acrylate vinylacetate-copolymer (adhesive), guar gum (absorbent), polyethylene terephathalate foil

Transcription

1 SCHEDULING STATUS Schedule 4 PROPRIETARY NAME (and dosage form) EVOREL 25 Transdermal Delivery System (TDS) EVOREL 5 Transdermal Delivery System (TDS) EVOREL 75 Transdermal Delivery System (TDS) EVOREL 1 Transdermal Delivery System (TDS) EVOREL is a matrix type transdermal patch. COMPOSITION EVOREL 25 (8 cm 2 ) patch contains 1,55 mg of oestradiol, formulated as 1,6 mg of oestradiol hemihydrate. EVOREL 5 (16 cm 2 ) patch contains 3,1 mg oestradiol, formulated as 3,2 mg of oestradiol hemihydrate. EVOREL 75 (24 cm 2 ) patch contains 4,65 mg oestradiol, formulated as 4,8 mg of oestradiol hemihydrate. EVOREL 1 (32 cm 2 ) patch contains 6,2 mg oestradiol, formulated as 6,4 mg of oestradiol hemihydrate. EVOREL TDS contains oestradiol hemihydrate as active ingredient. Inactive ingredients include: acrylate vinylacetate-copolymer (adhesive), guar gum (absorbent), polyethylene terephathalate foil (backing film). PHARMACOLOGICAL CLASSIFICATION A Oestrogens. PHARMACOLOGICAL ACTION EVOREL contains oestradiol hemihydrates (17β-oestradiol) which is a synthetically prepared oestrogen. CCDS: 9 June 211 Page 1 of 28

2 Pharmacodynamics Transdermal Delivery Systems deliver the hormone 17β-oestradiol into the systemic circulation. 17β-oestradiol, as in EVOREL provides a constant, controlled release of hormone for several days. The 17β-oestradiol does not undergo first-pass liver metabolism. Oestrogens are derived by aromatization of the A-ring mainly in the follicle apparatus in the ovary. Oestradiol is the main oestrogen of the ovary. The molecular mechanism of oestradiol action in the target organ oestrogen receptor sites follows the known mechanism of steroid-hormone action. Oestradiol binds to the intracellular receptors. An oestradiol-receptor complex is formed and various metabolic changes are induced, which leads to tissue differentiation and growth. The oestradiol/oestrone ratio in the plasma of post-menopausal women is between,2 and,5 which increases after transdermal application of oestradiol to approximately 1 (normal pre-menopausal levels, early follicular phase). Pharmacokinetics Serum oestradiol concentrations achieved in postmenopausal women following application of EVOREL are directly proportional to the size (dose) of the patches. Concentrations, averaged over an entire 4-day application period were approximately 23; 44; 71 and 11 pg/ml above baseline for EVOREL 25; 5; 75 and 1. Forty-eight hours after removal of the patch, oestradiol serum concentration returns to the baseline. Oestradiol's most important metabolites are oestriol/oestrone and conjugates (glucuronide and sulphate) which are far less active than oestradiol and undergo enterohepatic recirculation. Overall, 6-8 % of the oestrogens are excreted via the urine and 1 % via the faeces. The elimination half-life of the oestradiol in the plasma is approximately 1 hour. CCDS: 9 June 211 Page 2 of 28

3 INDICATIONS Treatment of symptoms associated with the menopause, either due to menopausal cessation of oestrogen production and secretion or surgical removal of the ovaries. In women with an intact uterus, a progestagen must be used as adjunct therapy for the prevention of endometrial hyperplasia and cancer. Prevention of oestrogen dependent post-menopausal osteoporosis. CONTRA-INDICATIONS Known hypersensitivity to oestrogen or to any of the inactive ingredients of this product. Known current or past or suspected breast cancer. Known or suspected oestrogen dependant malignant tumours (e.g. endometrial cancer) or pre-malignant tumours (e.g. untreated atypical endometrial hyperplasia). Undiagnosed genital bleeding. EVOREL must not be used during pregnancy or lactation. Active 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 previous arterial thromboembolic disease (e.g. cerebrovascular accident, myocardial infarction). Endometriosis Porphyria WARNINGS and SPECIAL PRECAUTIONS Before starting, and periodically during EVOREL therapy, it is recommended that the patient be given a thorough physical and gynaecological examination. A complete medical and family history of venous or arterial thrombophlebitis or thromboembolic disorders should be taken. Repeated breakthrough bleeding, unexpected vaginal bleeding and changes noticed during breast examination require further evaluation. CCDS: 9 June 211 Page 3 of 28

4 A careful appraisal of the risk/benefit ratio should be undertaken before initiation of long-term treatment with EVOREL. 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, in particular: Leiomyoma (uterine fibroids) or endometriosis. Risk factors for thromboembolic disorders (see below). Risk factors for oestrogen dependent tumours, 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. A history of endometrial hyperplasia (see below). Epilepsy. Mastopathy. Conditions which require monitoring while on oestrogen therapy: Oestrogens such as EVOREL 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. Cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy such as EVOREL in this condition. Reasons for immediate withdrawal of therapy: CCDS: 9 June 211 Page 4 of 28

