)
Method
Failure
Pearl Index
(95% CI)
0.61
(0.0,1.14)
0.67
(0,1.42)
0.28
(0,0.84)
1.02
(0.02,2.02)
1.30
(0.03,2.57)
0.72
(0.31,1.13)
*: 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.
5.2
Pharmacokinetic properties
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.
14
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.
5.3
Pre-clinical safety data
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.
15
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.
6.
6.1 List of excipients
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.
6.2 Incompatibilities
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.
6.3 Shelf-life
2 years
6.4 Special precautions for storage
Store in the original package in order to protect from light and moisture.
Do not refrigerate or freeze.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal and other handling
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
16
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.
7.
JANSSEN-CILAG INTERNATIONAL N.V.
Turnhoutseweg, 30
B-2340 Beerse
Belgium
8.
EU/1/02/223/001
EU/1/02/223/002
EU/1/02/223/003
9.
Date of first authorization: 22 August 2002.
Date of latest renewal: 22 August 2007.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/
17
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S)
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
18
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium
B.
CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The MAH will continue to submit yearly PSURs unless otherwise specified by the CHMP
19
ANNEX III
LABELLING AND PACKAGE LEAFLET
20
A. LABELLING
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BOX OF 3 PATCHES
BOX OF 9 PATCHES
BOX OF 18 PATCHES
1.
EVRA transdermal patch
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 patch of 20 cm
2
contains: 6 mg norelgestromin and 600 micrograms ethinyl estradiol
1 patch releases: 203 micrograms norelgestromin and 33.9 micrograms ethinyl estradiol per 24 hours
3.
LIST OF EXCIPIENTS
Other ingredients: polyisobutylene, polybutene, lauryl lactate, crospovidone, non-woven-polyester
fabric
4.
3 transdermal patches
9 transdermal patches
18 transdermal patches
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Transdermal use
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
22
9.
SPECIAL STORAGE CONDITIONS
Store in the original sachet and carton
Do not refrigerate or freeze
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Do not flush used or unused patches down the toilet. See enclosed leaflet for disposal instructions.
Marketing Authorisation holder:
Janssen-Cilag International N.V.
Turnhoutseweg, 30
B-2340 Beerse, Belgium
EU/1/02/223/001:
3 transdermal patches
EU/1/02/223/002:
9 transdermal patches
EU/1/02/223/003:
18 transdermal patches
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
EVRA
23
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SACHET LABEL
1.
EVRA transdermal patch
2.
METHOD OF ADMINISTRATION
Transdermal use
Read the package leaflet
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
Contains 1 transdermal patch
6.
OTHER
24
Reminder Stickers
Use these stickers on your calendar
to help you remember when to
change your patch
Current Cycle
Next Cycle
First Patch
Second Patch
Third Patch
Remove Patch First patch
(Week 1)
(Week 2)
(Week 3)
Get New Patch
Patch disposal label
PATCH DISPOSAL LABEL
To dispose of used patch:
1.
place used patch so that the sticky side covers the shaded area
2.
remove backing paper
3.
close adhesive label and seal
4.
discard with solid waste
25
B. PACKAGE LEAFLET
26
PACKAGE LEAFLET: INFORMATION FOR THE USER
EVRA transdermal patch
Norelgestromin and ethinyl estradiol
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What EVRA is and what it is used for
2.
Risks of using combined hormonal contraceptives
4.
How to use EVRA
5.
Possible side effects
6.
How to store EVRA
7.
Further information
1.
What EVRA is and what is it used for
The name of your medicine is EVRA transdermal patch. It is called ‘EVRA’ in this leaflet.
It is used to prevent pregnancy.
EVRA contains two types of hormones:
•
norelgestromin
•
ethinyl estradiol
Because it contains two hormones, EVRA is called a ‘combined hormonal contraceptive’.
2.
