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CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 1 of 52
PACKAGE INSERT
SCHEDULING STATUS
Schedule 4
PROPRIETARY NAME (and dosage form)
EVOREL® SEQUI (Transdermal Delivery System TDS).
EVOREL® SEQUI is a combination of a oestradiol matrix type transdermal patch and a
oestradiol/norethisterone acetate matrix type transdermal patch (sequential regimen).
COMPOSITION
EVOREL SEQUI is a transdermal therapy comprising:
(a) 4 EVOREL 50 TDSs, each containing 3,1 mg oestradiol, formulated as 3,2 mg of
oestradiol hemihydrate. Each EVOREL 50 patch delivers 50 µg of oestradiol per 24 hours.
(b) 4 EVOREL CONTI TDSs each containing 3,1 mg oestradiol formulated as 3,2 mg of
Oestradiol hemihydrate and 9,82 mg norethisterone, formulated as 11,2 mg of
norethisterone acetate. Each EVOREL CONTI delivers 50 µg of oestradiol and 170 µg of
norethisterone acetate per 24 hours.
The following are the inactive ingredients of EVOREL SEQUI:
EVOREL 50 TDS:
Adhesive: acrylate-vinylacetate copolymer
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 2 of 52
Guar gum
Backing film: polyethylene terephathalate foil
Release liner: siliconised polyethylene terephathalate foil is removed before
application
EVOREL CONTI TDS:
Adhesive: acrylate-vinylacetate copolymer
Guar gum
Backing film: polyethylene terephathalate foil
Release liner: siliconized polyethylene terephathalate foil is removed before
application
PHARMACOLOGICAL CLASSIFICATION
A 21.8.1 Oestrogens (EVOREL 50 TDS)
A 21.8.2 Progesterones with oestrogens (EVOREL CONTI TDS)
PHARMACOLOGICAL ACTION
Oestradiol (E2)
The active hormone of EVOREL SEQUI is 17 -oestradiol, the biologically most potent
oestrogen produced by the ovary. Its synthesis in the ovarian follicles is regulated by
pituitary hormones. Like all steroid hormones, oestradiol diffuses freely into target cells,
where it binds to specific macromolecules (receptors). The oestradiol-receptor complex
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 3 of 52
then interacts with genomic DNA to alter transcriptional activity. This results in either an
increase or decrease in protein synthesis and in changes of cellular functions.
Oestradiol is secreted at different rates during the menstrual cycle. The endometrium is
highly sensitive to oestradiol, which regulates endometrial proliferation during the follicular
phase of the cycle and together with progesterone, induces secretory changes during the
luteal phase. Around the menopause, oestradiol secretion becomes irregular and
eventually ceases altogether. The absence of oestradiol is associated with menopausal
symptoms such as vasomotor instability, sleep disturbances, depressive mood, signs of
vulvovaginal and urogenital atrophy and with increased bone loss. In addition, there is
growing evidence of an increased incidence of cardiovascular disease in the absence of
estrogen.
In contrast with oral oestrogen administration, stimulation of hepatic protein synthesis is
largely avoided with transdermal oestrogen administration. Consequently, there is a
lack of effect on circulating levels of renin substrate, thyroid-binding globulin, sex
hormone-binding globulin and cortisol-binding globulin. Similarly, coagulation factors
also appear to be unaffected.
Oestrogen replacement therapy has been found effective in most postmenopausal
women to compensate for the endogenous oestrogen depletion. It has been
demonstrated that transdermal oestradiol administration of 50 g /day is effective in the
treatment of menopausal symptoms and of postmenopausal bone loss.
In postmenopausal women, EVOREL SEQUI increases oestradiol to early follicular
levels, with a consequent significant decrease in hot flushes, improvement in
Kupperman Index and beneficial change in vaginal cytology.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 4 of 52
However, there is substantial evidence that estrogen replacement therapy is
associated with an increase in endometrial cancer. There is also compelling evidence
that adjunctive progestogen treatment protects against oestrogen-induced endometrial
cancer. Therefore, women with a uterus should receive combination estrogen-
progestogen hormone replacement therapy.
Norethisterone acetate (NETA)
Norethisterone acetate, used in the EVOREL CONTI TDS of EVOREL SEQUI, is
hydrolysed to norethisterone, a synthetic 19-nortestosterone derivative of the 13-methyl
gonane group with potent progestational activity. Transdermal norethisterone acetate
administration prevents oestrogen-related endometrial proliferation.
E2/NETA combination
Combined 17ß-oestradiol-norethisterone acetate therapy is effective in treating the deficits
associated with menopause.
Pharmacokinetics
Oestradiol
Oestradiol distributes widely in the body tissues and is bound to albumin ( 60 – 65 %) and
sex-hormone-binding globulin ( 35 – 45 %) in serum. Serum protein-binding fractions
remain unaltered following transdermal delivery of oestradiol.
Oestradiol is promptly eliminated from the systemic circulation. Oestradiol is metabolised
principally into the less pharmacologically active oestrone and its conjugates.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Oestradiol, oestrone and oestrone sulphate are interconverted to each other and are
excreted in urine as glucuronides and sulphates. The skin metabolises oestradiol only to a
small extent.
Norethisterone
Norethisterone acetate is hydrolysed to the active progestogen, norethisterone.
Transdermal delivery of norethisterone acetate produces a sustained and effective level of
norethisterone in the systemic circulation.
Norethisterone distributes widely in the body tissues and is bound to albumin ( 61 %) and
sex-hormone-binding globulin ( 36 %) in serum. Norethisterone is primarily metabolised
by the liver by reduction of the , ß -unsaturated ketone structure in ring A of the molecule.
Among the four possible stereoisomeric tetrahydrosteroids, the 5ß-, 3 -hydroxy-dervative
appears to be the predominant metabolite. These compounds are primarily excreted in
urine and faeces as sulphates and glucuronide conjugates.
E2/NETA combination
Oestradiol: In a single and multiple application study in postmenopausal women, serum
oestradiol concentrations increased rapidly from pre-treatment levels ( 5 pg/ml) after
application of a EVOREL CONTI TDS. At four hours after application, the mean serum
oestradiol concentration was about 19 pg/ml. A mean peak serum oestradiol
concentration of 41 pg/ml above the pre-treatment level was observed at about 23 hours
following application. Serum oestradiol concentrations remained elevated for the 3,5 day
application period. Concentrations returned rapidly to pre-treatment levels within 24 hours
following removal of the TDS. A serum half-life of 6,6 hours was determined following
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 6 of 52
removal of the TDS, indicative of the skin depot effect. Multiple applications of the
EVOREL CONTI TDS resulted in little or no accumulation of oestradiol in the systemic
circulation. Higher circulating levels of oestradiol were attained from EVOREL 50. Both
formulations were shown to be effective in achieving serum oestradiol concentration
typically seen in pre-menopausal women.
Prior to treatment, the mean serum oestradiol to oestrone concentration ratio (E2/E1) was
less than 0,3 in the postmenopausal women studied. During use of EVOREL CONTI TDS
the E2/E1 ratios increased rapidly and were maintained at physiological levels at
approximated 1. The E2/E1 ratios returned to pre-treatment levels within 24 hours after
removal of the TDS. An average E2/E1 ratio that approximated 1 was also maintained over
an entire 3,5 day application period following EVOREL 50 application.
Norethisterone: In a single and multiple application study in postmenopausal women,
serum norethisterone concentrations rose within 1 day after application of an EVOREL
CONTI TDS to a mean steady state level of 199 pg/ml. Mean steady state serum
norethisterone concentrations ranging between 141 - 224 pg/ml were maintained for the
entire 3,5 day application period following multiple application. Mean concentrations
declined rapidly to the lower limit of assay quantitation at 24 hours after removal of the
TDS. A serum half-life of 15 hours was determined following removal of the TDS;
indicative of the skin depot effect. As expected from the transdermal delivery only a
transient and limited increase in serum norethisterone concentration was observed
following multiple application of the TDS.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Relief of oestrogen-deficiency symptoms patterns (based on clinical trial data):
In healthy postmenopausal women aged 40 to 65 years, reduction of vasomotor symptoms
after 3 months of treatment was greater than 80 %, and after one year, greater than 90 %.
