CSP. Estradiol valerate oral tablets. Estradiol hemihydrate Transdermal Patch

Transcription

1 CSP Estradil valerate ral tablets Estradil hemihydrate Transdermal Patch 1

2 Table f Cntents 4.3 Cntraindicatins 4.4. Special warnings and precautins fr use 4.5 Interactins 4.6 Pregnancy and lactatin 4.7 Effects n ability t drive and use machines 4.8 Undesirable effects 4.9 Overdse 2

3 4.3 Cntraindicatins Knwn, past r suspected breast cancer Knwn r suspected estrgen dependent malignant tumurs (e.g. endmetrial cancer) Undiagnsed genital bleeding Untreated endmetrial hyperplasia Previus r current venus thrmbemblism (deep venus thrmbsis, pulmnary emblism) Knwn thrmbphilic disrders (eg. Prtein C, Prtein S, r antithrmbin deficiency, see sectin 4.4) Active r recent arterial thrmbemblic disease (e.g. angina, mycardial infarctin) Acute liver disease, r a histry f liver disease as lng as liver functins have failed t return t nrmal Knwn hypersensitivity t the active substance r any f the excipients Prphyria 4.4 Special warnings and precautins fr use Fr the treatment f pstmenpausal symptms, HRT shuld nly be initiated fr symptms that adversely affect quality f life. In all cases, a careful appraisal f the risks and benefits shuld be undertaken at least annually and HRT shuld nly be cntinued as lng as the benefit utweighs the risk. Evidence regarding the risks assciated with HRT in the treatment f premature menpause is limited. Due t the lw level f abslute risk in yunger wmen, hwever, the balance f benefits and risks fr these wmen may be mre favrable than in lder wmen. Medical examinatin/fllw-up Befre initiating r reinstituting HRT, a cmplete persnal and family medical histry shuld be taken. Physical (including pelvic and breast) examinatin shuld be guided by this and by the cntraindicatins and warnings fr use. During treatment, peridic check-ups are recmmended f a frequency and nature adapted t the individual wman. Wmen shuld be advised what changes in their breasts shuld be reprted t their dctr r nurse (see Breast cancer belw). Investigatins, including apprpriate imaging tls, e.g. mammgraphy, shuld be carried ut in accrdance with currently accepted screening practices, mdified t the clinical needs f the individual. Cnditins which need supervisin If any f the fllwing cnditins are present, have ccurred previusly, and/r have been aggravated during pregnancy r previus hrmne treatment, the patient shuld be clsely supervised. It shuld be taken int accunt that these cnditins may recur r be aggravated during treatment with Climara, in particular: leimyma (uterine fibrids) r endmetrisis risk factrs fr thrmbemblic disrders (see belw) risk factrs fr estrgen dependent tumurs, e.g. 1 st degree heredity fr breast cancer hypertensin liver disrders (e.g. liver adenma) diabetes mellitus with r withut vascular invlvement chlelithiasis migraine r (severe) headache systemic lupus erythematsus. a histry f endmetrial hyperplasia (see belw) epilepsy asthma tsclersis 3

4 Reasns fr immediate withdrawal f therapy: Therapy shuld be discntinued in case a cntra-indicatin is discvered and in the fllwing situatins: jaundice r deteriratin in liver functin significant increase in bld pressure new nset f migraine-type headache pregnancy Endmetrial hyperplasia and carcinma In wmen with an intact uterus the risk f endmetrial hyperplasia and carcinma is increased when estrgens are administered alne fr prlnged perids. The reprted increase in endmetrial cancer risk amng estrgen-nly users varies frm 2-t 12-fld greater cmpared with nn-users, depending n the duratin f treatment and estrgen dse (see sectin 4.8). After stpping treatment risk may remain elevated fr at least 10 years. The additin f a prgestagen cyclically fr at least 12 days per mnth/28 day cycle r cntinuus cmbined estrgen-prgestagen therapy in nn hysterectmised wmen prevent the excess risk assciated with estrgen-nly HRT. Fr ral dses f estradil >2mg, cnjugated equine estrgens >0.625 mg and patches >50 ug/day the endmetrial safety f added prgestagens has nt been demnstrated. Break-thrugh bleeding and sptting may ccur during the first mnths f treatment. If break-thrugh bleeding r sptting appears after sme time n therapy, r cntinues after treatment has been discntinued, the reasn shuld be investigated, which may include endmetrial bipsy t exclude endmetrial malignancy. Unppsed estrgen stimulatin may lead t premalignant r malignant transfrmatin in the residual fci f endmetrisis. Therefre, the additin f prgestgens t estrgen replacement therapy shuld be cnsidered in wmen wh have undergne hysterectmy because f endmetrisis, if they are knwn t have residual endmetrisis. Breast cancer The verall evidence suggests an increased risk f breast cancer in wmen taking cmbined estrgenprgestagen and pssibly als estrgen-nly HRT, that is dependent n the duratin f taking HRT. Cmbined estrgen-prgestagen therapy The randmised placeb-cntrlled trial the (Wmen s Health Initiative study (WHI), and epidemilgical studies are cnsistent in finding an increased risk f breast cancer in wmen taking cmbined estrgen-prgestagen fr HRT that becmes apparent after abut 3 years (see Sectin 4.8). Oestrgen-nly therapy The WHI trial fund n increase in the risk f breast cancer in hysterectmised wmen using estrgennly HRT. Observatinal studies have mstly reprted a small increase in risk f having breast cancer diagnsed that is substantially lwer than that fund in users f estrgen-prgestagen cmbinatins (see sectin 4.8). The excess risk becmes apparent within a few years f use but returns t baseline within a few (at mst five) years after stpping treatment HRT, especially estrgen-prgestagen cmbined treatment, increases the density f mammgraphic images which may adversely affect the radilgical detectin f breast cancer. 4