5 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. Endometrial hyperplasia The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods to women with an uterus. Oestrogen-only therapy in women with a uterus has been estimated to increase the risk of endometrial cancer with effects persisting for several years after oestrogen is stopped. To reduce, this risk, it is recommended that oestrogen therapy is combined with a progestagen for 12 to 14 days per cycle in non-hysterectomised women. Such a sequential oestrogen/oestrogen + progestagen regimen results in cyclic bleeding in the majority of women. Women with an intact uterus who cannot tolerate or use a progestagen, should not use EVOREL. Break-through bleeding and spotting may occur. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy. Unopposed oestrogen stimulation such as EVOREL may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of a progestagen to EVOREL therapy should be considered in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis. For patches > 5 μg/day, the addition of progestagens have not been demonstrated to protect against endometrial changes. Breast Cancer The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-progestagen and also oestrogen-only HRT. Combined oestrogen-progestagen therapy: CCDS: 9 June 211 Page 5 of 28

6 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. 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 Long- term (5 years or more) use of oestrogen-only HRT products such as EVOREL in hysterectomised women has been associated with an increased risk of ovarian cancer. Venous thromboembolism Hormone replacement therapy (HRT) is associated with a higher risk of developing venous thromboembolism (VTE), such as deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. Personal or a 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 EVOREL in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of EVOREL. 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, EVOREL treatment should be discontinued well ahead of surgery, if possible. Treatment should not be restarted until after the woman is completely mobilised. CCDS: 9 June 211 Page 6 of 28

7 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 therapy: Randomised controlled data found no protective effect in hysterectomised women of oestrogen-only therapy for the risk of CAD. Combined oestrogen-progestagen therapy: The relative risk of CAD during use of combined oestrogen-progestagen HRT is increased. Stroke Combined oestrogen-progestagen and oestrogen-only therapy such as EVOREL are associated with an up to 1,5-fold increase in risk of ischaemic stroke. Dementia HRT use does not improve cognitive function. There is evidence of increased risk of dementia in women who start using continuous combined or oestrogen-only HRT such as EVOREL. Other Conditions EVOREL is not to be used as contraception. Keep EVOREL away from children. INTERACTIONS Medicines with a high potential for liver enzyme induction, [e.g. barbiturates, hydantoin, carbamazepine, meprobamate, phenylbutazone, rifampicin, rifabutin, bosentan and certain nonnucleoside reverse inhibitors used in HIV treatments (e.g. nevirapine and efavirenz)] may interfere with the actions of EVOREL and decrease the efficacy of EVOREL. Ritonavir and nelfinavir, although known as strong inhibitors of the cytochrome P45 isoenzymes, by CCDS: 9 June 211 Page 7 of 28

8 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 P45 isoenzymes in the liver (e.g. CYP3A4) as well as P-glycoprotein. The induction of the P45 isoenzymes may reduce plasma concentrations of the oestrogen component of EVOREL possibly resulting in a decrease in therapeutic effects and increased vaginal bleeding. Estrogen-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 EVOREL 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 medicines together. Therefore, dosage adjustment of lamotrigine may be necessary. PREGNANCY AND LACTATION The use of EVOREL is contra-indicated in pregnancy or lactation. If pregnancy occurs during medication with EVOREL, treatment should be withdrawn immediately. DOSAGE AND DIRECTIONS FOR USE Adults In patients using oral oestrogens, treatment with EVOREL can be initiated one week after withdrawal. EVOREL should be applied twice weekly, i.e. the patch should be changed every 3 to 4 days. EVOREL is administered in a cyclic manner, 3 weeks of treatment (6 applications) followed by an interval of one week without treatment. During this treatment free week vaginal withdrawal bleeding may occur. Continuous non-cyclic therapy may be indicated in hysterectomised women and if climacteric symptoms occur during the treatment free week. Treatment is usually initiated with EVOREL 5. In further treatment courses, the dosage should be individually adapted. For treatment of post-menopausal symptoms the lowest effective dose should be used. EVOREL should not be continued for longer than 5 years. EVOREL 25 should be administered only to those patients who cannot tolerate the higher dose CCDS: 9 June 211 Page 8 of 28

9 Breast discomfort, breakthrough bleeding, water retention or bloating (if persisting for more than 6 weeks) are generally signs that the dose is too high and needs to be lowered. If, after 2 to 3 weeks, the dose selected fails to eliminate the signs and symptoms of oestrogen deficiency, a higher dose should be given. For maintenance one should always use the lowest effective dose therapy. For prevention of bone loss, EVOREL 5, 75 or 1 are recommended. The dose of 1 µg of oestradiol/24 hours should not be exceeded. Note that for women with a uterus, EVOREL 75 and EVOREL 1 are not recommended, as the endometrial safety of added progestagen has not been studied for transdermal doses of oestradiol above 5 µg/day. Insufficient data are available to guide dose adjustments for patients with severe liver or kidney function impairment. Progestagen treatment is recommended in any woman with a uterus: during 12 to 14 consecutive days of the calendar month during uninterrupted EVOREL treatment. or during the last 12 to 14 days (i.e. starting on cycle days 8 or 1) of the 21 day cycle during which treatment with EVOREL is provided., If there is a previous diagnosis of endometriosis, the addition of a progestagen to EVOREL may be considered also for hysterectomised women. Vaginal bleeding will normally occur after the start of the progestrogen treatment. Elderly Data are insufficient in regard to the use of EVOREL in the elderly (> 65 years old). Administration instructions The EVOREL patch 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 CCDS: 9 June 211 Page 9 of 28