Bleeding patterns (based on clinical trial data):
In a randomized study in which 153 postmenopausal women received EVOREL SEQUI for
1 year (13 x 28-day treatment periods), 88 % of women experienced bleeding, 6,5 % were
amenorrheic, and 5 % had spotting only (percentages add up to > 100 % due to rounding).
Of women experiencing bleeding, 55 % had regular bleeding episodes each treatment
period. The mean number of bleeding days/year was 48.
At the end of the trial, the mean number of hot flushes/day reported had decreased
significantly (by > 90 %) from that reported during the pretreatment period (P < 0.001).
80 % of women reported no hot flushes. Less than 2 % of women discontinued the
trial for inadequate control of vasomotor symptoms.
Transdermal addition of progestogen, whether continuous combined or sequential,
appears to be an effective and safe alternative to adjunctive oral sequential progestogen in
the treatment of menopausal symptoms.
INDICATIONS
Hormone replacement therapy [HRT] for the relief of menopausal symptoms (vasomotor
symptoms such as hot flushes and nocturnal sweating and atrophic vaginitis/vulvitis and/or
atrophic urethritis) for women with an intact uterus.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CONTRA-INDICATIONS
Known hypersensitivity to any component of this product.
Known current, past or suspected breast cancer.
Known or suspected oestrogen-dependent malignant tumours (e.g.
endometrial cancer) or pre-malignant tumours (e.g. untreated atypical
endometrial hyperplasia).
Undiagnosed genital bleeding.
Pregnancy and lactation.
Acute liver disease, or a history of liver disease as long as liver function tests have
failed to return to normal.
Previous or current venous thromboembolism (deep venous thrombosis, pulmonary
embolism).
Known thrombophilic conditions.
Active or recent past arterial thromboembolic disease (e.g. cerebrovascular
accident, myocardial infarction).
WARNINGS
Prior to commencing, and periodically during oestrogen replacement therapy, it is
recommended that the patient be given a thorough physical and gynecological examination.
A complete medical and family history of thrombophlebitis or thromboembolic disorders
should be taken. Repeated breakthrough bleeding, unexplained vaginal bleeding, and
changes noticed during breast examination require further evaluation.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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A careful appraisal of the risk/benefit ratio should be undertaken before the initiation of
long-term treatment.
Evidence regarding the risks associated with HRT in the treatment of premature
menopause is limited. Due to the low level of absolute risk in younger women, however,
the balance of benefits and risks for these women may be more favorable than in older
women.
Conditions which need supervision:
If any of the following conditions are present, have occurred previously, and/or have been
aggravated during pregnancy or previous hormone treatment, the patient should be closely
supervised. It should be taken into account that these conditions may recur or be
aggravated during treatment with EVOREL SEQUI in particular:
Leiomyoma (uterine fibroids) or endometriosis.
Risk factors for thromboembolic disorders (see below).
Risk factors for oestrogen dependent tumors, e.g. first degree relative with breast
cancer.
Hypertension.
Liver disorders (e.g. liver adenoma).
Diabetes mellitus.
Cholelithiasis.
Migraine or severe headache.
Systemic lupus erythematosus.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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A history of endometrial hyperplasia (see below) .
Epilepsy.
Mastopathy.
Conditions which require monitoring while on oestrogen therapy:
Oestrogens may cause fluid retention. Cardiac or renal dysfunction should be
carefully observed.
Disturbances or mild impairment of liver function.
History of cholestatic jaundice.
Pre-existing hypertriglyceridaemia. Rare cases of large increases of plasma
triglycerides leading to pancreatitis have been reported with oestrogen therapy in
this condition.
Reasons for immediate withdrawal of therapy:
Therapy should be discontinued in case a contraindication is discovered and in the
following situations:
Jaundice or deterioration in liver function.
Significant increase in blood pressure.
New onset of migraine-type headache.
Pregnancy.
Breast cancer
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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The overall evidence suggests an increased risk of breast cancer in women taking
combined oestrogen-progestagen and possibly also oestrogen-only HRT, that is
dependent on the duration of taking HRT.
Combined oestrogen-progestagen therapy:
The randomised placebo-controlled trial the (Women’s Health Initiative study (WHI), and
epidemiological studies are consistent in finding an increased risk of breast cancer in
women taking combined oestrogen-progestagen for HRT that becomes apparent after
about 3 years.
Oestrogen-only therapy:
The WHI trial found no increase in the risk of breast cancer in hysterectomised women
using oestrogen-only HRT. Observational studies have mostly reported a small increase
in risk of having breast cancer diagnosed that is lower than that found in users of
oestrogen-progestagen combinations.
The excess risk becomes apparent within a few years of use but returns to baseline within
a few (at most five) years after stopping treatment. HRT, especially oestrogen-
progestagen combined treatment, increases the density of mammographic images which
may adversely affect the radiological detection of breast cancer.
Ovarian Cancer
Ovarian cancer is much rarer than breast cancer. Long- term (at least 5 to 10 years) use of
oestrogen-only HRT products in hysterectomised women has been associated with an
increased risk of ovarian cancer in some epidemiological studies. Some studies including
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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CCDS: 09 June 2011 Page 12 of 52
the WHI trial suggest that the long-term use of combined HRTs may confer a similar, or
slightly smaller, risk.
Venous thromboembolism
Hormone replacement therapy [HRT] is associated with a higher relative risk of developing
venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One
randomized controlled trial and epidemiological studies found a two- to threefold higher
risk for users compared with non-users.
Personal or strong family history of recurrent thromboembolism or recurrent spontaneous
abortions should be investigated in order to exclude a thrombophilic predisposition. Until a
thorough evaluation of thrombophilic factors has been made or anticoagulant treatment
initiated, use of HRT in such patients should be viewed as contraindicated. Those women
already on anticoagulant treatment require careful consideration of the benefit-risk of use
of HRT.
The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma
or major surgery. Scrupulous attention should be given to prophylactic measures to
prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective
surgery, particularly abdominal or orthopaedic surgery to the lower limbs, HRT treatment
should be discontinued well ahead of surgery, if possible. Treatment should not be
restarted until after the woman is completely mobilised.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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If VTE develops after initiating therapy, EVOREL should be discontinued. Patients should
be told to contact their doctors immediately when they are aware of a potential
thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest,
dyspnoea).
Coronary artery disease (CAD)
Oestrogen-only:
Randomised controlled data found no increased risk of CAD in hysterectomised women
using oestrogen-only therapy. There is emerging evidence that initiation of oestrogen only
therapy in early menopause may reduce CAD risk.
Combined oestrogen-progestagen therapy:
The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly
increased. The absolute risk of CAD is strongly dependent on age. The number of extra
cases of CAD due to oestrogen-progestagen use is very low in healthy women close to
menopause, but will rise with more advanced age.
Stroke
There is an increased risk of stroke in healthy women during treatment with HRT.
Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up
to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age
or time since menopause. However, as the baseline risk of stroke is strongly age-
dependent, the overall risk of stroke in women who use HRT will increase with age.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Dementia
HRT use does not improve cognitive function. There is some evidence of increased risk of
probable dementia in women who start using continuous combined or oestrogen-only HRT
after the age of 65 years.
Other conditions
Administration of unopposed oestrogen in patients with uterus has been reported to
increase the risk of endometrial hyperplasia and of endometrial carcinoma. Therefore,
oestrogen in combination with progestogen as in EVOREL SEQUI is recommended in
women with uterus in order to reduce the risk of hyperplasia or endometrial carcinoma.
Concomitant administration of lamotrigine with medicines containing both ethinyl oestradiol
and a progestogen, such as EVOREL SEQUI, increases the risk of seizures in epileptic
patients (See INTERACTIONS).
EVOREL SEQUI is not to be used as contraception.
EVOREL SEQUI should be kept away from children.
