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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OSPHENA safely and effectively. See full prescribing information for OSPHENA. OSPHENATM (ospemifene) tablets, for oral use Initial U.S. Approval: 2013 WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS See full prescribing information for complete boxed warning. OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has estrogen agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer [see Warnings and Precautions (5.2)]. Estrogen-alone therapy has an increased risk of stroke and deep vein thrombosis (DVT). OSPHENA 60 mg had cerebral thromboembolic and hemorrhagic stroke incidence rates of 0.72 and 1.45 per thousand women, respectively vs. 1.04 and 0 per thousand women, respectively in placebo. For deep vein thrombosis, the incidence rate for OSPHENA 60 mg is 1.45 per thousand women vs. 1.04 per thousand women in placebo [see Warnings and Precautions (5.1)]. --------------INDICATIONS AND USAGE--------------------OSPHENA is an estrogen agonist/antagonist indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause (1) ---------------WARNINGS AND PRECAUTIONS----------- Venous Thromboembolism: Risk of DVT and pulmonary embolism (5.1) Known, suspected, or history of breast cancer (5.2) Severe Hepatic Impairment (5.3, 8.7, 12.3) -------------------ADVERSE REACTIONS---------------------- Adverse reactions (≥1 percent) include: hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-855-OSPHENA (1-855-677-4362) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -------------------DRUG INTERACTIONS--------------------- Do not use estrogens or estrogen agonist/antagonist concomitantly with OSPHENA (7.1,12.3) Do not use fluconazole concomitantly with OSPHENA. Fluconazole increases serum concentrations of OSPHENA (7.2, 12.3) Do not use rifampin concomitantly with OSPHENA. Rifampin decreases serum concentration of OSPHENA (7.2, 12.3) -------------USE IN SPECIFIC POPULATIONS------------- ------------DOSAGE AND ADMINISTRATION------------ One tablet taken orally once daily with food (2.1) -----------DOSAGE FORMS AND STRENGTHS------------ Tablet: 60 mg (3) Undiagnosed abnormal genital bleeding (4) Known or suspected estrogen-dependent neoplasia (4, 5.2) Revised: 02/2013 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Cardiovascular Disorders 5.2 Malignant Neoplasms 5.3 Severe Hepatic Impairment 6. ADVERSE REACTIONS 6.1 Clinical Trials Experience 7. DRUG INTERACTIONS 7.1 Estrogens and estrogen agonist/antagonist 7.2 Fluconazole 7.3 Rifampin 7.4 Ketoconazole 7.5 Warfarin 7.6 Highly Protein-Bound Drugs 7.7 Multiple Enzyme Inhibition 8. USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known whether OSPHENA is excreted in human breast milk (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling ---------------------CONTRAINDICATIONS------------------ Active DVT, pulmonary embolism (PE), or a history of these conditions (4, 5.1) Active arterial thromboembolic disease (for example, stroke and myocardial infarction [MI]), or a history of these conditions (4, 5.1) Known or suspected pregnancy (4, 8.1) 10. 11. 12. 13. 14. 16. 17. 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CLINICAL STUDIES HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling PATIENT COUNSELING INFORMATION 17.1 Hot Flashes or Flushes 17.2 Vaginal Bleeding * Sections or subsections omitted from the Full Prescribing Information are not listed. OSPH HENATM (OSPEM MIFENE) FULL PRESCRIBING G INFORMATION N WAR RNING: ENDOM METRIAL CANC CER AND CARDIIOVASCULAR DISORDE ERS Endometrial Cancer OSPH HENA is an estrog gen agonist/antag gonist with tissuee selective effects. In the endometrium, OSPHENA O has esstrogen agonisticc effects. There iss an inccreased risk of en ndometrial canceer in a woman with w a uterus who o uses u unopposed estro ogens. Adding