Before you use EVRA
Do not use EVRA if:
•
You are allergic (hypersensitive) to norelgestromin, ethinyl estradiol or any of the other
ingredients in EVRA (listed in Section 7 below)
•
You have ever had a heart attack or a type of chest pain called ‘angina’
•
You have ever had a stroke or signs which may lead to stroke. This includes a slight, temporary
stroke, without any after effects
•
You have high blood pressure
(160/100 mmHg or above)
•
You have diabetes with damaged blood vessels
•
You have bad headaches with neurological symptoms such as changes in vision or numbness in
any part of your body (migraine with focal aura)
•
You have ever had a blood clot (thrombosis) in your legs (deep vein thrombosis or DVT) or
lungs (pulmonary embolism) or another part of your body
•
You have an illness which runs in your family which affects the clotting of your blood (such as
‘protein C deficiency’ or ‘protein S deficiency’)
•
You have very high fat levels in your blood (cholesterol or triglycerides)
•
You have an illness which runs in your family which affects fat levels in your blood (called
dyslipoproteinemia)
•
You have ever had liver tumours or any problem with your liver
•
You have ever been told you might have breast cancer or cancer of the womb, cervix or vagina
•
You have unexplained vaginal bleeding.
27
-
This medicine has been prescribed for you. Do not pass it on to others.
3.
Before you use EVRA
Do not use EVRA if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before using EVRA.
Take special care with EVRA
Medical check-ups
Before using EVRA, you will need to see your doctor for a medical check-up.
Check with your doctor or pharmacist before using EVRA if you have any of the following or they
happen or get worse while using EVRA:
-
You weigh 90 kg (which is 14 stone 2 lb) or more
-
You, or any of your family, have high fat levels in the blood (triglycerides or cholesterol)
-
You have high blood pressure or your blood pressure gets higher
-
You have a blood problem called porphyria
-
You have an immune system problem called ‘SLE’ (systemic lupus erythematosus)
-
You have a blood problem which causes kidney damage called ‘HUS’ (haemolytic uremic
syndrome)
-
You have a hearing loss
-
You have epilepsy or any other problem that can cause fits (convulsions)
-
You have a problem of the nervous system involving sudden movements of the body called
‘Sydenham’s chorea’
-
You have diabetes
-
You have depression
-
You have gallstones
-
You have liver problems including yellowing of the skin and whites of the eye (jaundice)
-
You have an inflammatory illness of your gut (Crohn’s disease or ulcerative colitis)
-
You had a skin rash with blisters during pregnancy (called ‘herpes gestationis’)
-
You have ‘pregnancy spots’. These are yellowish-brown patches or spots, especially on your
face (called ‘chloasma’)
-
You think you might be pregnant.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before using
EVRA.
Taking other medicines:
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription, including herbal medicines.
Certain medicines and herbal remedies may stop EVRA from working properly. If this happens
you could get pregnant.
Tell your doctor if you are taking:
•
Medicines for HIV infection (such as ritonavir, nevirapine)
•
Medicines for infection (such as rifampicin and griseofulvin)
•
Medicines for epilepsy (such as topiramate, barbiturates, phenytoin sodium, carbamazepine,
primidone, oxcarbamazepine and felbamate)
•
Medicine for high blood pressure in the blood vessels in the lungs (bosentan)
•
St. John’s Wort - an herbal remedy used for depression.
If you take any of these medicines, you may need to use another method of birth control (such as a
condom, diaphragm or foam). The interfering effect of some of these medicines can last for up to 28
days after you have stopped taking them.
Blood levels of estrogen from EVRA may be increased if you take certain medicines or drink
grapefruit juice.
28
EVRA may make some other medicines less effective, such as:
•
medicines containing ciclosporin
•
the anti-epileptic lamotrigine (This can increase the risk of fits (seizures)).
Ask your doctor or pharmacist for advice before taking any medicine.
Using EVRA with food and drink
It is not expected that food or drink will affect the way EVRA works.
Pregnancy and breast-feeding
•
Do not use EVRA if you are pregnant or think you may be pregnant
•
Do not use EVRA if you are breast-feeding or planning to breast-feed.
Ask your doctor or pharmacist for advice before taking any medicine during pregnancy or while
breast-feeding.
Driving and using machines
You can drive or operate machinery while using EVRA.
Sexually transmitted disease
EVRA will not protect you against HIV infection (AIDS) or any other sexually transmitted disease.
These include chlamydia, genital herpes, genital warts, gonorrhoea, hepatitis B, syphilis. Always use
condoms to protect yourself from these diseases.
Medical tests
•
Tell your doctor or the person taking the sample, if you are having a blood or urine test. This is
because EVRA may affect some results of the tests.
3.