INTERACTIONS
Medicines, which induce microsomal liver enzyme activity, may alter oestrogen and
progestogen metabolism. Examples of such medicines are barbiturates, hydantoins,
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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carbamazepine, meprobamate, phenylbutazone, rifampicin, rifabutin, bosentan and certain
non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine and efavirenz).
Ritonavir and nelfinavir, although known as strong inhibitors of the cytochrome P450
isoenzymes, by contrast exhibit inducing properties when used concomitantly with steroid
hormones. Medicine metabolism may be affected by St. John’s wort preparations
(Hypericum perforatum), which induce certain cytochrome P450 isoenzymes in the liver (e.g.
CYP 3A4) as well as P-glycoprotein. The induction of the P450 isoenzymes may reduce
plasma concentrations of the oestrogen component of EVOREL possibly resulting in a
decrease in therapeutic effects and unscheduled bleeding. With transdermal administration,
the first-pass effect in the liver is avoided and, thus, transdermally applied estrogens might
be less affected by enzyme inducers than oral hormones. It is possible that induction of
these same isoenzymes may also reduce circulating concentrations of the progestin
component of EVOREL SEQUI which could result in a diminished effect against oestrogen-
induced endometrial hyperplasia.
Oestrogen-containing oral contraceptives have been shown to significantly decrease plasma
concentrations of lamotrigine when co-administered due to induction of lamotrigine
glucuronidation. This may reduce seizure control. Although the potential interaction
between oestrogen-containing hormone replacement therapy and lamotrigine has not been
studied, it is expected that a similar interaction exists, which may lead to a reduction in
seizure control among women taking both medicine together. Therefore, dosage adjustment
of lamotrigine may be necessary (See WARNINGS).
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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PREGNANCY AND LACTATION
The use of EVOREL SEQUI is contra-indicated in pregnancy or lactation.
If pregnancy occurs during medication with EVOREL SEQUI, treatment should be
withdrawn immediately.
DOSAGE AND DIRECTIONS FOR USE
Dosage
ADULTS:
EVOREL 50 and EVOREL CONTI should be applied individually in the following
sequence: four EVOREL 50 TDSs followed by four EVOREL CONTI TDSs. The cycle
should be repeated without interruption. Patches should be applied twice weekly, every
three to four days, to the trunk below the waist.
Insufficient data are available to guide dose adjustments for patients with severe liver or
kidney function impairment.
For treatment of post- menopausal symptoms the lowest effective dose should be used.
HRT should be continued for no longer than 5 years.
It is important that the patch be used in the correct sequence to ensure regular cyclic
bleeding. Most patients will experience vaginal bleeding after the start of the progestogen
therapy.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Should a patch fall off, it should be replaced immediately with a new equivalent EVOREL
50 or EVOREL CONTI patch. However, the usual day of changing patches should be
maintained.
It is not necessary to remove the patch during bathing or showering. It is recommended,
however, that the patch be removed prior to a sauna bath, and that a new patch is applied
immediately thereafter.
If a patch change is missed, the missed patch should be applied as soon as remembered.
However, the usual day of changing patches should be maintained. Forgetting a dose
may increase the likelihood of break-through bleeding and spotting.
ELDERLY:
Data are insufficient in regard to the use of EVOREL SEQUI in the elderly (> 65 years old).
Directions for use/handling
The EVOREL SEQUI TDS should be placed on a clean, dry, healthy, intact area of skin,
on the trunk of the body below the waist. Creams, lotions or powders may interfere with
the adhesive properties of the patch. The patch should not be applied on or near the
breasts. The area of application should be changed, with an interval of at least one week
allowed between applications to a particular site. The skin area selected should not be
damaged or irritated. The waistline should not be used because excessive rubbing of the
patch may occur.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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The patch should be used immediately after opening the sachet. Remove one part of the
protecting foil. Apply the exposed part of adhesive to the application site from the edge to
the middle; avoid wrinkling of the patch. The second part of the protective foil should now
be removed and the freshly exposed adhesive applied. Wrinkling should again be avoided
and the palm of the hand used to press the patch onto the skin and to bring the patch to
skin temperature at which the adhesive effect is optimized.
The patient should avoid contact between fingers and the adhesive part of the patch
during application.
Should a patch fall off, it should be replaced immediately with a new equivalent EVOREL
50 or EVOREL CONTI patch. However, the usual day of changing patches should be
maintained. It is not necessary to remove the patch during bathing or showering. It is
recommended, however, that the patch be removed prior to a sauna bath, and that a new
patch is applied immediately thereafter.
When using EVOREL SEQUI for the first two weeks, one of the EVOREL 50 patches
should be applied and changed twice weekly. During the following two weeks of EVOREL
SEQUI, one of the EVOREL CONTI patches should be applied, also to be changed twice
weekly. The patient then starts again with a new box of EVOREL SEQUI.
To remove the EVOREL patch, peel away an edge of the patch and pull smoothly away
from the skin. The EVOREL patch should be disposed of in household waste (do not flush
down the toilet).
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Any adhesive that remains on the skin after removal of EVOREL patch may be removed by
washing with soap and water or rubbing it off with the fingers.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Clinical Trial Data
The safety of EVOREL SEQUI was evaluated in 165 subjects in 2 active controlled clinical
trials. Adverse drug reactions (ADRs) reported for ≥ 1 % of EVOREL SEQUI-treated
subjects are shown in Table 1.
Table 1. Adverse Drug Reactions Reported by ≥ 1 % of EVOREL SEQUI-treated
Subjects in 2 Clinical Trials of EVOREL SEQUI
System/Organ Class
Adverse reaction
EVOREL
SEQUI
%
(N = 165)
Psychiatric Disorders
Depression
Insomnia
Nervousness
Affect lability
5,5
3,6
2,4
1,2
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Nervous System Disorders
Headache
7,9
Vascular Disorders
Hypertension
4,2
Gastrointestinal Disorders
Abdominal pain
Gastrointestinal Disorder
Nausea
4,9
1,8
1,8
Skin and Subcutaneous Tissue Disorders
Pruritus
Rash erythematous
1,2
1,2
Musculoskeletal and Connective Tissue Disorders
Arthralgia
2,4
Reproductive System and Breast Disorders
Breast pain
Menorrhagia
Dysmenorrhoea
Menstrual disorder
6,1
3,0
1,2
1,2
General Disorders and Administration Site
Conditions
Application site reaction
Oedema
Malaise
14,6
2,4
1,8
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Investigations
Increased weight
3,0
ADRs reported by < 1 % of EVOREL SEQUI-treated subjects (N = 165) in the above
clinical trial dataset are shown in Table 2.
Table 2. Adverse Drug Reactions Reported by < 1 % EVOREL SEQUI-treated
Subjects in 2 Clinical Trials of EVOREL SEQUI
System/Organ Class Side effect
Neoplasms Benign, Malignant and
Unspecified (Incl Cysts and
Polyps)
Breast cancer female,
Fibroadenoma of breast
Psychiatric Disorders Decreased libido, increased
libido.
Nervous System Disorders Disturbance in attention,
Dizziness
Reproductive System and Breast
Disorders
Endometrial hyperplasia,
Metrorrhagia
General Disorders and
Administration Site Conditions
Fatigue
Additional ADRs reported in clinical trials with EVOREL (oestradiol alone) in
postmenopausal women are shown in Table 3.
CCDS June 2011: Revisions to several section in PI, additional Contra-Indication for known thrombolic conditions, including revision of Special precautions, interactions, pregnancy and lactation. Date of submission: 27 January 2012 Submission reference: RR/01/023/mz
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Table 3. Adverse Drug Reactions Reported by EVOREL-treated Subjects in
15 Clinical Trials (N = 2 584) of EVOREL
System/Organ Class Side effect
Infections and Infestations Genital candidiasis
Neoplasms Benign, Malignant and
Unspecified (Incl. Cysts and Polyps
Breast cancer
Immune System Disorders Hypersensitivity
Nervous System Disorders Epilepsy
Cardiac Disorders Palpitations
Vascular Disorders Thrombosis
Gastrointestinal Disorders Diarrhoea, Flatulence
Skin and Subcutaneous Tissue
Disorders
Rash
Musculoskeletal and Connective
Tissue Disorders
Myalgia
General Disorders and
Administration Site Conditions
Application site rash*,
Application site pruritus*,
Application site erythema*,
Application site oedema*,
Generalised oedema,
Peripheral oedema,
Pain
* Solicited signs/symptoms (recorded as yes/no) in 8 clinical trials of EVOREL (N = 1 739).