5 Ovarian cancer Ovarian cancer is much rarer than breast cancer. Lng-term (at least 5-10 years) use f estrgen-nly HRT prducts has been assciated with a slightly increased risk f varian cancer (see sectin 4.8). Sme studies including the WHI trial suggest that the lng-term use f cmbined HRTs may cnfer a similar, r slightly smaller, risk (see Sectin 4.8). Venus thrmbemblism HRT is assciated with a fld risk f develping venus thrmbemblism (VTE), i.e. deep vein thrmbsis r pulmnary emblism. The ccurrence f such an event is mre likely in the first year f HRT than later (see Sectin 4.8). Patients with a histry f VTE r knwn thrmbphilic states have an increased risk f VTE and HRT may add t this risk. Generally recgnised risk factrs fr VTE include, use f estrgens, lder age, majr surgery, prlnged immbilisatin, besity (BMI > 30 kg/m2), pregnancy/pstpartum perid, systemic lupus erythematsus (SLE), and cancer. There is n cnsensus abut the pssible rle f varicse veins in VTE. As in all pstperative patients, prphylactic measures need be cnsidered t prevent VTE fllwing surgery. If prlnged immbilisatin is t fllw elective surgery temprarily stpping HRT 4 t 6 weeks earlier is recmmended. Treatment shuld nt be restarted until the wman is cmpletely mbilised. In wmen with n persnal histry f VTE but with a first degree relative with a histry f thrmbsis at yung age, screening may be ffered after careful cunselling regarding its limitatins (nly a prprtin f thrmbphilic defects are identified by screening). If a thrmbphilic defect is identified which segregates with thrmbsis in family members r if the defect is severe (e.g, antithrmbin, prtein S, r prtein C deficiencies r a cmbinatin f defects) Climara shuld nly be used after careful risk/benefit evaluatin. Wmen already n chrnic anticagulant treatment require careful cnsideratin f the benefit-risk f use f HRT. If VTE develps after initiating therapy, the drug shuld be discntinued. Patients shuld be tld t cntact their dctrs immediately when they are aware f a ptential thrmbemblic symptm (e.g. painful swelling f a leg, sudden pain in the chest, dyspnea). Crnary artery disease (CAD) There is n evidence frm randmised cntrlled trials f prtectin against mycardial infarctin in wmen with r withut existing CAD wh received cmbined estrgen-prgestagen r estrgennly HRT. Cmbined estrgen-prgestagen therapy: The relative risk f CAD during use f cmbined estrgen+prgestagen HRT is slightly increased. As the baseline abslute risk f CAD is strngly dependent n age, the number f extra cases f CAD due t estrgen+prgestagen use is very lw in healthy wmen clse t menpause, but will rise with mre advanced age. Oestrgen-nly: Randmised cntrlled data fund n increased risk f CAD in hysterectmised wmen using estrgennly therapy. 5