Risks of using combined hormonal contraceptives
The following information is based on information about combined birth control pills. As the EVRA
transdermal patch contains similar hormones to those used in combined birth control pills, it is likely
to have the same risks. All combined birth control pills have risks, which may lead to disability or
death.
It has not been shown that a transdermal patch like EVRA is safer than a combined birth control pill
taken by mouth.
Combined hormonal contraceptives and blood clots (thrombosis)
Using combined hormonal contraceptives, including EVRA, increases the chances of getting a
thrombosis (blood clots). It is possible that the risk of blood clots in the legs and/or lungs with EVRA
is more than the risk with combined birth control pills. This risk of developing blood clots is not
affected by how long you use the medicine. The risk returns to normal, a few months after you stop
using the medicine.
Blood clots can cause a blockage in a vein or artery and this may make you permanently disabled or
even cause death.
•
Blood clots can form in a vein in your leg (deep vein thrombosis or DVT) and travel to the
lungs. This can cause chest pain and make you breathless or collapse. This is called a
‘pulmonary embolism’ or PE
•
Very rarely, blood clots can form in the blood vessels of the heart (causing a heart attack) or the
brain (causing a stroke)
•
In extremely rare cases, blood clots can happen in other places such as the liver, gut, kidney or
eye. Blood clots in the eye may cause loss of eyesight or double vision.
Tell your doctor immediately if you notice any possible signs of a blood clot, such as:
•
Pain or swelling in either leg
•
Pain in the chest, which may spread to the arm
29
•
Sudden shortness of breath or sudden coughing
•
Unusual, severe or long-lasting headache
•
Vision problems
•
Difficulty speaking
•
Feeling dizzy or fainting spells
•
Feeling weak or numb on one side or one part of the body
•
Difficulty walking or holding things
•
Sudden stomach pain
If you think you might have any of these, talk to your doctor immediately.
Your chance of getting a blood clot increases:
•
As you get older
•
If blood clots in blood vessels (veins or arteries) runs in the family
•
If you smoke, especially if you are over 35 years of age
•
If you stay in bed for many days
•
If you are very overweight
•
If you have just had a baby, miscarriage or abortion
•
If you have had a serious injury, particularly of the leg or hip
•
If you have had or are going to have a major operation or need to have bed rest for a long time.
Normally you should not use EVRA for two weeks before or two weeks after surgery
•
If you have ever had blood clots before
•
If you have problems with your blood fats (cholesterol or triglycerides)
•
If you have high blood pressure
•
If you have heart problems (problems with heart valves, abnormal heart rhythm).
Combined hormonal contraceptives and cancer
Breast cancer
Breast cancer has been found more often in women who take combined hormonal contraceptives.
However, it is possible that the combined hormonal contraceptive is not the
cause
of more women
having breast cancer. It may be that women taking the combined hormonal contraceptive are examined
more often. This might mean that there is a better chance of the breast cancer being noticed. The
increased risk gradually goes down after stopping the combined hormonal contraceptive. After 10
years, the risk is the same as for people who have never used the combined hormonal contraceptive.
Cervical cancer
Cervical cancer also has been found more often in women taking combined hormonal contraceptives.
However, this may be due to other causes. These include more sexual partners and sexually
transmitted disease.
Liver cancer
In rare cases, liver tumours which are not cancer have been found in women taking combined
hormonal contraceptives. Even more rarely, liver tumours which are cancer have been found. This can
cause bleeding inside the body with very bad pain in the stomach area.
If this happens to you, talk to
your doctor immediately.
4.
How to use EVRA
Always use EVRA exactly as described in this leaflet.
•
If you do not, you may increase your risk of getting pregnant
•
Check with your doctor or pharmacist if you are not sure
•
Always keep non-hormonal contraceptives (such as condoms, foam or sponge) as a back-up in
case you make a mistake when using the patch.
Talk to your doctor about using EVRA after having a baby or after an abortion or miscarriage.
30
How many patches to use
•
Weeks 1, 2 & 3: Put on one patch and leave it on for exactly seven days
•
Week 4: Do
not
put on a patch this week.