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Post-marketing Data
Adverse drug reactions first identified during post-marketing experience with oestradiol are
included in Table 4.
Table 4. Adverse Drug Reactions Identified During Post-Marketing Experience with
Oestradiol and Norethisterone Estimated from Spontaneous Reporting Rates
Infections and Infestations Candidiasis
Neoplasms Benign, Malignant and
Unspecified (Incl Cysts and Polyps)
Endometrial cancer
Immune System Disorders Hypersensitivity
Psychiatric Disorders Mood swings
Nervous System Disorders Cerebrovascular accident, Migraine,
Paraesthesia
Cardiac Disorders Palpitations
Vascular Disorders Deep vein thrombosis
Respiratory, Thoracic and
Mediastinal Disorders
Pulmonary embolism
Gastrointestinal Disorders Abdominal distension
Hepatobiliary Disorders Cholelithiasis
Skin and Subcutaneous Tissue
Disorders
Stevens-Johnson syndrome
Musculoskeletal, Connective Tissue, Back pain
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and Bone Disorders
Reproductive System and Breast
Disorders
Breast enlargement
General Disorders and
Administration Site Conditions
Application site erythema,
Application site pruritus, Application
site rash
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENTS
Symptoms of overdose of oestrogen and progestogen therapy may include nausea, break-
through bleeding, breast tenderness, abdominal cramps and/or bloating. These symptoms
can be reversed by removing the transdermal patch.
IDENTIFICATION
EVOREL SEQUI is composed of EVOREL 50 and EVOREL CONTI.
EVOREL 50 is a flexible, square, colourless adhesive patch of 16 cm2 with convex edges
and rounded corners. The adhesive surface of the patch is covered with a protective foil
with an S-shaped incision. Each TDS is marked in the centre of the lower margin of the
outside of the backing film: CE50.
EVOREL CONTI is a flexible, square, colourless adhesive patch of 16 cm2 with convex
edges and rounded corners. The adhesive surface of the patch is covered with a
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protective foil with an S-shaped incision. Each TDS is marked in the centre of the lower
margin on the outside of the backing film: CEN1.
PRESENTATION
One EVOREL SEQUI box contains 4 EVOREL 50 TDS and 4 EVOREL CONTI TDS,
packed in individual foil-lined pouches.
The pouch comprises a 4 layer laminate including an aluminium barrier and paper exterior
surface.
STORAGE INSTRUCTIONS
Store at or below 25 °C. Do not freeze.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER
31/21.8.2/0538
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NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF
REGISTRATION
JANSSEN PHARMACEUTICA (PTY) LTD
(Reg. No. 1980/011122/07)
Building 6, Country Club Estate
21 Woodlands Drive
Woodmead
2191
www.janssen.co.za
DATE OF PUBLICATION OF THIS PACKAGE INSERT
January 2012
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VOUBILJET
SKEDULERINGSTATUS
Skedule 4.
EIENDOMSNAAM (en doseervorm)
EVOREL® SEQUI (Transdermale Leweringstelsel TDS)
EVOREL SEQUI is ’n kombinasie van ’n estradiol- matrikstipe transdermale plakker en ’n
estradiol/noretisteroonasetaat- matrikstipe transdermale plakker (opvolgbehandeling).
SAMESTELLING
EVOREL SEQUI is ‘n transdermale terapie bestaande uit:
(a) 4 EVOREL 50 TDS’e, elk bevattende
3,1 mg estradiol, geformuleer as 3,2 mg estradiolhemihidraat.
Elke EVOREL 50 pleister stel 50 µg estradiol per 24 uur vry.
(b) 4 EVOREL CONTI TDS’e, elk bevattende:
3,1 mg estradiol geformuleer as 3,2 mg estradiol hemihidraat en 9,82 mg noretisteroon
geformuleer as 11,2 mg noretisteroonasetaat.
Elke EVOREL CONTI stel 50 µg estradiol en 170 µg noretisteroonasetaat per 24 uur vry.
EVOREL SEQUI bevat die volgende onaktiewe bestanddele:
• EVOREL 50 TDS:
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Kleefmiddel: akrilaat-vinielasetaat kopolimeer
Guar gom
Steunlagie: poliëtileen-tereftalaat foelie
Vrystellingsvoering: gesilikoniseerde poliëtileen tereftalaatfoelie wat verwyder word voor
aanwending.
• EVOREL CONTI TDS:
Kleefmiddel: akrilaat-vinielasetaat kopolimeer
Guar gom
Steunlagie: poliëtileen-tereftalaat foelie
Vrystellingsvoering: gesilikoniseerde poliëtileen tereftalaatfoelie word verwyder voor
aanwending
FARMAKOLOGIESE KLASSIFIKASIE
A 21.8.1 Estrogene (EVOREL 50 TDS)
A 21.8.2 Progesterone met estrogene (EVOREL CONTI TDS)
FARMAKOLOGIESE WERKING
Estradiol (E2)
Die aktiewe hormoon van EVOREL SEQUI is 17 -estradiol, die biologies mees kragtige
estrogeen wat deur die ovarium vervaardig word. Die sintese daarvan in die ovariale
follikels word deur pituïtêre hormone beheer. Soos alle steroïedhormone, diffundeer
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estradiol vryelik in teiken-selle in, waar dit aan spesifieke makromolekules (reseptore) bind.
Die estradiol-reseptorkompleks het dan ’n interaksie met DNA-genoom om transkripsie-
aktiwiteit te verander. Dit lei tot óf ’n toename óf ’n afname in sintese van proteïene en
veranderinge in sellulêre funksies.
Estradiol word met ’n verskillende tempo tydens die menstruasiesiklus uitgeskei. Die
endometrium is hoogs gevoelig vir estradiol, wat endometriale proliferasie tydens die
follikulêre fase van die siklus reguleer en saam met progesteroon sekretoriese
veranderings tydens die luteale fase induseer. Om en by die menopouse word estradiol
afskeiding ongereeld en hou dit uiteindelik heeltemal op. Die afwesigheid van estradiol
word in verband gebring met menopousale simptome soos vasomotoriese onstabiliteit,
slaapversteurings, depressiewe gemoed, tekens van vulvovaginale en urogenitale atrofie
en ’n toename in beenverlies. Daarbenewens is daar toenemend bewys van ’n verhoogde
insidensie van kardiovaskulêre siekte in die afwesigheid van estrogeen.
Anders as by orale toediening van estrogeen, word stimulering van sintese van proteïene in
die lewer grotendeels vermy deur die transdermale toediening van estrogeen. Gevolglik is
daar ’n gebrek aan effek op sirkulerende vlakke van renien-substraat,
tiroïedbindingsglobulien, geslagshormoonbindingsglobulien en kortisolbindingsglobulien.
Insgelyks is stollingsfaktore ook skynbaar onveranderd.
Estrogeen-vervangende terapie is by die meeste postmenopousale vroue doeltreffend
bevind om te kompenseer vir endogene estrogeen-uitputting. Daar is aangetoon dat die
transdermale estradiol toediening van 50 g /dag doeltreffend is vir die behandeling van
menopousale simptome en van postmenopousale beenverlies.
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By postmenopousale vroue verhoog EVOREL SEQUI die estradiol tot vroeë follikulêre
vlakke, met gevolglike beduidende afname in warmgloede, verbetering in die Kupperman
Index en voordelige verandering in vaginale sitologie.
Daar is egter aansienlike bewys dat estrogeen-vervangende terapie met ’n toename in
endometriale kanker geassosieer kan word. Daar is ook onomstootlike bewys dat
bykomende behandeling met progestogeen beskerm teen estrogeen-geïnduseerde
endometriale kanker. Gevolglik moet vroue met ’n uterus kombinasie estrogeen-
progestogeen hormoonvervangingsterapie kry.