10 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 of excessive rubbing of the patch may occur. The patch should be used immediately after opening the sachet. Remove one part of the protecting foil. Apply the exposed part of the 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 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 optimised. The patient should avoid contact between fingers and the adhesive part of the patch during application. Should a patch fall off, a new patch should be applied immediately. However, the usual day of changing patches should be maintained. It is not necessary to remove the patch during bathing and showering. It is recommended, however, that the patch be removed prior to sauna bath, and the 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. To remove a patch, peel away the edge of the patch and pull smoothly away from the skin. The patch should be folded and disposed of in the household waste (do not flush down the toilet). Any adhesive that remains on the skin after removal of the patch may be removed by washing with soap and water or rubbing it off with the fingers. SIDE EFFECTS Clinical Trial Data Table 1: Adverse Reactions Reported by 1 % of EVOREL treated Subjects and With an Incidence Greater Than in Placebo-treated Subjects in 1 Double-blind, Placebo-Controlled Clinical Trial of EVOREL in 12 women CCDS: 9 June 211 Page 1 of 28

11 System/Organ Class EVOREL % (N = 12) Placebo % (N = 52) Infections and Infestations Genital candidiasis 8,8 Immune System Disorders Hypersensitivity 2,9 1,9 Nervous System Disorders Headache Dizziness 2,6 1, 19,2 Cardiac Disorders Palpitations 1, Gastrointestinal Disorders Flatulence Diarrhoea 4,9 1, Skin and Subcutaneous Tissue Disorders Pruritus Rash 3,9 2,9 1,9 Musculoskeletal and Connective Tissue Disorders Myalgia Arthralgia 5,9 2, Reproductive System and Breast Disorders Breast pain Metrorrhagia Dysmenorrhoea 12,7 6,9 2,9 3,9 1,9 General Disorders and Administration Site Conditions Pain Peripheral oedema Generalised oedema Oedema 7,8 5,9 3,9 2,9 3,9 1,9 1,9 Investigations Increased weight 3,9 Adverse drug reactions not reported in Table 1 that were reported by 1 % of EVOREL treated subjects (N = 2 584) in 15 clinical trials of EVOREL are shown in Table 2. Table 2: Adverse Reactions Reported by 1 % of EVOREL treated Subjects in 15 Clinical Trials of CCDS: 9 June 211 Page 11 of 28

12 EVOREL EVOREL System/Organ Class % (N = 2 584) Gastrointestinal Disorders Nausea 2,4 Abdominal pain 1,8 General Disorders and Administration Site Conditions Application site rash* 2,8 # Application site pruritus* 19,8 # Application site erythema* 8,5 # Application site reaction 3,3 Application site oedema* 1,6 # * Solicited signs/symptoms (recorded as yes/no) in 8 clinical trials of EVOREL. # Percentages based on N = in 8 clinical trials of EVOREL Adverse Drug Reactions reported by < 1 % of EVOREL treated subjects (N = 2 584) in the above clinical trial dataset are shown in Table 3 Table 3: Adverse Drug Reactions Reported by < 1 % of EVOREL treated Subjects in 15 Clinical Trials of EVOREL Neoplasms benign, malignant and unspecified (Incl. cysts and polyps) Nervous system disorders Vascular disorders Breast cancer Epilepsy Arterial or venous thrombosis Post-marketing Data Adverse reactions first identified during post-marketing experience with EVOREL are included in Table 4: Table 4: Adverse Reactions Identified during Post-Marketing experience with EVOREL Neoplasms Benign, Malignant and Unspecified (Incl. Cysts and Polyps) Psychiatric Disorders Nervous System Disorders Endometrial cancer Depressed mood Cerebrovascular accident, migraine CCDS: 9 June 211 Page 12 of 28

13 Cardiac Disorders Vascular disorders, Respiratory, Thoracic and Mediastinal Disorders Gastrointestinal Disorders Hepatobiliary Disorders Skin and Subcutaneous Tissue Disorders Reproductive System and Breast Disorders Myocardial infarction Deep vein thrombosis Pulmonary embolism Abdominal distension Cholelithiasis Angioedema Breast enlargement KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT Symptoms of overdose may include breast pain or tenderness, nausea, break-through bleeding, abdominal cramps and/or bloating. Removing the patch can reverse these symptoms. Treatment is symptomatic and supportive. IDENTIFICATION EVOREL 25 is an adhesive patch of 8 cm 2 with rounded corners. The outside of the backing film is marked CE 25 in the centre of the lower margin. EVOREL 5 is an adhesive patch of 16 cm 2 with rounded corners. The outside of the backing film is marked CE 5 in the centre of the lower margin. EVOREL 75 is an adhesive patch of 24 cm 2 with rounded corners. The outside of the backing film is marked CE 75 in the centre of the lower margin. EVOREL 1 is an adhesive patch of 32 cm 2 with rounded corners. The outside of the backing film is marked CE 1 in the centre of the lower margin. The adhesive surface of the patch is covered with a protective foil with an S-shaped incision. PRESENTATION Cartons containing one or more patches. Each patch is sealed in a pouch. STORAGE INSTRUCTIONS Store at or below 25 C. Do not freeze. KEEP OUT OF REACH OF CHILDREN. CCDS: 9 June 211 Page 13 of 28

14 REGISTRATION NUMBERS 25, 75, 1-3/21.8.1/27/8/9 5 - Z/21.8.1/339 Nam. Reg. No.: 25, 5, 75, 1 4/21.8.1/278/9/8/81 NS 1 Botswana Reg No.: 5 BOT9767 S2 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION JANSSEN PHARMACEUTICA (Pty) Ltd (Reg. No.: 198/11122/7) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) RA-JACZA-Medinfo@its.jnj.com DATE OF PUBLICATION OF THIS PACKAGE INSERT August 214 CCDS: 9 June 211 Page 14 of 28