6 Ischaemic Strke Cmbined estrgen-prgestagen and estrgen-nly therapy are assciated with an up t 1.5-fld increase in risk f ischaemic strke. The relative risk des nt change with age r time since menpause. Hwever, as the baseline risk f strke is strngly age-dependent, the verall risk f strke in wmen wh use HRT will increase with age (see sectin 4.8). Other cnditins Oestrgens may cause fluid retentin, and therefre patients with cardiac r renal dysfunctin shuld be carefully bserved.. Wmen with pre-existing hypertriglyceridemia shuld be fllwed clsely during estrgen replacement r hrmne replacement therapy, since rare cases f large increases f plasma triglycerides leading t pancreatitis have been reprted with estrgen therapy in this cnditin. Oestrgens increase thyrid binding glbulin (TBG), leading t increased circulating ttal thyrid hrmne, as measured by prtein-bund idine (PBI), T4 levels (by clumn r by radiimmunassay) r T3 levels (by radi-immunassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 cncentratins are unaltered. Other binding prteins may be elevated in serum, i.e. crticid binding glbulin (CBG), sex- hrmne-binding glbulin (SHBG) leading t increased circulating crticsterids and sex sterids, respectively. Free r bilgical active hrmne cncentratins are unchanged. Other plasma prteins may be increased (angitensingen/renin substrate, alpha-i-antitrypsin, cerulplasmin). HRT use des nt imprve cgnitive functin. There is sme evidence f increased risk f prbable dementia in wmen wh start using cntinuus cmbined r estrgen-nly HRT after the age f Interactin with ther medicinal prducts and ther frms f interactin The metablism f estrgens may be increased by cncmitant use f substances knwn t induce drugmetablising enzymes, specifically cytchrme P450 enzymes, such as anticnvulsants (e.g. phenbarbital, phenytin, carbamezapin) and anti- infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). Ritnavir and nelfinavir, althugh knwn as strng inhibitrs, by cntrast exhibit inducing prperties when used cncmitantly with sterid hrmnes. Herbal preparatins cntaining St.Jhn s wrt (Hypericum Perfratum) may induce the metablism f estrgens. At transdermal administratin, the first-pass effect in the liver is avided and, thus, transdermally applied estrgens might be less affected than ral hrmnes by enzyme inducers. Clinically, an increased metablism f estrgens and prgestgens may lead t decreased effect and changes in the uterine bleeding prfile. 4.6 Pregnancy and lactatin Pregnancy Tradename is nt indicated during pregnancy. If pregnancy ccurs during medicatin with Tradename treatment shuld be withdrawn immediately. The results f mst epidemilgical studies t date relevant t inadvertent fetal expsure t estrgens indicate n teratgenic r fettxic effects. Lactatin 6

7 Tradename is nt indicated during lactatin. 4.7 Effects n ability t drive and use machines N studies n the effects n the ability t drive and use machines have been perfrmed. 4.8 Undesirable effects Explanatry nte: The belw infrmatin shuld nly be included in the SmPC f relevant prducts t allw deviatins when implementing the CSP fr different prducts. Mre than X patients have been treated with Tradename in clinical trials. Cmment [a1]: additin f paragraph with infrmatin abut number f patients Serius undesirable effects assciated with the use f hrmne replacement therapy are als mentined in sectin 4.4 Special warnings and precautins fr use The table belw reprts undesirable effects, that have been reprted in users f hrmne replacement therapy (HRT) by MedDRA system rgan classes (MedDRA SOCs). System Organ Class Cmmn ( 1/100, <1/10) Uncmmn ( 1/1,000, <1/100) Rare <1/1,000) Immune system Hypersensitivity reactin disrders Metablism and nutritin disrders Weight increase r Weight decrease Psychiatric disrders Depressed md Anxiety, Libid decreased r Libid increased Nervus system disrders Headache Dizziness Migraine Eye disrders Visual disturbances Cntact lens intlerance Cardiac disrders Palpitatins Gastrintestinal Abdminal pain, Nausea Dyspepsia Blating, Vmiting disrders Skin and subcutaneus Rash, Pruritus Erythema ndsum, Hirsutism, Acne tissue disrders Urticaria Musculskeletal and Muscle cramps cnnective tissue disrders Reprductive system and Uterine/Vaginal bleeding Breast pain, Breast Dysmenrrhea, breast disrders including Sptting tenderness Vaginal discharge, Premenstrual-like syndrme, Breast enlargement General disrders and Edema Fatigue administratin site cnditins 7