Noretisteroonasetaat (NETA)
Noretisteroonasetaat, soos bevat word in die EVOREL CONTI TDS van EVORAL SEQUI,
word gehidroliseer tot noretisteroon, ‘n sintetiese 19-nortestosteroon derivaat van die 13-
metiel gonaangroep met kragtige progestasionele aktiwiteit. Transdermale
noretisteroonasetaat-toediening voorkom estrogeenverwante endometriale proliferasie.
E2/NETA kombinasie
Gekombineerde 17ß-estradiol-noretisteroonasetaat terapie is doeltreffend vir die
behandeling van gebreke geassosieer met menopouse.
Farmakokinetika
Estradiol
Estradiol word wyd in die liggaamsweefsels versprei en word in die serum aan albumien (≈
60 – 65 %) en aan sekshormoonbindingsglobulien (≈ 35-45 %) gebind. Na transdermale
vrystelling van estradiol bly serumgebonde proteïenfraksies onveranderd.
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Estradiol word gou uit die sistemiese sirkulasie verwyder. Estradiol word hoofsaaklik na
minder aktiewe estrone en hul konjugate gemetaboliseer.
Estradiol, estroon en estroonsulfate is verwisselbaar met mekaar en word in die urine as
glukoroniede en sulfate uitgeskei. Die vel metaboliseer estradiol slegs tot ‘n geringe mate.
Noretisteroon
Noretisteroonasetaat word na die aktiewe progestogeen, noretisteroon, gehidroliseer.
Transdermale vrystelling van noretisteroonasetaat verskaf ‘n volgehoue en doeltreffende
vlak van noretisteroon aan die sistemiese sirkulasie.
Noretisteroon word wyd in die liggaamsweefsels versprei en word in die serum aan
albumien (≈ 61 %) en aan die sekshormoonbindingsglobulien (≈ 36 %) gekoppel.
Noretisteroon word hoofsaaklik in die lewer gemetaboliseer deur reduksie van die α, ß -
onversadigde ketoonstruktuur in die A-ring van die molekule. Onder die vier moontlike
stereo-isomeriese tetrahidrosteroïede, wil dit voorkom of die 5ß-, 3α-hidroksie- derivaat die
belangrikste metaboliet is. Hierdie verbindings word hoofsaaklik in die urine en feses as
sulfate en glukuronied-konjugate uitgeskei.
E2/NETA kombinasie
Estradiol: In ‘n enkel- en veelvoudige toedieningstudie oor postmenopousale vroue nadat
‘n EVOREL CONTI TDS toegedien is, het die serum estradiolkonsentrasies vinnig
toegeneem vanaf voorbehandelingsvlakke (≈ 5 pg/ml). Die gemiddelde serum
estradiolkonsentrasie vier uur na die toediening was ongeveer ≈ 19 pg/ml. ‘n Gemiddelde
piek serum estradiolkonsentrasie van ≈ 41 pg/ml hoër as die voorbehandelingsvlak was
ongeveer 23 uur na toediening waargeneem. Serum-estradiolkonsentrasies bly verhoog vir
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die 3,5 dag toedieningsperiode. Konsentrasies keer vinnig terug na voor-
behandelingsvlakke binne 24 uur nadat die TDS verwyder is. Nadat die TDS verwyder is,
was ‘n serum halfleeftyd van ≈ 6,6 uur bepaal, wat ‘n vel - depoteffek aandui. Veelvoudige
toedienings van die EVOREL CONTI TDS het min of geen akkumulasie van estradiol in die
sistemiese sirkulasie veroorsaak nie. Hoër vlakke van estradiol is in die bloedsomloop
bereik met EVOREL 50. Dit is aangetoon dat albei formulerings doeltreffend is vir die
bereiking van ’n serum-estradiolkonsentrasie wat tipies by pre-menopousale vroue
voorkom.
Voor behandeling was die gemiddelde serum estradiol- tot estroonkonsentrasie verhouding
(E2/E1) minder as 0,3 onder die postmenopousale vroue wat bestudeer is. Gedurende
gebruik van EVOREL CONTI TDS het die E2/E1 verhoudings vinnig toegeneem en is dit
volgehou op fisiologiese vlakke van ongeveer 1. Die E2/E1 verhoudings het teruggekeer na
die voorbehandelingsvlakke binne 24 uur nadat die TDS verwyder is. ’n Gemiddelde E2/E1
verhouding van by benadering 1 is ook oor die hele 3,5 dag toedieningstydperk behou met
die toediening van EVOREL 50.
Noretisteroon: In ‘n enkel en veelvoudige toedieningstudie oor postmenopousale vroue
het die serum noretisteroonkonsentrasies toegeneem binne 1 dag nadat ‘n EVOREL
CONTI TDS toegedien is om ‘n gemiddelde vastevlak van ≈ 199 pg/ml te bereik. Na
veelvoudige toedienings wissel die gemiddelde serum vastevlak van
noretisteroonkonsentrasies tussen ≈ 141– 224 pg/ml en word volgehou oor die hele 3,5 dag
toedieningsperiode. Gemiddelde konsentrasies neem vinnig af na die laagste limiet van
gehaltebepaling, 24 uur nadat die TDS verwyder is. Nadat die TDS verwyder is, was ‘n
serum halfleeftyd van ≈ 15 uur bepaal, wat ‘n vel-depoteffek aandui. Soos verwag kan
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word van transdermale vrystelling, was daar slegs ‘n verbygaande en beperkte toename in
serum-noretisteroonkonsentrasies na veelvoudige TDS- toedienings waargeneem.
Verligting van estrogeen-gebreksimptoom patrone (gegrond op inligting uit kliniese
proewe):
By gesonde postmenopousale vroue, 40 tot 65 jaar oud, was die vermindering van
vasomotoriese simptome na 3 maande van behandeling meer as 80 % en na een jaar meer
as 90 %.
Bloedingspatrone (gegrond op inligting uit kliniese proewe):
In ’n ewekansige navorsingstudie waar 153 postmenopousale vroue EVOREL SEQUI vir 1
jaar (13 x 28-dag behandelingsperiodes) ontvang het, het 88 % vroue bloeding ervaar; 6,5
% het amenorree gehad en 5 % slegs stippeling (die som van die persentasies is > 100 %
as gevolg van afronding). Van die vroue wat bloeding ervaar het, het 55 % gereelde
bloedingsepisodes na elke behandelingsperiode gehad. Die mediane aantal
bloedingsdae/jaar was 48.
Aan die einde van die proef het die mediane aantal warmgloede/dag wat aangemeld is,
beduidend verminder (met > 90 %) ten opsigte van dié aangemeld in die voor-
behandelingsperiode (P < 0.001). Geen warmgloede is by 80 % van die vroue aangemeld
nie. Minder as 2 % van die vroue het die proef verlaat vanweë onvoldoende beheer oor hul
vasomotoriese simptome.
Die toevoeging van progestogeen tot transdermale toediening, hetsy deurlopend of
opeenvolgend, blyk ’n doeltreffende en veilige alternatief te bied tot bykomende orale
opvolg-progestogeen in die behandeling van menopousale simptome.
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INDIKASIES
Hormoonvervangingsterapie (HVT) vir die verligting van menopousale simptome
(vasomotoriese simptome soos warmgloede, nagsweet en atrofiese vaginitis/vulvitis en/of
atrofiese uretritis) vir vroue met ‘n intakte uterus.
KONTRA-INDIKASIES
Bekende hipersensitiwiteit vir enige komponent van hierdie produk.
Bekende huidige, vorige, of vermoedelike borskanker.
Bekende of vermoedelike estrogeen-afhanklike maligne tumore (bv. endometriale
kanker) of pre-maligne tumore (bv. onbehandelde atipiese endometriale hiperplasie)
Ongediagnoseerde genitale bloeding
Swangerskap en laktasie
Akute lewersiekte, of ’n geskiedenis van lewersiekte solank as lewerfunksie toetse nog
nie na normaal teruggekeer het nie
Vorige of huidige veneuse tromboëmbolisme (diep-veneuse trombose, pulmonêre
embolisme)
Bekende trombofiliese toestande.
