package insert scheduling status proprietary … · evorel sequi is a transdermal 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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CCDS: 09 June 2011 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


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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


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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.


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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.


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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


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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.


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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.


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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.


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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.


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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


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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


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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.


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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.


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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,


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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).


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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 postmenopausal 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.


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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.


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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).


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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


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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.


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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


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



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


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



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

http://www.janssen.co.za/


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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


____________________________________________________________


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


____________________________________________________________


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


____________________________________________________________


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.


____________________________________________________________


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


____________________________________________________________


pasiënte wat met EVOREL behandel is (N = 2584) in 15

EVOREL -kliniese proewe

Sisteem/Orgaanklas Newe-effek

Infeksies en infestasies Genitale kandidiase


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 *


____________________________________________________________


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


kwaadaardig en ongespesifiseer

(insluitend siste en poliepe)

Endometriale kanker

Immuunstelsel siektes Hipersensitiwiteit

Psigiatriese siektes Gemoed skommelings

Senuweestelsel siektes Serebrovaskulêre voorval

Migraine


____________________________________________________________


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.


____________________________________________________________


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.


____________________________________________________________


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

http://www.janssen.co.za/

package insert scheduling status proprietary … · evorel sequi is a transdermal therapy...

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