PACKAGE INSERT. oestradiol/norethisterone acetate matrix type transdermal patch (sequential regimen).

Transcription

1 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 Page 1 of 52

2 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 Oestrogens (EVOREL 50 TDS) A Progesterones with oestrogens (EVOREL CONTI TDS) PHARMACOLOGICAL ACTION Oestradiol (E 2 ) 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 Page 2 of 52

3 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. Page 3 of 52

4 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 estrogenprogestogen 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. E 2 /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 ( %) and sex-hormone-binding globulin ( %) 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. Page 4 of 52

5 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. E 2 /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 Page 5 of 52

6 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 (E 2 /E 1 ) was less than 0,3 in the postmenopausal women studied. During use of EVOREL CONTI TDS the E 2 /E 1 ratios increased rapidly and were maintained at physiological levels at approximated 1. The E 2 /E 1 ratios returned to pre-treatment levels within 24 hours after removal of the TDS. An average E 2 /E 1 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 norethisterone concentrations ranging between 199 pg/ml. Mean steady state serum 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. Page 6 of 52

7 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. Page 7 of 52

8 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. Page 8 of 52

9 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. Page 9 of 52

10 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 Page 10 of 52

11 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 oestrogenprogestagen 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 Page 11 of 52

12 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. Page 12 of 52

13 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 agedependent, the overall risk of stroke in women who use HRT will increase with age. Page 13 of 52

14 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, Page 14 of 52

15 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 oestrogeninduced 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). Page 15 of 52

16 PREGNANCY AND LACTATION The use of EVOREL SEQUI is contra-indicated in pregnancy or lactation. If pregnancy occurs during medication with EVOREL SEQUI, treatment should be withdrawn immediately. DOSAGE AND DIRECTIONS FOR USE Dosage ADULTS: EVOREL 50 and EVOREL CONTI should be applied individually in the following sequence: four EVOREL 50 TDSs followed by four EVOREL CONTI TDSs. The cycle should be repeated without interruption. Patches should be applied twice weekly, every three to four days, to the trunk below the waist. Insufficient data are available to guide dose adjustments for patients with severe liver or kidney function impairment. For treatment of post- menopausal symptoms the lowest effective dose should be used. HRT should be continued for no longer than 5 years. It is important that the patch be used in the correct sequence to ensure regular cyclic bleeding. Most patients will experience vaginal bleeding after the start of the progestogen therapy. Page 16 of 52

17 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. Page 17 of 52

18 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). Page 18 of 52

19 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 Page 19 of 52

20 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 14,6 2,4 1,8 Malaise Page 20 of 52

21 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 Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Side effect Breast cancer female, Fibroadenoma of breast Polyps) Psychiatric Disorders Decreased libido, increased libido. Nervous System Disorders Disturbance in attention, Dizziness Reproductive System and Breast Disorders General Disorders and Endometrial hyperplasia, Metrorrhagia Fatigue Administration Site Conditions Additional ADRs reported in clinical trials with EVOREL (oestradiol alone) in postmenopausal women are shown in Table 3. Page 21 of 52

22 Table 3. Adverse Drug Reactions Reported by EVOREL-treated Subjects in 15 Clinical Trials (N = 2 584) of EVOREL System/Organ Class Infections and Infestations Neoplasms Benign, Malignant and Side effect Genital candidiasis Breast cancer Unspecified (Incl. Cysts and Polyps Immune System Disorders Nervous System Disorders Cardiac Disorders Vascular Disorders Gastrointestinal Disorders Skin and Subcutaneous Tissue Hypersensitivity Epilepsy Palpitations Thrombosis Diarrhoea, Flatulence Rash Disorders Musculoskeletal and Connective Myalgia Tissue Disorders General Disorders and Administration Site Conditions Application site rash*, Application site pruritus*, Application site erythema*, Application site oedema*, Generalised oedema, Peripheral oedema, Pain * Solicited signs/symptoms (recorded as yes/no) in 8 clinical trials of EVOREL (N = 1 739). Page 22 of 52

23 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 Neoplasms Benign, Malignant and Candidiasis Endometrial cancer Unspecified (Incl Cysts and Polyps) Immune System Disorders Psychiatric Disorders Nervous System Disorders Hypersensitivity Mood swings Cerebrovascular accident, Migraine, Paraesthesia Cardiac Disorders Vascular Disorders Respiratory, Thoracic and Palpitations Deep vein thrombosis Pulmonary embolism Mediastinal Disorders Gastrointestinal Disorders Hepatobiliary Disorders Skin and Subcutaneous Tissue Abdominal distension Cholelithiasis Stevens-Johnson syndrome Disorders Musculoskeletal, Connective Tissue, Back pain Page 23 of 52

24 and Bone Disorders Reproductive System and Breast Breast enlargement Disorders General Disorders and Administration Site Conditions Application site erythema, Application site pruritus, Application site rash KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENTS Symptoms of overdose of oestrogen and progestogen therapy may include nausea, breakthrough 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 cm 2 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 cm 2 with convex edges and rounded corners. The adhesive surface of the patch is covered with a Page 24 of 52

25 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 Page 25 of 52

26 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 DATE OF PUBLICATION OF THIS PACKAGE INSERT January 2012 Page 26 of 52

27 SKEDULERINGSTATUS Skedule 4. VOUBILJET 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: Page 27 of 52

28 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 A Estrogene (EVOREL 50 TDS) Progesterone met estrogene (EVOREL CONTI TDS) FARMAKOLOGIESE WERKING Estradiol (E 2 ) 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 Page 28 of 52

29 estradiol vryelik in teiken-selle in, waar dit aan spesifieke makromolekules (reseptore) bind. Die estradiol-reseptorkompleks het dan n interaksie met DNA-genoom om transkripsieaktiwiteit 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. Page 29 of 52

30 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 estrogeenprogestogeen 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. E 2 /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 ( %) en aan sekshormoonbindingsglobulien ( %) gebind. Na transdermale vrystelling van estradiol bly serumgebonde proteïenfraksies onveranderd. Page 30 of 52

31 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. E 2 /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 Page 31 of 52

32 die 3,5 dag toedieningsperiode. Konsentrasies keer vinnig terug na voorbehandelingsvlakke 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 (E 2 /E 1 ) minder as 0,3 onder die postmenopousale vroue wat bestudeer is. Gedurende gebruik van EVOREL CONTI TDS het die E 2 /E 1 verhoudings vinnig toegeneem en is dit volgehou op fisiologiese vlakke van ongeveer 1. Die E 2 /E 1 verhoudings het teruggekeer na die voorbehandelingsvlakke binne 24 uur nadat die TDS verwyder is. n Gemiddelde E 2 /E 1 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 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 Page 32 of 52

33 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 voorbehandelingsperiode (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. Page 33 of 52

34 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 Page 34 of 52

35 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. Page 35 of 52

36 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 Page 36 of 52

37 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. Waarnemingstudies 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 Page 37 of 52

38 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 tweetot 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. Page 38 of 52

39 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 estrogeenprogestageen 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 estrogeenprogestageen 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 Page 39 of 52

40 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, Page 40 of 52

41 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). Page 41 of 52

42 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. Page 42 of 52