15 SKEDULERINGSTATUS Skedule 4 HANDELSNAAM (en doseervorm) EVOREL 25 Transdermale leweringstelsel (TDS) EVOREL 5 Transdermale leweringstelsel (TDS) EVOREL 75 Transdermale leweringstelsel (TDS) EVOREL 1 Transdermale leweringstelsel (TDS) EVOREL is 'n matrikstipe transdermale plakker. SAMESTELLING EVOREL 25 (8 cm 2 ) plakker bevat 1,55 mg estradiol, geformuleer as 1,6 mg estradiolhemihidraat. EVOREL 5 (16 cm 2 ) plakker bevat 3,1 mg estradiol, geformuleer as 3,2 mg estradiolhemihidraat. EVOREL 75 (24 cm 2 ) plakker bevat 4,65 mg estradiol, geformuleer as 4,8 mg estradiolhemihidraat. EVOREL 1 (32 cm 2 ) plakker bevat 6,2 mg estradiol, geformuleer as 6,4 mg estradiolhemihidraat. EVOREL TDS bevat estradiolhemihidraat as die aktiewe bestanddeel. Die onaktiewe bestanddele sluit in: akrilaat-vinielasetaat-kopolimeer (kleefmiddel), guargom (absorbeerder), poliëtileen tereftalaatfoelie (steunlaag). FARMAKOLOGIESE KLASSIFIKASIE A Estrogene. FARMAKOLOGIESE WERKING EVOREL bevat estradiolhemihidraat (17ß-estradiol) wat 'n sinteties-bereide estrogeen is. Farmakodinamika Transdermale leweringstelsels lewer die hormoon 17β-estradiol aan die sistemiese sirkulasie. 17β-estradiol, soos in EVOREL, voorsien 'n konstante, gekontroleerde vrystelling van die hormoon vir etlike dae. Die 17β-estradiol ondergaan nie eerste-deurgang lewermetabolisme nie. CCDS: 9 June 211 Page 15 of 28

16 Estrogene word verkry deur die aromatisering van die A-ring, hoofsaaklik in die follikelapparaat in die ovarium. Estradiol is belangrikste estrogeen van die ovarium. Die molekulêre meganisme van estradiolwerking op die teikenorgaan se estrogeen-reseptorareas volg die bekende meganisme van steroïedhormoonwerking. Estradiol bind aan die intrasellulêre reseptore. 'n Estradiol-reseptorkompleks word gevorm en verskeie metaboliese veranderinge word veroorsaak, wat lei tot weefseldifferensiasie en groei. Die estradiol/estroonverhouding in die plasma van postmenopousale vroue is tussen,2 en,5 en dit neem toe na transdermale aanwending van estradiol tot ongeveer 1 (normale pre-menopousale vlakke, vroeë follikulêre fase). Farmakokinetika Die serum-estradiolkonsentrasies wat by postmenopousale vroue na aanwending van EVOREL bereik word, is direk eweredig aan die grootte (dosis) van die plakkers. Die gemiddelde konsentrasies, bepaal oor 'n hele 4-dag toedieningsperiode, was ongeveer 23; 44; 71 en 11 pg/ml bo basislyn vir EVOREL 25, 5, 75 en 1. Agt en veertig uur na verwydering van die plakker, val die estradiolkonsentrasie in die serum terug tot die basislyn. Estradiol se belangrikste metaboliete is estriol/estroon en konjugate (glukuronied en sulfaat), wat heelwat minder aktief is as estradiol en wat enterohepatiese hersirkulasie ondergaan. Algeheel word 6-8 % van die estrogene deur die urien en 1 % deur die ontlasting uitgeskei. Die eliminasie-halfleeftyd van die estradiol in die plasma is ongeveer 1 uur. INDIKASIES Behandeling van simptome wat verband hou met die menopouse, hetsy weens staking van estrogeenvervaardiging en -afskeiding, of chirurgiese verwydering van die ovaria. CCDS: 9 June 211 Page 16 of 28

17 By vroue met 'n ongeskonde baarmoeder moet 'n progestageen as bykomende behandeling vir die voorkoming van hiperplasie van die endometrium en kanker gebruik word. Voorkoming van estrogeen-afhanklike postmenopousale osteoporose. KONTRA-INDIKASIES Bekende hipersensitiwiteit vir estrogeen of vir enige van die onaktiewe bestanddele van hierdie produk. Bekende huidige, of vorige, of vermeende borskanker. Bekende of vermeende estrogeengevoelige kwaadaardige gewasse (bv. endometriumkanker) of pre-maligne gewasse (bv. onbehandelde atipiese hiperplasie van die endometrium). Ongediagnoseerde genitale bloeding. EVOREL moet nie tydens swangerskap of borsvoeding gebruik word nie. Akute lewersiekte, of 'n geskiedenis van lewersiekte, solank die lewerfunksiewaardes nie genormaliseer het nie. Veneuse tromboëmbolisme (diepvenetrombose, pulmonêre embolisme), tans of voorheen. Bekende trombofiele aandoenings. Aktiewe of onlangse arteriële tromboëmboliese siektetoestand (bv. serebrovaskulêre voorval, miokardiale infarksie). Endometriose. Porfirie WAARSKUWINGS en SPESIALE VOORSORGMAATREËLS Dit word aanbeveel dat die pasiënt voor behandeling met EVOREL en ook periodiek tydens behandeling, 'n deeglike fisiese en ginekologiese ondersoek ondergaan. 'n Volledige mediese en familiegeskiedenis van veneuse of arteriële tromboflebitis of tromboëmboliese versteurings moet geneem word. Herhaalde deurbraakbloeding, onverwagte vaginale bloeding en veranderinge wat tydens borsondersoek opgemerk word, verg verdere evaluering. 'n Deeglike evaluering van die risiko/voordeel-verhouding moet voor aanvang van langtermynbehandeling met EVOREL onderneem word. CCDS: 9 June 211 Page 17 of 28