Aktiewe of onlangse arteriële tromboëmboliese siekte (bv. serebrovaskulêre voorval,
miokardiale infarksie).
WAARSKUWINGS
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Voor aanvang, en periodiek tydens estrogeen-vervangingsterapie word dit aanbeveel dat
die pasiënt ‘n volledige fisiese en ginekologiese ondersoek ondergaan. ‘n Volledige
mediese en familiegeskiedenis van tromboflebitis of tromboëmboliese siekte, moet bepaal
word. Herhaalde deurbraakbloeding, onverklaarbare vaginale bloeding en veranderings
tydens borsondersoeke waargeneem, verlang verdere evaluasie.
’n Deeglike bepaling van die risiko/voordeelverhouding moet onderneem word voordat
langtermyn- behandeling onderneem word.
Bewyse oor die risiko’s geassosieer met HVT vir die behandeling van voortydige
menopouse is beperk. Te wyte aan die lae vlak van absolute risiko by jonger vroue, kan die
voordeel-risiko balans egter by hierdie vroue meer gunstig wees as by ouer vroue.
Toestande waar toesig nodig is:
Indien enige van die volgende toestande teenwoordig is, voorheen voorgekom het en/of
erger geword het tydens swangerskap of vorige hormoonbehandeling, moet die pasiënt
deeglik gemoniteer word. Daar moet in ag geneem word dat hierdie toestande weer kan
voorkom met EVOREL SEQUI, veral:
Leiomioom (baarmoeder-veselspiergewasse) of endometriose.
Risikofaktore vir tromboëmboliese versteurings (kyk hieronder)
Risikofaktore vir estrogeen-afhanklike tumore, bv. eerstegraadse familielid met
borskanker
Hipertensie.
Lewersiektes (bv. lewer adenoom).
Diabetes mellitus.
Cholelitiase.
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Migraine of erge hoofpyn.
Sistemiese lupus eritematose.
’n Geskiedenis van endometriale hiperplasie (kyk hieronder) .
Epilepsie.
Mastopatie.
Toestande wat monitering verg terwyl estrogeenbehandeling ondergaan word:
Estrogene kan vog-retensie veroorsaak. Kardiale of renale disfunksie moet noukeurig
dopgehou word.
Versteurings of ligte inkorting van lewerfunksie.
Geskiedenis van cholestatiese geelsug.
Reeds bestaande hipertrigliseridemie. Seldsame gevalle van aansienlike toename in
plasma-trigliseriede, wat lei tot pankreatitis, is met estrogeen-behandeling waar hierdie
toestand teenwoordig is, aangemeld.
Redes vir onmiddellike onttrekking van terapie
Terapie moet gestaak word ingeval ’n kontraïndikasie ontdek word en met die volgende
toestande:
Geelsug of agteruitgang van lewerfunksie.
Beduidende toename in bloeddruk.
Nuwe-aanvang migraine-agtige hoofpyn.
Swangerskap
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Borskanker
Saamgevoegde bewyse dui op ’n verhoogde risiko vir borskanker, by vroue wat
gekombineerde estrogeen-progestageen en moontlik ook estrogeen-alleen HVT neem, wat
afhanklik is van die tydperk wat die HVT geneem is.
Kombinasie estrogeen-progestageen terapie:
Die ewekansige plasebo-gekontroleerde navorsingstudie, die “Women’s Health Initiative
study (WHI)” en epidemiologiese navorsingstudies is konsistent in hul bevinding dat daar ’n
verhoogde risiko vir borskanker is by vroue wat gekombineerde estrogeen-progestageen vir
HVT neem en dat dit eers duidelik word na ongeveer 3 jaar.
Estrogeen-alleen terapie:
Die WHI – navorsingstudie het geen toename in die risiko vir borskanker by vroue wat ’n
histerektomie gehad het en estrogeen-alleen HVT gebruik het, gevind nie. Waarneming-
studies het meestal gedui op ’n klein toename in risiko vir ’n borskanker-diagnose, wat
minder is as dié wat aangetref word by gebruikers van estrogeen-progestageen
kombinasies.
Die buitensporige risiko word duidelik binne ’n paar jaar van gebruik, maar keer terug na
basislyn binne ’n paar (hoogstens vyf) jaar vandat behandeling gestaak is. HVT, veral
estrogeen-progestageen gekombineerde behandeling, verhoog die digtheid van
mammografiese aftastings, wat die radiologiese opsporing van borskanker kan affekteer.
Ovariumkanker
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Ovariumkanker is baie meer seldsaam as borskanker. Langtermyn (ten minste 5 tot
10 jaar) gebruik van estrogeen-alleen HVT-produkte by vroue wat ’n histerektomie gehad
het, is geassosieer met ’n verhoogde risiko vir ovariumkanker in sommige epidemiologiese
navorsingstudies. Sommige navorsingstudies, ook die WHI-navorsingstudie, dui daarop
dat die langtermyn gebruik van gekombineerde HVT-produkte ’n soortgelyke of effens
kleiner risiko bied.
Veneuse tromboëmbolisme
Hormoonvervangingsterapie (HVT) word met ‘n relatief hoër risiko vir die ontstaan van
veneuse tromboëmbolisme (VTE), i.e. diepvenetrombose of pulmonêre embolisme,
geassosieer. Een ewekansige, beheerde proef en ook epidemiologiese studies, het ‘n twee-
tot drievoudige hoër risikoverhoging onder gebruikers, vergeleke met nie-gebruikers, getoon.
‘n Persoonlike of duidelike familiegeskiedenis van die herhaalde voorkoms van
tromboëmbolisme of herhaalde spontane aborsies moet ondersoek word om trombofiliese
vatbaarheid uit te sluit. Totdat ‘n deeglike evaluasie van trombofiliese faktore gemaak is, of
teenstolterapie begin is, moet die gebruik van HVT by sodanige pasiënte as teenaangewese
beskou word. Vroue wat alreeds op teenstolterapie is, benodig deeglike oorweging
aangaande die voordeel-risiko van gebruik van HVT.
Die risiko vir VTE kan tydelik hoër wees met langdurige immobilisering, ernstige trouma of
gevorderde sjirurgie. Sorgvuldige aandag moet aan profilaktiese maatreëls geskenk word
om VTE na sjirurgie te voorkom. Wanneer langdurige immobiliteit waarskynlik sal volg op
selektiewe sjirurgie, veral buik- of ortopediese sjirurgie aan die bene, moet dit oorweeg word
om indien moontlik HVT geruime tyd voor die sjirurgie te staak. Behandeling moet nie hervat
word voordat die vrou weer heeltemal beweeglik is nie.
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Indien VTE ontwikkel nadat behandeling begin is, moet EVOREL gestaak word. Pasiënte
moet aangeraai word om dadelik met hulle dokters in verbinding te tree as hulle bewus word
van ‘n moontlike tromboëmboliese simptoom (bv. pynlike swelling van ‘n been, skielike
borspyn, dispnee).
Kroonslagaarsiekte (KVS)
Estrogeen-alleen terapie:
Ewekansige gekontroleerde inligting het nie gedui op ’n verhoogde risiko vir KVS by vroue
wat ’n histerektomie gehad het en estrogeen-alleen terapie gebruik nie. Daar is groeiende
bewys dat die inleiding van estrogeen-alleen behandeling in die vroeë menopouse die
KVS-risiko kan verlaag.
Gekombineerde estrogeen-progestageen terapie:
Die relatiewe risiko vir KVS tydens die gebruik van gekombineerde estrogeen-
progestageen HVT is effens verhoog. Die absolute risiko vir KVS hang baie duidelik af van
die ouderdom. Die aantal addisionele gevalle van KVS te wyte aan estrogeen-
progestageen gebruik is baie min by gesonde vroue naby menopouse, maar dit sal
toeneem met ouderdom.
Beroerte
Daar is ’n verhoogde risiko vir beroerte by gesonde vroue tydens behandeling met HVT.