Important information to follow when using the patch
•
Change EVRA on the same day of each week. This is because it is designed to work over 7 days
•
Never go without wearing a patch for more than 7 days in a row
•
Only wear one patch at a time
•
Do not put the patch on skin that is red, irritated or cut
•
To work properly the patch must stick firmly to your skin
-
Do not use creams, oils, lotions, powder or makeup on the skin where you are placing a patch or
near a patch you are wearing. This may make the patch come loose
•
Do not put a new patch on the same area of skin as the old patch. If you do you are more likely
to cause irritation
•
Check each day to make sure the patch has not fallen off
•
Keep using the patches even if you do not have sex very often.
How to use the patch:
If this is the first time you are using EVRA, wait until the day you get your
menstrual period.
•
Apply your first patch during the first 24 hours of your period
•
If the patch is put on after the first day of your period, use a non-
hormonal contraceptive until Day 8, when you change your patch
•
The day you apply your first patch will be Day 1. Your “Patch
Change Day” will be on this day of the week every week.
Choose a place on your body to put the patch.
•
Always put your patch on clean, dry, hairless skin
•
Put it on the buttock, abdomen, upper outer arm or upper back -
places where it won’t be rubbed by tight clothing
•
Never put the patch on your breasts
.
Using your fingers, open the foil sachet
•
Open it by tearing it along the edge (do not use scissors)
•
Firmly grasp a corner of the patch and gently take it from the foil
sachet
•
There is a clear protective covering on the patch
•
Sometimes patches can stick to the inside of the sachet – be
careful not to accidentally remove the clear covering as you
remove the patch
•
Then peel away half of the clear protective covering (see picture).
Try not to touch the sticky surface.
Put the patch on your skin
•
Then take off the other half of the covering
•
Press down firmly on the patch with the palm of your hand for 10
seconds
•
Make sure that the edges stick well.
31
-
Press the patch down firmly until the edges stick well
Wear the patch for 7 days (one week)
•
On the first “Patch Change Day”, Day 8, take off the used patch
•
Put on a new patch immediately.
•
On Day 15 (Week 3), take off the used patch
•
Put on another new one.
This makes a total of three weeks with the patches.
To help stop irritation, do not put the new patch on exactly the same
area of your skin as your last patch
.
Do not wear a patch on Week 4 (Day 22 through Day 28).
•
You should have your period during this time
•
During this week you are protected from getting pregnant only if you
start your next patch on time.
For your next four week cycle
•
Put on a new patch on your normal “Patch Change Day”, the day
after Day 28
•
Do this
no matter when your period begins or ends
.
If you want to change your “Patch Change Day” to a different day of the week talk to your doctor.
Everyday activities while using the patches
•
Normal activities such as having a bath or shower, using a sauna and exercising should not
affect how well the patch works
•
The patch is designed to stay in place during these types of activities
•
However, you should check that the patch has not fallen off after doing these activities.
If you need to place the patch on a new area on your body on a day other than your “Patch
Change Day”
If the patch causes irritation or you become uncomfortable wearing it:
•
You can take it off and replace it with a new patch in a different place on your body until your
next “Patch Change Day”
•
You may only use one patch at a time.
If you have trouble remembering to change your patch
•
Talk to your doctor or another healthcare professional at the clinic. He/she may be able to
make
patch changing easier for you. He/she may also talk about whether you need to use another
method of contraception.
32
If your patch becomes loose, lifts at the edges or falls off
For less than one day
(up to 24 hours)
:
•
Try to put it on again or put on a new patch immediately
•
Back-up contraception is not needed
•
Your “Patch Change Day” should remain the same
•
Do not try to put a patch back on if:
-
it is no longer sticky
-
it has become stuck to itself or another surface
-
it has other material stuck to it
-
it is the second time it has become loose or has fallen off
•
Do not use tapes or wrapping to keep the patch in place
•
If you cannot get a patch back on, put on a new patch immediately.
For more than one day
(24 hours or more)
or if you are not sure for how long:
•
Start a new four week cycle immediately
by putting on a new patch
•
You now have a new Day 1 and a new “Patch Change Day”
•
You must use non-hormonal contraception as back up for the first week of your new cycle.
You may get pregnant if you do not follow these instructions.
If you forget to change your patch
At the start of any patch cycle (Week 1 (Day 1)):
If you forget to put on your patch,
you may be at particularly high risk of becoming pregnant
.