18 Toestande wat toesig verg: Indien enige van die volgende toestande teenwoordig is, voorheen plaasgevind het, en/of vererger het tydens swangerskap of vorige hormoonbehandeling, moet daar deeglik toesig gehou word oor die pasiënt. Dit moet in ag geneem word dat hierdie toestande weer kan voorkom, of vererger kan word tydens behandeling met EVOREL, veral: Leiomioom (baarmoederveselspiergewasse) of endometriose. Risikofaktore vir tromboëmboliese versteurings (kyk onder). Risikofaktore vir estrogeengevoelige gewasse, bv. eerstegraadse familielid met borskanker. Hipertensie. Lewerversteurings (bv. leweradenoom). Diabetes mellitus. Cholelitiase. Migraine, of ernstige hoofpyn. Sistemiese lupus eritematose. 'n Geskiedenis van endometriumhiperplasie (kyk onder). Epilepsie. Mastopatie. Toestande wat monitering tydens estrogeenbehandeling vereis: Estrogene soos EVOREL kan vloeistofretensie veroorsaak. Kardiale of renale disfunksie moet deeglik dopgehou word. Versteurde of effens verswakte lewerfunksie. 'n Geskiedenis van cholestatiese geelsug. Reeds bestaande hipertrigliseridemie. Gevalle van groot toename in plasmatrigliseriede, wat lei tot pankreatitis, is by hierdie toestand met estrogeenbehandeling, soos EVOREL, aangemeld. Redes vir onmiddellike onttrekking van behandeling: Behandeling moet gestaak word in geval daar 'n kontra-indikasie ontdek word en ook onder die volgende omstandighede: Geelsug of agteruitgang van die lewerfunksie. Beduidende toename in bloeddruk. CCDS: 9 June 211 Page 18 of 28

19 Nuwe aanvang van migraine-tipe hoofpyn. Swangerskap. Hiperplasie van die endometrium. Die risiko van hiperplasie van die endometrium en karsinoom is hoër wanneer estrogene vir 'n onbepaalde tyd alleen toegedien word aan vroue met 'n baarmoeder. Daar word beraam dat estrogeen-alleen behandeling by vroue met 'n uterus die risiko van kanker van die endometrium verhoog, met gevolge wat vir etlike jare nadat die estrogeen gestaak is, voortduur. Om hierdie risiko te verminder, word aanbeveel dat estrogeenbehandeling met 'n progestageen gekombineer word vir 12 tot 14 dae per siklus by vroue wat nie 'n histerektomie gehad het nie. So 'n opeenvolgende estrogeen/estrogeen + progestageen doseringsplan lei tot sikliese bloeding by die meeste vroue. Vroue met 'n intakte uterus wat nie progestageen kan gebruik of verdra nie, moet nie EVOREL gebruik nie. Deurbraakbloeding en spikkelbloeding kan voorkom. Indien daar met verloop van tyd deurbraakbloeding of spikkelbloeding met die behandeling voorkom, of as dit voortduur nadat die behandeling gestaak is, moet die rede ondersoek word; dit kan biopsie van die endometrium insluit om endometriumkanker uit te sluit. Ongeopponeerde stimulasie deur 'n estrogeen soos bv. EVOREL kan lei tot pre-maligne of maligne transformasie in die residuele foci van endometriose. Daarom moet die toevoeging van 'n progestageen by die behandeling met EVOREL oorweeg word by vroue wat 'n histerektomie as gevolg van endometriose ondergaan het, veral as dit bekend is dat hulle oorblywende endometriose het. Daar is nie vir plakkers > 5 µg/dag aangetoon dat die toevoeging van progestagene teen endometriale veranderinge beskerm nie. Borskanker Alle beskikbare data dui op 'n verhoogde risiko vir borskanker wanneer vroue 'n kombinasie van estrogeen en progestageen as HVT gebruik en moontlik ook wanneer hulle slegs estrogeen as HVT gebruik. Gekombineerde estrogeen-progestageenterapie: CCDS: 9 June 211 Page 19 of 28

20 Beide die ewekansige plasebogekontroleerde navorsingstudie, die Women's Health Initiative Study (WHI) en die epidemiologiese studies het konsekwent 'n verhoogde risiko op borskanker getoon by vroue wat 'n gekombineerde estrogeen-progestageen HVT gebruik; die risiko word duidelik na ongeveer 3 jaar. Estrogeen monoterapie: In die WHI studie is daar geen verhoogde risiko vir borskanker gevind by vroue wat 'n histerektomie ondergaan het en estrogeen monoterapie as HVT gebruik nie. Die verhoogde risiko word binne enkele jare van gebruik duidelik, maar neem weer af tot die aanvangswaarde binne enkele (maksimum vyf) jaar na die beëindiging van die behandeling. HVT, veral die gekombineerde estrogeen-progestageen behandeling, verhoog die digtheid van mammografie beelde, wat die radiologiese opsporing van borskanker kan benadeel. Ovariumkanker Langdurige (ten minste 5 jaar) gebruik van HVT met produkte wat slegs estrogeen bevat, soos EVOREL, by vroue wat 'n histerektomie ondergaan het, is in verband gebring met 'n verhoogde risiko vir ovariumkanker. Veneuse tromboëmbolisme Hormoonvervangingsterapie (HVT) is geassosieer met 'n hoër risiko vir die ontstaan van veneuse tromboëmbolisme (VTE), soos diepvenetrombose of pulmonêre embolisme. Een ewekansige gekontroleerde proef en epidemiologiese studies het 'n twee-tot drievoudige hoër risiko vir gebruikers in vergelyking met nie-gebruikers gevind. 'n Persoonlike of 'n familiegeskiedenis van wederkerende tromboëmbolisme of wederkerende spontane aborsies moet ondersoek word ten einde 'n neiging tot bloedklonting uit te sluit. Die gebruik van EVOREL by hierdie pasiënte word as teenaangedui beskou totdat daar 'n deeglike evaluering van die trombofiele faktore gedoen is, of behandeling met 'n teenstolmiddel begin is. n Deeglike oorweging van die voor-en nadele van EVOREL vir vroue wat reeds op antistollingsterapie is, moet gedoen word. Die risiko van VTE kan tydelik verhoog met langdurige immobilisasie, ernstige trouma of 'n groot chirurgiese ingreep. Sorgvuldige aandag moet aan voorkomende maatreëls gegee word om VTE na CCDS: 9 June 211 Page 2 of 28