8 The mst apprpriate MedDRA term is used t describe a certain reactin and its synnyms and related cnditins. B reast cancer risk An up t 2-fld increased risk f having breast cancer diagnsed is reprted in wmen taking cmbined estrgen-prgestagen therapy fr mre than 5 years. Any increased risk in users f estrgen-nly therapy is substantially lwer than that seen in users f estrgen-prgestagen cmbinatins. The level f risk is dependent n the duratin f use (see sectin 4.4). Results f the largest randmised placeb-cntrlled trial (WHI-study) and largest epidemilgical study (MWS) are presented. Millin Wmen study Estimated additinal risk f breast cancer after 5 years use Age Additinal cases per Risk rati # Additinal cases per range 1000 never-users f 1000 HRT users ver 5 (years) HRT ver a 5 year years (95% CI) perid*2 Oestrgen nly HRT (0-3) Cmbined estrgen-prgestagen (5-7) *2 Taken frm baseline incidence rates in develped cuntries. # Overall risk rati. The risk rati is nt cnstant but will increase with increasing duratin n use. Nte: since the backgrund incidence f breast cancer differs by EU cuntry, the number f additinal cases f breast cancer differs by EU cuntry, the number f additinal cases f breast cancer will als change prprtinately. US WHI studies - additinal risk f breast cancer after 5 year s use A ge Incidence per 1000 Risk rati & 95%CI Additinal cases per 1000 range (years) wmen in placeb arm ver 5 years HRT users ver 5 years (95% CI) CEE estrgen nly ( ) -4 (-6-0)*3 CEE + MPA estrgen & prgestagens ( ) +4 (0-9) *3 WHI study in wmen with n uterus, which did nt shw an increase f breast cancer. When the analysis was restricted t wmen wh had nt used HRT prir t the study there was n increased risk apparent during the first 5 years f treatment: after 5 years the risk was higher than in nn-users. Endmetrial cancer risk Pstmenpausal wmen wi th an uterus The endmetrial cancer risk is abut 5 in every 1000 wmen with an uterus nt using HRT. In wmen with an uterus, use f estrgen-nly HRT is nt recmmended because it increases the risk f endmetrial cancer (see sectin 4.4). Depending n the duratin f estrgen-nly use and estrgen dse, the increase in risk f endmetrial cancer in epidemilgy studies varied frm between 5 and 55 extra cases diagnsed in every 1000 wmen between the ages f 50 and 65. 8

9 Adding a prgestagen t estrgen-nly therapy fr at least 12 days per cycle can prevent this increased risk. In the Millin Wmen Study the use f five years f cmbined (sequential r cntinuus) HRT did nt increase risk f endmetrial cancer (RR f 1.0 ( )). O varian cancer risk: Lng-term use f estrgen-nly and cmbined estrgen-prgestagen HRT has been assciated with a slightly increased risk f varian cancer. In the Millin Wmen Study 5 years f HRT resulted in 1 extra case per 2500 users. R isk f venus thrmbemblism: HRT is assciated with a fld increased relative risk f develping venus thrmbemblism (VTE), i.e. deep vein thrmbsis r pulmnary emblism. The ccurrence f such an event is mre likely in the first year f using HT (see sectin 4.4). Results f the WHI studies are presented: WHI Studies - Additinal risk f VTE ver 5 years use Age range (years) Incidence per 1000 wmen Risk rati & 95%CI Additinal cases per 1000 in placeb arm ver 5 years HRT users Oral, estrgen-nly* ( ) 1 (-3-10) Oral cmbined, estrgen -prgesterna ( ) 5 (1-13) *4 Study in wmen with n uterus. R isk f crnary artery disease: The risk f crnary artery disease is slightly increased in users f cmbined estrgenprgestagen HRT ver the age f 60 (see sectin 4.4). R isk f ischaemic strke: The use f estrgen-nly and estrgen + prgestagen therapy is assciated with an up t 1.5 fld increased relative risk f ischaemic strke. The risk f haemrrhagic strke is nt increased during use f HRT. This relative risk is nt dependent n age r n duratin f use, but as the baseline risk is strngly agedependent, the verall risk f strke in wmen wh use HRT will increase with age, see sectin 4.4. WHI studies cmbined - Additinal risk f ischaemic strke*5 ver 5 years use. Age range (years) Incidence per 1000 wmen Risk rati & 95%CI Additinal cases per 1000 in placeb arm ver 5 years HRT users ( ) 3 (1 5) *5 N differentiatin was mad e between ischaemic and haemrrhagic strke. Other adverse reactins have been reprted in assciatin with estrgen/prgestagen treatment: Gall bladder disease. Skin and subcutaneus disrders: chlasma, erythema multifrme, erythema ndsum, vascular purpura. Prbable dementia ver the age f 65 (see sectin 4.4) Overdse Acute txicity studies did nt indicate a risk f acute adverse effects in case f inadvertent intake f a multiple f the daily therapeutic dse. 9

10 Overdsage is unlikely with trasndermal applicatin. Nausea, vmiting and withdrawal bleeding may ccur in sme wmen. There is n specific antidte and treatment shuld be symptmatic. The patch(es) shuld be remved. 10