a progestin to estrogen e therapy y reducees the risk of endometrial hyperpllasia, which may be a precursor to o endom metrial cancer. Adequate A diagnosstic measures, in ncluding directed d and raandom endometriial sampling when n indicated, shou uld be undertaken n to rulle out malignanccy in postmenop pausal women with w undiagnosed d persisttent or recurring abnormal gen nital bleeding [seee Warnings and d Precau utions (5.2)]. Cardiovascular Disorders There is a reported in ncreased risk of stroke and deep vein thrombosiss (DVT)) in postmenopau usal women (50 to 79 years of ag ge) who received d daily ooral conjugated estrogens (CE) [0.625 mg]-alone therapy over 7.1 1 years aas part of the Wo omen’s Health In nitiative (WHI) [ssee Warnings and d Precau utions (5.1)]. In thee clinical trials for f OSPHENA (duration ( of trea atment up to 15 5 month hs), the incidence rates of thrombo oembolic and hem morrhagic strokee were 00.72 and 1.45 perr thousand women, respectively in i OSPHENA 60 0 mg trreatment group and 1.04 and 0 in placebo [seee Warnings and d Precau utions (5.1)]. The incidence of DVT T was 1.45 per tho ousand women in n OSPH HENA 60 mg treeatment group an nd 1.04 per thousand women in n placeb bo [see Warningss and Precautions (5.1)]. OSPH HENA should bee prescrribed for the shorrtest duration consistent with trea atment goals and d risks ffor the individual woman. 1. IN NDICATIONS AN ND USAGE OSPHE ENA is indicated for f the treatment of o moderate to seveere dyspareunia, a symptoom of vulvar and vaginal v atrophy, du ue to menopause. 2. DO OSAGE AND AD DMINISTRATIO ON OSPHE ENA is an estrog gen agonist/antago onist which has ag gonistic effects on n the enddometrium. Generrally, when a prod duct with estrogen n agonistic effectss on the endometrium is prescribed p for a po ostmenopausal wom man with a uterus, onsidered to reducce the risk of endo ometrial cancer. A a progestin should be co us does not need d a progestin [seee Warnings and d womann without a uteru Precauutions (5.2)]. Use oof OSPHENA should be for the shortest duration n consistent with h treatmeent goals and risk ks for the individu ual woman. Postm menopausal women n shouldd be re-evaluated periodically p as cliinically appropriaate to determine iff treatmeent is still necessarry. 2.1 Treatment of Modeerate to Severe Dy yspareunia, a Sym mptom of Vulvar d to Menopausee and Vaaginal Atrophy, due OSPH HENATM (OSPEM MIFENE) OSPH HENA is contrainddicated in womenn who are or mayy become pregnant. OSPH HENA may cause fetal harm when administered to a pregnant woman n. Ospem mifene was embryyo-fetal lethal withh labor difficultiess and increased pu up deathss in rats at doses below clinical exxposures, and embbryo-fetal lethal in rabbitss at 10 times the cclinical exposure bbased on mg/m2. If this drug is used duringg pregnancy, or if a woman becomess pregnant while taaking this drug, sh he shouldd be apprised of thhe potential hazardd to a fetus. 5. W WARNINGS AND D PRECAUTION NS 5.1 Caardiovascular Dissorders Risk factors for carddiovascular disordders, arterial vascular disease (fo or a, exampple, hypertension, diabetes mellitus, tobacco use, hyppercholesterolemia and obbesity) and/or vennous thromboembolism (VTE) (for example, persona al historyy or family historyy of VTE, obesity, and systemic luppus erythematosus), shouldd be managed apprropriately. Strokee In thee WHI estrogen-allone substudy, a sstatistically signifiicant increased risk E of strooke was reported in women 50 to 79 years of age rreceiving daily CE (0.6255 mg)-alone com mpared to women in the same agge group receivin ng placebbo (45 versus 33 per ten thousand women-years). T The increase in risk was deemonstrated in yeaar 1 and persisted. In thee clinical trials forr OSPHENA (duraation of treatmentt up to 15 months), the inccidence rates of thhromboembolic annd