21 chirurgie te voorkom. Wanneer langdurige immobilisasie noodwendig na elektiewe chirurgie kan volg, veral na abdominale of ortopediese chirurgie van die onderste ledemate, moet behandeling met EVOREL 'n hele tyd voor die ingreep gestaak word, indien moontlik. Behandeling moet nie hervat word voordat die vrou eers heeltemal gemobiliseer is nie. As VTE na aanvang van behandeling ontwikkel, moet EVOREL gestaak word. Pasiënte moet ingelig word om hul dokters onmiddellik te kontak wanneer hulle bewus word van 'n potensiële tromboëmboliese simptoom (bv. pynlike swelling van 'n been, skielike pyn in die bors, dispnee). Kroonslagaarsiekte (KSS) Estrogeen monoterapie: Ewekansige gekontroleerde data het nie gedui op 'n beskermende effek teen KSS by vroue wat 'n histerektomie ondergaan het en estrogeen monoterapie gebruik nie. Gekombineerde estrogeen-progestageenterapie: Die relatiewe risiko van KSS tydens die gebruik van gekombineerde estrogeen-progestageen HVT is hoër. Beroerte Gekombineerde estrogeen-progestageen terapie en estrogeen monoterapie is geassosieer met 'n tot 1,5-voudige hoër risiko vir 'n iskemiese beroerte. Demensie Die gebruik van HVT verbeter nie die kognitiewe funksie nie. Daar is getuienis van 'n verhoogde risiko vir demensie by vroue wat begin met onafgebroke gekombineerde, of slegs-estrogeen HVT, soos EVOREL. Ander toestande EVOREL moet nie as voorbehoedmiddel gebruik word nie. Hou EVOREL weg van kinders. INTERAKSIES Medisyne met 'n hoë potensiaal vir lewerensiem-induksie, [bv. barbiturate, hidantoïen, CCDS: 9 June 211 Page 21 of 28

22 karbamasepien, meprobamaat, fenielbutasoon, rifampisien, rifabutien, bosentaan en sekere nienukleosied-trutranskriptaseremmers gebruik by MIV-behandelings (bv. nevirapien en efavirens)] kan inmeng met die werksaamheid van EVOREL en die doeltreffendheid van EVOREL verminder. Ritonavir en nelfinavir, hoewel bekend as sterk remmers van die sitochroom-p45-isosieme, toon in teenstelling daarmee induserende eienskappe wanneer hulle gelyktydig met steroïedhormone gebruik word. Medisyne se metabolisme kan deur Sint Janskruidpreparate (Hypericum perforatum) aangetas word; dit induseer sekere sitochroom-p45-isosieme in die lewer (bv. CYP3A4) en ook P- glikoproteïen. Die induksie van die P45-isosieme kan plasmakonsentrasies van die estrogeenkomponent van EVOREL verminder, wat moontlik tot 'n afname in terapeutiese doeltreffendheid en verhoogde vaginale bloeding kan lei. Daar is aangetoon dat orale voorbehoedmiddels wat estrogen bevat die plasmakonsentrasies van lamotrigien beduidend verlaag wanneer dit gelyktydig toegedien word, weens die induksie van glukuronidasie van lamotrigien. Dit kan beheer oor toevalle verminder. Hoewel die potensiële interaksie tussen EVOREL en lamotrigien nie ondersoek is nie, word verwag dat daar 'n soortgelyke interaksie is, wat kan lei tot 'n vermindering in beheer oor toevalle by vroue wat beide medisynes gelyktydig neem. Gevolglik kan aanpassing in die dosis van lamotrigien nodig wees. SWANGERSKAP EN LAKTASIE Die gebruik van EVOREL is teenaangedui by swangerskap of laktasie. Indien swangerskap voorkom tydens toediening van EVOREL, moet die behandeling onmiddellik gestaak word. DOSIS EN GEBRUIKSAANWYSINGS Volwassenes By pasiënte wat orale estrogene neem, kan behandeling met EVOREL binne een week nadat dit gestaak is, begin word. EVOREL moet tweemaal per week aangewend word, d.w.s. die plakker moet elke 3 tot 4 dae vervang word. EVOREL word op 'n sikliese wyse toegedien, 3 weke van behandeling (6 aanwendings), gevolg deur 'n interval van een week sonder behandeling. Tydens hierdie behandelingsvrye week kan vaginale onttrekkingsbloeding voorkom. Deurlopende nie-sikliese terapie kan aangedui wees vir vroue wat 'n histerektomie gehad het en CCDS: 9 June 211 Page 22 of 28