•
You must use non-hormonal contraception as back up for one week
•
Put on the first patch of your new cycle as soon as you remember
•
You now have a new “Patch Change Day” and new Day 1.
In the middle of your patch cycle
(Week 2 or 3):
If you forget to change your patch for
one or two days
(up to 48 hours):
•
You must put on a new patch as soon as you remember
•
Put on your next patch on your normal “Patch Change Day”.
No back up contraception is needed.
For more than 2 days
(48 hours or more)
:
•
If you forget to change your patch for
more than 2 days
,
you may become pregnant
•
You must start a new four week cycle as soon as you remember by putting on a new patch
•
You now have a different “Patch Change Day” and a new Day 1
•
You must use back-up contraception for the first week of your new cycle.
At the end of your patch cycle (Week 4):
If you forget to take off your patch:
•
Take it off as soon as you remember
•
Start your next cycle on your normal “Patch Change Day”, the day after Day 28.
No back-up contraception is needed.
If you switch from the oral contraceptive pill to EVRA
If you are switching from an oral contraceptive pill to EVRA:
•
Wait until you get your menstrual period
•
Put on your first patch during the first 24 hours of your period.
If the patch is applied after Day 1 of your period, you should:
•
Use a non-hormonal contraceptive until Day 8 when you change your patch.
If you do not get your period within 5 days of taking the last contraceptive pill, check with your doctor
before starting EVRA.
33
If you switch from the mini-pill to EVRA
•
You may start EVRA any day after stopping the mini-pill
•
The first day after stopping the mini-pill, put on a patch
•
Use a non-hormonal contraceptive until Day 8, when you change your patch.
If you have absent or irregular bleeding with EVRA
EVRA may cause unexpected vaginal bleeding or spotting during the weeks when you are wearing the
patch
•
This usually stops after the first few cycles
•
Mistakes in using your patches can also cause spotting and light bleeding
•
Continue using EVRA and if the bleeding lasts more than the first three cycles, talk to your
doctor or pharmacist.
If you do not get your period during the EVRA
patch-free week (Week 4), you should still use a new
patch on your usual “Patch Change Day”.
•
If you have been using EVRA correctly and you do not have a period, this does not necessarily
mean that you are pregnant
•
However, if you miss two periods in a row, talk to your doctor or pharmacist as you may
be
pregnant.
If you use more than one EVRA patch at any one time
Take the patches off and talk to a doctor immediately.
Using too many patches may cause you to have the following:
•
Feeling sick (nausea) and being sick (vomiting)
•
Bleeding from the vagina.
If you stop using EVRA
You may get irregular, little or no bleeding. This usually happens in the first 3 months and especially
if your periods were not regular before you started using EVRA.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
5.
Possible side effects
Like all medicines, EVRA can cause side effects although not everybody gets them.
Tell your doctor if you notice any unwanted effects. If you think that you have a serious side effect
when using EVRA, take off the patch and speak to your doctor or pharmacist immediately. In the
meantime, you should use another method of contraception.
Serious side effects associated with combined hormonal contraceptives are described in Section 3
above (“Risks of using combined hormonal contraceptives”).
Please read this section for additional
information.
Very common side effects (affects more than 1 in 10 women):
•
Headache
•
Feeling sick (nausea)
•
Breast tenderness.
Common side effects (affects less than 1 in 10 women):
•
Vaginal yeast infection, sometimes called thrush
•
Mood problems such as depression, change in mood or mood swings
•
Feeling dizzy
•
Migraine
•
Stomach pain or bloating
•
Being sick (vomiting) or diarrhoea
•
Acne, skin itching or skin irritation
•
Muscle spasms
34
•
Breast pain or enlargement
•
Uterine cramps, painful or heavy periods, bleeding between periods or vaginal discharge
•
Problems where the patch has been on the skin (such as redness, irritation, itching or rash)
•
Feeling tired or generally unwell
•
Weight gain.
Uncommon side effects (affects less than 1 in 100):
•
Swelling due to water retention in the body
•
High levels of fats in the blood (such as cholesterol or triglycerides)
•
Uncontrollable emotions
•
Anxiety
•
Problems sleeping (insomnia)
•
Less interest in sex
•
Skin rash, redness of the skin
•
Swelling of the breasts, lumps in the breast or abnormal breast milk production
•
Premenstrual syndrome
•
Vaginal bleeding or dryness
•
Problems where the patch has been on the skin (such as swelling, discoloured skin, pain, spots,
blisters or the skin feeling over-sensitive)
•
Swelling
•
Rise in blood pressure.