hemorrhagic strroke were 0.72 and 1.45 pper thousand wom men, respectively inn OSPHENA 60 m mg treatment grou up and 1..04 and 0 per thoussand women in plaacebo. Shouldd thromboembolicc or hemorrhagic sstroke occur or be suspected, OSPH HENA should be diiscontinued immeddiately. Coronnary Heart Diseasee In thee WHI estrogen-aalone substudy, nno overall effect on coronary hearrt diseasse (CHD) events (ddefined as nonfataal MI, silent MI, oor CHD death) wa as he reportted in women recceiving estrogen-aalone compared tto placebo. In th HENA clinical triaals, a single MI occcurred in a womaan receiving 60 mg m OSPH of osppemifene. Venouus Thromboemboliism In thee WHI estrogen-aalone substudy, thhe risk of VTE (D DVT and PE), wa as increaased for women receiving daily C CE (0.625 mg)-aalone compared to t placebbo (30 versus 22 per ten thousandd women-years), although only th he increaased risk of DVT reached statisticaal significance (233 versus 15 per ten thousaand women-years)). The increase inn VTE risk was deemonstrated durin ng the firrst 2 years. In the OSPHENA cliniccal trials, the inciddence of DVT wass 1.45 per thousan nd womeen in OSPHENA 660 mg treatment ggroup and 1.04 peer thousand women PHENA should be b in plaacebo. Should a VTE occur or bee suspected, OSP disconntinued immediateely. Take oone 60 mg tablet with w food once daily y. If feassible, OSPHENA should be disconntinued at least 4 to 6 weeks beforre surgerry of the type assoociated with an inccreased risk of thrromboembolism, or o duringg periods of prolonnged immobilizatioon. 3. DO OSAGE FORMS AND STRENGT THS 5.2 M Malignant Neoplassms OSPHE ENA tablets are white w to off-white,, oval, biconvex, film f coated tabletss containning 60 mg of ospeemifene and engraaved with “60” on one side. Endom metrial Cancer 4. CO ONTRAINDICAT TIONS OSPHE ENA is contraindiicated in women with w any of the following conditions: U Undiagnosed abnorrmal genital bleeding K Known or suspecteed estrogen-depend dent neoplasia A Active DVT, pulmonary embolism (P PE), or a history of these conditions A Active arterial thro omboembolic diseaase [for example, stroke s and m myocardial infarctiions (MI)], or a hisstory of these cond ditions OSPH HENA is an estroggen agonist/antagoonist with tissue sselective effects. In the enndometrium, OSPH HENA has agonisttic effects. In the O OSPHENA clinica al trials ((60 mg treatment group), no cases oof endometrial canncer were seen witth exposuure up to 52 we eks. There was a single case of simple hyperplasiia withouut atypia. Endomeetrial thickening equal to 5 mm or ggreater was seen in the O SPHENA treatmeent groups at a raate of 60.1 per thousand women vss. o 21.2 pper thousand woomen for placebo. The incidencee of any type of prolifeerative (weakly pllus active plus dissordered) endomettrium was 86.1 pe er thousaand women in OS SPHENA vs. 13.33 per thousand w women for placebo o. Uterinne polyps occurredd at an incidence of 5.9 per thousandd women vs. 1.8 pe er thousaand women for plaacebo. 2 OSPH HENATM (OSPEM MIFENE) HENATM (OSPEM MIFENE) OSPH An inccreased risk of en ndometrial cancer has been reporteed with the use off unoppoosed estrogen th herapy in a wom man with a uterrus. The reported d endom metrial cancer risk among unopposeed estrogen users is about 2 to 12 2 times greater than in non-users, and appears a dependen nt on duration off gen dose. Most stu udies show no sig gnificant increased d treatmeent and on estrog risk associated with the use u of estrogens fo or less than 1 yearr. The greatest risk k appearrs to be associated with prolonged usse, with increased risks of 15- to 24-fold foor 5 to 10 years or more. This risk has h been shown to persist for at leastt 8 to 15 years after estro ogen therapy is discontinued. d Addiing a progestin to o b shown to reeduce the risk off postmeenopausal estrogeen therapy has been endom