Gekombineerde estrogeen-progestageen en estrogeen-alleen terapie word geassosieer
met tot ’n 1,5-voudige toename in risiko vir iskemiese beroerte. Die relatiewe risiko
verander nie met ouderdom of tyd na menopouse nie. Aangesien die basislyn-risiko vir
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beroerte baie duidelik afhanklik is van ouderdom, neem die algehele risiko vir beroerte by
vroue wat HVT gebruik, toe met ouderdom.
Demensie
HVT verbeter nie kognitiewe funksie nie. Daar is ’n mate van getuienis van verhoogde risiko
vir moontlike demensie by vroue wat deurlopende gekombineerde of estrogeen-alleen HVT
na 65-jarige ouderdom begin gebruik.
Ander toestande
Daar is gerapporteer dat die toediening van ongeopponeerde estrogeen aan pasiënte met
’n uterus die risiko van endometriale hiperplasie en endometriale karsinoom verhoog.
Gevolglik word estrogeen in kombinasie met ’n progestogeen, soos met EVOREL SEQUI,
aanbeveel by vroue wat ’n uterus het, ten einde die risiko vir hiperplasie of endometriale
karsinoom te verminder.
Gesamentlike toediening van lamotrigien met medisyne wat etinielestradiol sowel as ’n
progestogeen bevat, soos EVOREL SEQUI, verhoog die risiko vir toevalle by epileptiese
pasiënte (kyk INTERAKSIES).
EVOREL SEQUI moet nie as voorbehoedmiddel gebruik word nie.
Die EVOREL SEQUI moet weggesteek word vir kinders.
INTERAKSIES
Medisyne wat die aktiwiteit van die mikrosomale lewerensieme induseer kan estrogeen- en
progesteroonmetabolisme verander. Voorbeelde van sulke middels is barbiturate,
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hidantoïene, karbamasepiem, meprobamaat, fenielbutasoon, rifampisien, rifabutien,
bosentaan en sekere nie-nukleosied omkeerbare transkriptaseremmers (bv. nevirapien en
efavirens).
Ritonavier en nelfinavier, alhoewel bekend as sterk inhibeerders van sitochroom P450
isoënsieme, vertoon daarteenoor induserende eienskappe wanneer dit saam met
steroïedhormone gebruik word. Geneesmiddelmetabolisme kan deur St. John’s wort
preparate (Hypericum perforatum) beïnvloed word, wat sekere sitochroom P450 iso-ensieme
in die lewer (bv. CYP3A4) asook P-glikoproteïne, induseer. Die induksie van hierdie P450
iso-ensieme kan die plasmakonsentrasie van die estrogeenkomponent in EVOREL verlaag,
wat moontlik ‘n afname in terapeutiese effek en ongeskeduleerde bloeding tot gevolg kan hê.
Met transdermale toediening word die eerste-deurgang effek in die lewer vermy en gevolglik
kan transdermaal-toegediende estrogene minder deur ensiem-induseerders aangetas word
as orale hormone. Dit is moontlik dat induksie van dieselfde iso-ensieme ook sirkulerende
konsentrasies van die progestienkomponent van EVOREL SEQUI kan verlaag met gevolglik
‘n verswakte beskermende effek teen estrogeen-geïnduseerde endometriale hiperplasie
Daar is aangetoon dat estrogeenbevattende orale voorbehoedmiddels die
plasmakonsentrasies van lamotrigien, wanneer dit gesamentlik toegedien word, beduidend
verlaag vanweë glukuronidering van lamotrigien. Dit kan beheer oor stuipe verminder.
Alhoewel die moontlike interaksie tussen estrogeen-bevattende
hormoonvervangingsterapie en lamotrigien nie bestudeer is nie, word dit verwag dat daar ’n
soortgelyke interaksie bestaan, wat kan lei tot verminderde beheer oor stuipe by vroue wat
albei middels saam gebruik. Gevolglik kan dit nodig wees om die dosis van lamotrigien aan
te pas (Sien WAARSKUWINGS).
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SWANGERSKAP EN LAKTASIE
Die gebruik van EVOREL SEQUI word teenaangedui tydens swangerskap en laktasie.
Indien swangerskap tydens medikasie met EVOREL SEQUI plaasvind moet behandeling
onmiddellik gestaak word.
DOSIS EN GEBRUIKSAANWYSINGS
Dosis
VOLWASSENES:
EVOREL 50 en EVOREL CONTI moet individueel in die volgende volgorde aangewend
word: vier EVOREL 50 TDS’e, gevolg deur vier EVOREL CONTI TDS’e. Die siklus moet
herhaal word sonder onderbreking. Die TDS’e moet twee keer per week, elke drie tot vier
dae, sonder onderbreking, aan die romp onder die middellyf geplak word.
Onvoldoende data is beskikbaar om leiding te gee vir dosisaanpassings vir pasiënte met
ernstige lewer- of nierfunksie ontoereikendheid.
Vir behandeling van post-menopousale simptome moet die laagste doeltreffende dosis
gebruik word. HVT moet nie vir langer as 5 jaar volgehou word nie.
Dit is belangrik dat die plakker in die regte volgorde gebruik word om gereelde sikliese
bloeding te verseker. Die meeste pasiënte sal vaginale bloeding ervaar na aanvang van
die progestogeen terapie.
Indien ’n plakker afval, moet dit dadelik met ’n nuwe soortgelyke EVOREL 50 of EVOREL
CONTI-plakker vervang word. Die gewone vervangingsdag moet egter behou word.
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Dit is nie nodig om die plakker met bad of stort te verwyder nie. Daar word egter aanbeveel
dat die plakker net voor ’n sauna-bad verwyder word en dat ’n nuwe plakker onmiddellik
daarna aangewend word.
Indien ’n plakker oorgeslaan is, moet die oorgeslaande plakker aangewend word sodra dit
onthou word. Die gewone dag vir omruil van plakkers moet egter behou word. As ’n dosis
vergeet word, kan daar ’n hoër kans wees vir deurbraak-bloeding en stippeling.
BEJAARDES:
Daar is onvoldoende data aangaande die gebruik van EVOREL SEQUI by bejaardes
(> 65 jaar).
Aanwysings vir gebruik/hantering
Die EVOREL SEQUI TDS moet op ’n skoon, droë, gesonde en heel area op die vel geplaas
word, op die romp van die liggaam onder die middel. Rome, velmiddels of poeiers kan die
kleefeienskappe van die plakker versteur. Die plakker moet nie op of naby die borste
aangewend word nie. Die plek waar dit toegedien word, moet afgewissel word, met ‘n
ruskans van ten minste een week vir ‘n spesifieke plek. Die gebied van die vel wat gekies
word, moet nie beskadig of geïrriteerd wees nie. Die middellyn moet nie gebruik word nie,
aangesien daar te veel wrywing met die plakker kan voorkom.
Die plakker moet onmiddellik nadat die sasjet oopgemaak is, gebruik word. Verwyder ‘n
gedeelte van die beskermende foelie. Plaas die oop kleefkant op die toedieningsarea - begin
plak van die kant af na die middel toe; verhoed dat voutjies in die plakker gemaak word. Die
ander deel van die beskermende foelie moet nou afgehaal word en die nuut-ontblote
gedeelte van die oop kleefkant geplak word. Voorkom dat kreukels vorm en gebruik die
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handpalm om die plakker op die vel vas te druk en ook om die plakker veltemperatuur te laat
bereik; dan is die kleefeienskappe van die plakker optimaal.
Die pasiënt moet tydens die toediening van die plakker enige vingeraanraking met die
kleefkant van die plakker vermy.
Indien ‘n plakker afval, moet ‘n nuwe soortgelyke EVOREL 50 of EVOREL CONTI-plakker
dadelik aangewend word. Die gebruiklike dag van plakkervervanging moet egter behou
word. Dit is nie nodig om die plakker af te haal tydens ‘n bad of stort nie. Dit word egter
aanbeveel dat die plakker voor ‘n sauna bad afgehaal word en ‘n nuwe plakker dadelik
daarna aangewend word.