23 indien menopousale simptome tydens die behandelingsvrye week voorkom. Die behandeling word gewoonlik begin met EVOREL 5. Met daaropvolgende behandelingskursusse moet die dosis individueel aangepas word. Vir behandeling van postmenopousale simptome moet die laagste doeltreffende dosis gebruik word. EVOREL moet nie vir langer as 5 jaar gebruik word nie. EVOREL 25 moet slegs aan pasiënte toegedien word wat nie die hoër dosis kan verdra nie. Teer borste, deurbraakbloeding, vogretensie of opgesette buik (indien dit aanhou vir meer as 6 weke) is gewoonlik tekens dat die dosis te hoog is en verlaag moet word. Indien die gekose dosis na 2 tot 3 weke nie die tekens en simptome van estrogeengebrek kon uitskakel nie, moet 'n hoër dosis gegee word. Vir instandhoudingsterapie moet 'n mens altyd die laagste doeltreffende dosis gebruik. Vir die voorkoming van beenverlies word EVOREL 5, 75 of 1 aanbeveel. Die dose van 1 µg estradiol/24 uur moet nie oorskry word nie. Let daarop dat EVOREL 75 en EVOREL 1 nie vir vroue met 'n uterus aanbeveel word nie, aangesien die endometriale veiligheid van bykomende prostageen nie vir transdermale dosisse van estradiol bo 5 µg/dag ondersoek is nie. Daar is nie voldoende data beskikbaar om aanbevelings te gee oor dosisaanpassings vir pasiënte met ernstig ingekorte lewer-of nierfunksie nie. Behandeling met 'n progestageen word vir 'n vrou met 'n uterus aanbeveel: vir die duur van 12 tot 14 opeenvolgende dae van die kalendermaand tydens ononderbroke behandeling met EVOREL. of tydens die laaste 12 tot 14 dae (d.w.s. beginnende op siklus dae 8 of 1) van die 21-dag siklus waartydens behandeling met EVOREL verskaf word. As daar 'n vorige diagnose van endometriose is, kan die toevoeging van 'n prostageen by EVOREL ook oorweeg word vir vroue wat 'n histerektomie gehad het. CCDS: 9 June 211 Page 23 of 28

24 Vaginale bloeding sal normaalweg ná aanvang van die progestageenbehandeling voorkom. Ouer pasiënte Data is onvoldoende met betrekking tot die gebruik van EVOREL by die bejaarde (>65 jaar oud). Wyse van toediening Die EVOREL plakker moet op 'n skoon, droë, gesonde, ongeskonde oppervlakte van die vel, op die romp van die liggaam onder die middellyf geplaas word. Rome, smeermiddels of poeiers kan inmeng met die kleefvermoë van die plakker. Die plakker moet nie op of naby die borste aangewend word nie. Die gebied van aanwending moet afgewissel word, met 'n periode van ten minste een week tussen aanwendings op 'n bepaalde plek. Die gekose plek op die vel moet nie beskadig of geïrriteerd wees nie. Die middellyf moet nie gebruik word nie, omdat oormatige wrywing van die plakker kan plaasvind. Die plakker moet onmiddellik nadat die sakkie oopgemaak is, gebruik word. Verwyder een gedeelte van die beskermende foelie. Plak die blootgestelde deel van die gomkant op die plek van aanwending, begin by die rand tot in die middel; verhoed dat die plakker kreukel. Die ander deel van die beskermende foelie moet nou verwyder word en die vars blootgestelde gomkant ook aangewend word. Kreukels moet vermy word en die handpalm moet gebruik word om die plakker op die vel te druk en om die plakker veltemperatuur te laat bereik, waarby die kleefvermoë geoptimaliseer is. Die pasiënt moet tydens toediening kontak tussen die vingers en die gomkant van die plakker vermy. Indien 'n plakker afval, moet 'n nuwe plakker dadelik aangewend word. Die gewone dag wat die plakker moes geruil word, moet egter steeds behou word. Dit is nie nodig om die plakker te verwyder met 'n bad en stort nie. Dit word egter aangeraai om die plakker te verwyder voor 'n saunabad, en 'n nuwe plakker moet onmiddellik daarna aangewend word. Indien vervanging van 'n plakker oorgeslaan is, moet dit aangewend word sodra daarvan onthou word. Die gewone dag wat die plakker moes geruil word, moet egter steeds behou word. As 'n dosis vergeet word, kan dit die moontlikheid van deurbraakbloeding en spikkelbloeding verhoog. Om 'n plakker te verwyder, maak die rand van die plakker los en trek dit egalig af van die vel. Die plakker moet toegevou en by die huishoudelike afval weggegooi word (moenie in die toilet wegspoel nie). CCDS: 9 June 211 Page 24 of 28

25 Enige gom wat op die vel agterbly na verwydering van die plakker kan verwyder word deur dit met seep en water te was of dit met die vingers af te vryf. NEWE-EFFEKTE Data uit kliniese proewe Tabel 1: Ongunstige reaksies aangemeld by 1 % van die persone wat met EVOREL behandel is en met 'n hoër insidensie as by persone wat met plasebo behandel is, in 1 dubbelblinde, plasebogekontroleerde kliniese studie met EVOREL in 12 vroue Sisteem/orgaanklas EVOREL % (N = 12) Plasebo % (N = 52) Infeksies en infestasies Genitale kandidiase 8,8 Immuunstelselversteurings Hipersensitiwiteit 2,9 1,9 Senuweestelselversteurings Hoofpyn Duiseligheid 2,6 1, 19,2 Hartversteurings Palpitasies 1, Gastroïntestinale siektes Winderigheid Diarree 4,9 1, Vel- en onderhuidse weefselversteurings Pruritus Veluitslag 3,9 2,9 1,9 Skeletspierstelsel- en bindweefselversteurings Mialgie Artralgie 5,9 2, Voortplantingstelsel- en borsversteurings Pynlike borste Metrorragie Dismenorree 12,7 6,9 2,9 3,9 1,9 Algemene versteurings en toestande by die plek van toediening CCDS: 9 June 211 Page 25 of 28