Rare side effects (affects less than 1 in 1000 women):
•
Abnormal crying
•
Increased interest in sex
•
Blood clot in the lung
•
Inflammation of the gall bladder
•
Yellow-brown pigment spots on the face
•
Irregular periods
•
A bumpy rash (hives) where the patch has been on the skin
•
Rise in cholesterol levels.
Very rare side effects (affects less than 1 in 10,000 women):
•
Aggression
•
Having more periods than normal.
Other side effects include:
•
Other problems where the patch has been on the skin, skin reactions or allergic reactions
•
Non-cancerous (benign) tumours in your breast or liver
•
Breast, cervical or liver cancer
•
Fibroids in the womb (uterus)
•
Abnormal blood sugar, cholesterol or insulin levels
•
Blood clots, blocked arteries, heart attack or stroke
•
Problems when wearing contact lenses
•
High blood pressure
•
Inflammation of the colon
•
Gallstones or blockage of the bile duct
•
Abnormal taste
•
Yellowing of the skin and whites of the eyes
•
Hair loss
•
Sensitivity to sunlight
•
Less frequent, light or no periods
•
Anger, feeling irritable or frustrated.
35
If you have an upset stomach
•
The amount of hormones you get from EVRA should not be affected by being sick (vomiting)
or diarrhoea
•
You do not need to use extra contraception if you have an upset stomach.
You may have spotting or light bleeding or breast tenderness or may feel sick during the first 3 cycles.
The problem will usually go away but if it doesn’t, check with your doctor or pharmacist.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
6.
How to store EVRA
Keep out of the reach and sight of children.
Store in the original container to protect from light and moisture.
Do not refrigerate or freeze.
Do not use EVRA after the expiry date, which is stated on the label. The expiry date refers to the last
day of that month.
Used patches still contain some active hormones. To protect the environment, the patches should be
disposed of with care. To discard the used patch, you should:
•
Peel back the disposal label on the outside of the sachet
•
Place the used patch within the open disposal label so that the sticky surface covers the shaded
area
•
Close the label sealing the used patch within and discard, keeping out of reach of children.
Used patches should not be flushed down the toilet or placed in liquid disposal systems. Ask your
pharmacist how to dispose of any patches no longer required. These measures will help to protect the
environment.
7.
Further information
What EVRA contains
The active substances
in EVRA are norelgestromin 6mg and ethinyl estradiol 600 micrograms. The
active substances are released over 7 days with an average of 203 micrograms norelgestromin and 34
micrograms ethinyl estradiol being released each 24 hours.
The other ingredients
in the patch are polyisobutylene, polybutene, crospovidone, non-woven
polyester fabric and lauryl lactate.
What EVRA looks like and contents of the pack
EVRA is a thin, beige, plastic transdermal patch. The sticky adhesive side is stuck to the skin after
removal of the clear, plastic, protective covering.
EVRA is available in the following pack sizes: Cartons containing 3, 9 or 18 patches in individual foil-
lined sachets, wrapped per three in a transparent perforated plastic film.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Janssen-Cilag International N.V. Turnhoutseweg, 30, B-2340
Beerse, Belgium.
Manufacturer: Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
36
België/Belgique/Belgien
JANSSEN-CILAG N.V./S.A.
Roderveldlaan 1
B-2600 Berchem
Tél/Tel: + 32 3 280 54 11
Luxembourg/Luxemburg
JANSSEN-CILAG N.V./S.A.
Roderveldlaan 1
B-2600 Berchem
Tél: +32 3 280 54 11
България
Johnson & Johnson d.o.o.
Бизнес Парк София,
Младост 4, сграда 4, етаж 3
София 1715
Тел.: +359 2 489 94 00 (05)
Magyarország
JANSSEN-CILAG Kft.
H-2045 Törökbálint, Tó Park
Tel. : +36 23 513-800
Česká republika
JANSSEN-CILAG s.r.o.