Wanneer EVOREL SEQUI vir die eerste twee weke gebruik word, moet een van die
EVOREL 50 plakkers aangewend word en twee-weekliks vervang word. Gedurende die
twee weke van EVOREL SEQUI, moet een van die EVOREL CONTI plakkers aangewend
word en ook twee-weekliks vervang word. Die pasiënt begin dan met ’n nuwe karton
EVOREL SEQUI.
Om die EVOREL plakker af te haal, lig dit op by die rand en trek egalig van die vel af. Die
EVOREL plakker moet toegevou word en met die huishoudelike vullis weggedoen word
(moenie in die toilet afspoel nie).
Enige gom wat aan die vel agterbly na verwydering van die plakker, kan verwyder word deur
met seep en water te was of dit met die vingers af te vryf.
NEWE-EFFEKTE EN SPESIALE VOORSORGSMAATREËLS
Newe-effekte
Kliniese proef data
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Die veiligheid van EVOREL SEQUI is geëvalueer by 165 pasiënte in
2 aktief-gekontroleerde kliniese proewe. Ongunstige geneesmiddelreaksies (OGRs)
aangemeld by ≥ 1 % van die pasiënte wat met EVOREL SEQUI behandel is, word in Tabel
1 weergegee..
Tabel 1. Ongunstige geneesmiddelreaksies wat by ≥ 1 % van
die pasiënte aangemeld is wat met EVOREL SEQUI behandel is
in 2 EVOREL SEQUI - kliniese proewe
Sisteem/Orgaanklas
EVOREL
SEQUI
%
(N = 165)
Psigiatriese siektes
Depressie
Slaaploosheid
Senuweeagtigheid
Affek wisseling
5,5
3,6
2,4
1,2
Senuweestelsel siektes
Hoofpyn
7,9
Vaskulêre siektes
Hipertensie
4,2
Gastroïntestinale siektes
Buikpyn
4,9
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Maagdermkanaal aandoening
Naarheid
1,8
1,8
Vel- en onderhuidse weefsel siektes
Pruritus
Uitslag - eritemateus
1,2
1,2
Skeletspier en bindweefsel siektes
Artralgie
2,4
Voortplantingstelsel en bors siektes
Pynlike borste
Menorragie
Dismenorree
Menstruele siekte
6,1
3,0
1,2
1,2
Algemene siektes en toestande by die
plek van toediening
Reaksie by plek van toediening
Edeem
Siek gevoel
14,6
2,4
1,8
Ondersoeke
Gewigstoename
3,0
OGRs aangemeld deur < 1 % van die pasiënte wat met EVOREL SEQUI behandel is (N =
165) in die bogenoemde kliniese proef datastel, word in Tabel 2 weergegee.
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Tabel 2. Ongunstige geneesmiddelreaksies aangemeld deur <
1 % pasiënte wat met EVOREL SEQUI behandel is in 2 EVOREL
SEQUI- kliniese proewe
Sisteem/orgaanklas Newe-effek
Neoplasmas goedaardig,
kwaadaardig en
ongespesifiseer
(Insluitende siste en
poliepe)
Borskanker by vroue,
Fibroadenoom van bors
Psigiatriese siektes Libido neem af, libido neem
toe
Senuweestelsel siektes Aandag versteurd,
Duiseligheid
Voortplantingstelsel en
bors siektes
Endometrium hiperplasie,
Metrorragie
Algemene siektes en
toestande by die plek van
toediening
Moegheid
Verdere OGRs wat vermeld word in kliniese proewe met EVOREL (estradiol-alleen) by
postmenopousale vroue, word in Tabel 3 weergegee.
Tabel 3. Ongunstige geneesmiddelreaksies aangemeld by
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pasiënte wat met EVOREL behandel is (N = 2584) in 15
EVOREL -kliniese proewe
Sisteem/Orgaanklas Newe-effek
Infeksies en infestasies Genitale kandidiase
Neoplasmas goedaardig,
kwaadaardig en
ongespesifiseer (insluitend
siste en poliepe)
Borskanker
Immuunstelsel siektes Hipersensitiwiteit
Senuweestelsel siektes Epilepsie
Hartsiektes Palpitasies
Vaskulêre siektes Trombose
Gastroïntestinale siektes Diarree, winderigheid
Vel- en onderhuidse
weefsel siektes
Uitslag
Skeletspier en bindweefsel
siektes
Mialgie
Algemene siektes en
toestande by die plek van
toediening
Uitslag by plek van
toediening *
Pruritus by plek van
toediening *
Eriteem by plek van
toediening *
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Edeem by plek van
toediening *
Perifere edeem,
Pyn
* Tekens/ simptome op navraag (aangeteken as ja/nee) in 8
kliniese proewe met EVOREL (N = 1 739).
Data na bemarking:
Ongunstige geneesmiddelreaksies wat eers tydens ervaring na bemarking met estradiol
waargeneem is, word by Tabel 4 weergegee.
Tabel 4
Ongunstige geneesmiddelreaksies, waargeneem met estradiol en
noretisteroon met ervaring na bemarking, geskat uit die spontane
aanmeldings
Sisteem/Orgaanklas Newe-effek
Infeksies en infestasies Kandidiase
Neoplasmas goedaardig,
kwaadaardig en ongespesifiseer
(insluitend siste en poliepe)
Endometriale kanker
Immuunstelsel siektes Hipersensitiwiteit
Psigiatriese siektes Gemoed skommelings
Senuweestelsel siektes Serebrovaskulêre voorval
Migraine
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Parestesie
Hartsiektes Palpitasies
Vaskulêre siektes Diep-veneuse trombose
Respiratoriese, bors- en
mediastinale siektes
Pulmonêre embolisme
Gastroïntestinale siektes Buik opgehewe
Hepatobiliêre siektes Cholelitiase
Vel- en onderhuidse weefsel
siektes
Stevens-Johnson-siekte
Skeletspier, bindweefsel en been
siektes
Rugpyn
Voortplantingstelsel en bors
siektes
Borste vergroot
Algemene siektes en toestande
by die plek van toediening
Eriteem by plek van toediening,
Pruritus by plek van toediening
Uitslag by plek van toediening
BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE
BEHANDELING DAARVAN
Simptome van oordosering van estrogeen en progestogeenterapie kan insluit: naarheid,
deurbraak-bloeding, bors-teerheid, buikkrampe en/of opgeblaasdheid . Hierdie simptome
kan omgekeer word deur die transdermale plakker te verwyder.
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IDENTIFIKASIE
EVOREL SEQUI bestaan uit EVOREL 50 en EVOREL CONTI.
EVOREL 50 is ‘n buigbare, vierkantige, kleurlose plakker van 16 cm2 met konvekse kante en
geronde hoeke. Die klewerige deel van die plakker is bedek met ‘n beskermde foelie met ‘n
S-vormige insnyding. Elke TDS is gemerk in die middel van die onderste kantlyn van die
agterste film: CE50
EVOREL CONTI is ‘n buigbare, vierkantige, kleurlose plakker van 16 cm2 met konvekse
kante en geronde hoeke. Die klewerige deel van die plakker is bedek met ‘n beskermde
foelie met ‘n S-vormige insnyding. Elke TDS is gemerk in die middel van die onderste kantlyn
van die agterste film: CEN1
AANBIEDING
Een EVOREL SEQUI houer bevat 4 EVOREL 50 TDS en 4 EVOREL CONTI TDS,
individueel verpak in sakkies wat met foelie uitgevoer is.
Die sakkie bestaan uit 4 gelamineerde lae insluitende ‘n aluminium versperring en ‘n
buitenste papier oppervlak.
BERGINGSAANWYSINGS
Bewaar teen of benede 25 °C. Moenie vries nie.
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CCDS: 09 June 2011 Page 52 of 52
HOU BUITE BEREIK VAN KINDERS.
REGISTRASIENOMMER
31/21.8.2/0538
NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIE SERTIFIKAAT
JANSSEN PHARMACEUTICA (EDMS) BPK
(Regnr. 1980/011122/07)
Building 6, Country Club Estates
21 Woodlands Drive, Woodmead, 2191
www.janssen.co.za
DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET
Janaury 2012