metrial hyperplasiaa, which may be a precursor to en ndometrial cancer. There are, however, po ossible risks that may m be associated d with the use off o estrogen-alone regimens. Thesee progestins with estrogeens compared to r of breast can ncer. The use of progestins with h includee an increased risk OSPHE ENA therapy was not evaluated in th he clinical trials. Tablee 1: Clinicaal surveillance of all women using OSPHENA is imp portant. Adequatee diagnoostic measures, in ncluding directed or random endo ometrial sampling g when indicated, shou uld be undertakeen to rule outt malignancy in n n with undiagnoseed persistent or reecurring abnormall postmeenopausal women genitall bleeding. Breast Cancer ENA 60 mg has not been adequately studied in women w with breastt OSPHE cancer; therefore, it should not be used in women with kn nown or suspected d breast cancer or with a history of breast can ncer. 5.3 Sevvere Hepatic Imp pairment OSPHE ENA should not be b used in women with w severe hepatiic impairment [seee Use in Specific Populatio ons (8.7), and Clin nical Pharmacolog gy (12.3)]. Adverse Reactions Repoorted More Com mmon in the NA Treatment Grroup (60 mg Oncee Daily) and at OSPHEN Frequenccy ≥1.0% in th he Double-Blind d, Controlled Clinical T Trials with OSPH HENA vs. Placeboo Ospemifene 60 mg Placebo (N=1242) (N=958) % % 7.5 2.6 Vaaginal discharge 3.8 0.3 enital discharge Gen 1.3 0.1 3.2 0.9 1.6 0.6 Vascuular Disorders Hoot flush Reprooductive System annd Breast Disordders Muscuuloskeletal and Coonnective Tissuee Disorders Muuscle spasms Skin aand Subcutaneous Tissuee Disorders Hyyperhidrosis 6. AD DVERSE REACT TIONS 7. D DRUG INTERAC CTIONS The foollowing serious adverse reaction ns are discussed elsewhere in thee labelinng: OSPH HENA is primarilyy metabolized byy CYP3A4 and CY YP2C9. CYP2C19 and otther pathways conttribute to the metaabolism of ospemiffene. 6.1 Cardiovascular Disorders [see Boxed B Warning, Warnings W and Precautions (5.1)] ( Malignant Neeoplasms [see Boxxed Warning, Warn nings and Precautions (5.2)] ( Clinical Tria als Experience Becausse clinical trials arre conducted underr widely varying conditions, c adversee reactioon rates observed in the clinical trials t of a drug cannot c be directly y compaared to rates in the clinical trials of another a drug and may m not reflect thee rates obbserved in practicee. The saafety of OSPHENA A has been assesseed in nine phase 2/3 2 trials (N=1892)) with ddoses ranging from m 5 to 90 mg perr day. The duratio on of treatment in n these sstudies ranged from m 6 weeks to 15 months. m Most wom men (N=1370) had d a treatm ment period of at least 12 weeks, 40 09 had at least 52 weeks (1 year) off exposuure. The incidence rates of th hromboembolic an nd hemorrhagic strroke were 0.72 perr ported case of thrromboembolic stro oke) and 1.45 perr thousannd women (1 rep thousannd women (2 rep ported cases of hemorrhagic strokee), respectively in n OSPHE ENA 60 mg treaatment group and 1.04 and 0 per thousand women, respecttively in placebo. The incidence off deep vein throm mbosis (DVT) wass 1.45 per thousand womeen in OSPHENA 60 mg treatment group (2 reported d n placebo. cases oof DVT) and 1.04 (1 case of DVT) in Table 1 lists adverse reacctions occurring more m frequently in the t OSPHENA 60 0 mg treaatment group than n in placebo and at a frequency ≥1%.. 7.1 Esstrogens and estroogen agonist/antaagonist OSPH HENA should not be used concom mitantly with estroogens and estrogen agonissts/antagonists. T The safety of conncomitant use off OSPHENA witth estroggens and estrogen aagonists/antagonissts has not been stuudied. 