26 Pyn Perifere edeem Algemene edeem Edeem 7,8 5,9 3,9 2,9 3,9 1,9 1,9 Ondersoeke Toename in gewig 3,9 Ongunstige geneesmiddelreaksies waarvan nie in Tabel 1 berig is nie en wat aangemeld is deur 1 % van die persone wat met EVOREL behandel is (N = 2 584) in 15 kliniese proewe met EVOREL, word in Tabel 2 aangetoon. Tabel 2: Ongunstige reaksies aangemeld deur 1 % van die persone wat met EVOREL behandel is in 15 kliniese studies met EVOREL EVOREL Sisteem/orgaanklas % (N = 2 584) Gastroïntestinale versteurings Naarheid 2,4 Buikpyn 1,8 Algemene versteurings en toestande by die plek van toediening Uitslag by die plek van toediening* 2,8 # Pruritus by die plek van toediening* 19,8 # Eriteem by die plek van toediening* 8,5 # Reaksie by die plek van toediening* 3,3 Edeem by die plek van toediening* 1,6 # * Aangevraagde tekens/simptome (aangeteken as ja/nee) in 8 kliniese proewe met EVOREL. # Persentasies gebaseer op N = in 8 kliniese proewe met EVOREL Ongunstige geneesmiddelreaksies aangemeld deur < 1 % van die persone (N = 2 584) wat in die bogenoemde kliniese proef se datastel aangemeld is, word in Tabel 3 aangetoon. Tabel 3: Ongunstige geneesmiddelreaksies aangemeld deur < 1 % van die persone wat met EVOREL behandel is in 15 kliniese proewe met EVOREL: Neoplasmas - goedaardig, kwaadaardig en nie Borskanker gespesifiseer nie (insluitende siste en poliepe) CCDS: 9 June 211 Page 26 of 28

27 Senuweestelselversteurings Bloedvatversteurings Epilepsie Arteriële of veneuse trombose Nabemarkingsdata Ongunstige reaksies wat eers met ervaring na bemarking van EVOREL waargeneem is, is by Tabel 4 ingesluit. Tabel 4: Ongunstige reaksies wat met ervaring na bemarking van EVOREL waargeneem is Neoplasmas - goedaardig, kwaadaardig en nie gespesifiseer nie (insluitende siste en poliepe) Psigiatriese versteurings Senuweestelselversteurings Hartversteurings Bloedvatversteurings Respiratoriese, bors- en mediastinale versteurings Gastroïntestinale versteurings Hepatobiliêre versteurings Vel- en onderhuidse weefselversteurings Voortplantingstelsel- en borsversteurings Endometriumkanker Neerslagtige bui Serebrovaskulêre voorval, migraine Miokardiale infarksie Diepvenetrombose Pulmonêre embolisme Opgehewe buik Cholelitiase Angio-edeem Vergrote borste BEKENDE SIMPTOME VAN OORDOSERING EN BESONDERHEDE VAN DIE BEHANDELING DAARVAN Simptome van oordosering kan borspyn of teerheid, naarheid, deurbraakbloeding, buikkrampe en/of buikopsetting behels. Die verwydering van die plakker kan hierdie simptome omkeer. Behandeling is simptomaties en ondersteunend. IDENTIFIKASIE EVOREL 25 is 'n kleefplakker van 8 cm 2 met afgeronde hoeke. Die buitekant van die steunlaag is gemerk CE 25 in die middel van onderste kantlyn. EVOREL 5 is 'n kleefplakker van 16 cm 2 met afgeronde hoeke. Die buitekant van die steunlaag is gemerk CE 5 in die middel van onderste kantlyn. EVOREL 75 is 'n kleefplakker van 24 cm 2 met afgeronde hoeke. Die buitekant van die steunlaag is gemerk CE 75 in die middel van onderste kantlyn. CCDS: 9 June 211 Page 27 of 28

28 EVOREL 1 is 'n kleefplakker van 32 cm 2 met afgeronde hoeke. Die buitekant van die steunlaag is gemerk CE 1 in die middel van onderste kantlyn. Die kleefoppervlakte van die plakker is bedek met beskermende foelie met 'n S-vormige insnyding. AANBIEDING Kartonne wat een of meer plakkers bevat. Elke plakker is in 'n sakkie verseël. BERGINGSINSTRUKSIES Bewaar by of onder 25 C. Moenie vries nie. HOU BUITE BEREIK VAN KINDERS. REGISTRASIENOMMERS 25, 75, 1-3/21.8.1/27/8/9 5 - Z/21.8.1/339 Nam. Reg. nr: 25, 5, 75, 1 4/21.8.1/278/9/8/81 NS 1 BOTSWANA Reg.: 5 BOT9767 S2 NAAM EN BESIGHEIDSADRES VAN DIE HOUER VAN DIE REGISTRASIESERTIFIKAAT JANSSEN PHARMACEUTICA (Pty) Ltd (Reg nr: 198/11122/7) Building 6, Country Club Estate, 21 Woodlands Drive, Woodmead, 2191 Tel: +27 (11) RA-JACZA-Medinfo@its.jnj.com DATUM VAN PUBLIKASIE VAN HIERDIE VOUBILJET Augustus 214 CCDS: 9 June 211 Page 28 of 28