Karla Engliše 3201/6
CZ-150 00 Praha 5
Tel. +420 227 012 222
Malta
A.M.Mangion Ltd
Triq Ġdida fi Triq Valletta
Luqa LQA 6000
Malta
tel:+356 2397 6000
Danmark
JANSSEN-CILAG A/S
Hammerbakken 19
Postboks 149
DK-3460 Birkerød
Tlf: +45 45 94 82 82
Nederland
JANSSEN-CILAG B.V.
Postbus 90240
NL-5000 LT Tilburg
Tel: +31 13 583 73 73
Eesti
Janssen-Cilag Polska Sp.z o.o.
Eesti filiaal
Lõõtsa 2
EE-11415 Tallinn
Tel: +372 617 7410
Österreich
JANSSEN-CILAG Pharma GmbH.
Pfarrgasse 75
A-1232 Wien
Tel:+43 1 610 300
Ελλάδα
JANSSEN-CILAG Φαρμακευτική
Α.Ε.Β.Ε.
Λεωφόρος Ειρήνης 56
GR-151 21 Πεύκη, Αθήνα
Tηλ: 0030 210 8090000
Polska
JANSSEN–CILAG Polska Sp. z o.o., ul.
Iłżecka 24,
PL- 02-135 Warszawa
Tel.: + 48 22 –237 60 00
España
JANSSEN-CILAG, S.A.
Paseo de las Doce Estrellas, 5-7
Campo de las Naciones
E-28042 Madrid
Tel: +34 91 722 81 00
Portugal
JANSSEN-CILAG FARMACÊUTICA, LDA
Estrada Consiglieri Pedroso, 69 A
Queluz de Baixo
2734-503 Barcarena
Tel: +351 21-4368835
France
JANSSEN-CILAG
1, rue de Camille Desmoulins
TSA 91003
F-92787 Issy Les Moulineaux Cedex 9
Tel: 0800 25 50 75 or
+ 33 1 55 00 44 44
România
Johnson & Johnson d.o.o. Rep.Office Janssen-
Cilag
Str. Tipogrfilor nr.11 - 15
013714Bucureşti
Tel: +4 0212071800
37
Deutschland
JANSSEN-CILAG GmbH
Johnson & Johnson Platz 1
D-41470 Neuss
Tel: +49 2137-955- 955
Norge
JANSSEN-CILAG A.S.
Hoffsveien 1 D
N- 0275 Oslo
Tlf: + 47 24 12 65 00
Ireland
JANSSEN-CILAG Ltd.
50-100 Holmers Farm Way
High Wycombe
UK - HP12 4EG Buckinghamshire
Tel: +44 1 494 567 567
Slovenija
Johnson & Johnson d.o.o.
Šmartinska cesta 53
Sl-1000, Ljubljana
Tel. + 386 1 401 18 30
Ísland
JANSSEN-CILAG AB
c/o Vistor hf.
Hörgatún 2
IS-210 Garðabær
Iceland
tel. (+354) 535 7000
Slovenská republika
Johnson&Johnson s.r.o.
Plynárenská 7/B
SK- 824 78 Bratislava 26
tel. +421 233 552 600
Italia
JANSSEN-CILAG SpA
Via M.Buonarroti, 23
I-20093 Cologno Monzese MI
Tel: +39 02/2510.1
Suomi/Finland
JANSSEN-CILAG OY
Vaisalantie/Vaisalavägen 2
FI-02130 Espoo/Esbo
Puh/Tel: +358 20 7531 300
Κύπρος
Βαρνάβας Χατζηπαναγής Λτδ
7 Ανδροκλέους
CY-1060 Λευκωσία
Tηλ: +357 22 755 214
Sverige
JANSSEN-CILAG AB
Box 7073
SE-192 07 Sollentuna
Tel: +46 8 626 50 00
Latvija
Janssen-Cilag Polska Sp. z o.o.
filiāle Latvijā
Matrožu iela 15
Rīga, LV-1048
Tel: + 371 678 93561
United Kingdom
JANSSEN-CILAG Ltd.
50-100 Holmers Farm Way
High Wycombe
UK - HP12 4EG Buckinghamshire
Tel: +44 1 494 567 567
Lietuva
UAB „Johnson & Johnson“
Geležinio Vilko g. 18A
LT-08104 Vilnius
Tel: +370 5 278 68 88
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu/.
38
Source: European Medicines Agency
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