7.2 Flluconazole Fluconnazole, a moderaate CYP3A / stroong CYP2C9 / m moderate CYP2C19 inhibittor, should not bbe used with OSP PHENA. Fluconaazole increases th he system mic exposure of oospemifene by 2.7-fold. Administrattion of fluconazolle with ospemifene mayy increase the riisk of OSPHEN NA-related adversse Pharmacology (122.3)]. reactioons [see Clinical P 7.3 Riifampin Rifam mpin, a strong CY YP3A4 / moderaate CYP2C9 / m moderate CYP2C19 induceer, decreases the ssystemic exposuree of ospemifene bby 58%. Therefore e, co-adm ministration of OS SPHENA with drrugs such as rifam mpin which induc ce CYP3 A4, CYP2C9 andd/or CYP2C19 acttivity would be exxpected to decreasse ct the syystemic exposure oof ospemifene, whhich may decreasee the clinical effec [see C Clinical Pharmacoology (12.3)]. 7.4 Keetoconazole Ketoc onazole, a strong CYP3A4 inhibitoor increases the syystemic exposure of o mifene by 1.4-foldd. Administrationn of ketoconazolee chronically witth ospem ospem mifene may increasse the risk of OSPH HENA-related advverse reactions [se ee Cliniccal Pharmacology (12.3)]. 7.5 W Warfarin Repeaated administrationn of ospemifene haad no effect on thee pharmacokinetic cs of a ssingle 10 mg dosee of warfarin. No study was conduucted with multiplle mifene on clottingg time such as th he doses of warfarin. Thee effect of ospem ot Internnational Normalizeed Ratio (INR) oor prothrombin tiime (PT) was no studie d [see Clinical Phharmacology (12.33)]. 3 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) 7.6 Higghly Protein-Bou und Drugs 8.7 Heepatic Impairmen nt Ospem mifene is more thaan 99% bound to serum s proteins and might affect thee proteinn binding of otherr drugs. Use of OSPHENA O with otther drug productss that arre highly protein bound b may lead to t increased expossure of either thatt drug orr ospemifene [see Clinical Pharmaccology (12.3)]. The ppharmacokinetics of ospemifene haas not been studieed in women witth severee hepatic impairm ment (Child-Pughh Class C); therrefore, OSPHENA A shouldd not be used in w women with severre hepatic impairm ment [see Warning gs and Pr Precautions (5.3), aand Clinical Pharm macology (12.3)]. 7.7 Mu ultiple Enzyme In nhibition No cllinically importantt pharmacokineticc differences withh OSPHENA werre men with mild too moderate hepatiic impairment an nd observved between wom healthhy women [see Cliinical Pharmacoloogy (12.3)]. Co-adm ministration of OS SPHENA with a drug d known to inh hibit CYP3A4 and d CYP2C C9 isoenzymes may m increase the risk of OSPHEN NA-related adversee reactioons. 8. US SE IN SPECIFIC C POPULATIONS S No doose adjustment off OSPHENA is reequired in womenn with mild (Child dPugh C Class A) or moderrate (Child-Pugh C Class B) hepatic im mpairment. 8.1 Preegnancy 10. O OVERDOSAGE Teratoogenic effects: There is no specific antiidote for OSPHEN NA. Pregnaancy Category X [see [s Contraindicatiions (4)]. Risk S Summary Based on animal data, OSPHENA is lik kely to increase th he risk of adversee outcom mes during pregnaancy and labor. Adverse A findings at a maternally toxicc doses iincluded embryofeetal lethality in rats and rabbits, and neonatal mortality y and difficult labor in raats. The reproductive effects observ ved are consistentt d to estrogen recceptor activity off with aand are considereed to be related OSPHE ENA. 11. D DESCRIPTION OSPH HENA is an estrogeen agonist/antagonnist. The chemicall structure of ospem mifene is shown in Figure 1. Animaal Data The efffects of OSPHEN NA on embryo-fetaal development were w studied in ratss (0.1, 1 or 4 mg/kg/day)) and rabbits (3, 10, or 30 mg/kg/d day) when treated d mplantation throug gh organogenesis. In rabbits, there was w an increase in n from im the inccidence of total resorptions at 30 0 mg/kg/day (10 times the human n exposuure based on surfface area mg/m2). Drug-induced maalformations weree not obsserved in either ratts or rabbits. The efffects of OSPHEN NA on pre-and posstnatal developmen nt were studied in n pregnaant rats (0.01, 0.0 05, and 0.25 mg//kg/day) treated from f implantation n throughh lactation. Pregn nant rats given 0.05 or 0.25 mg/k kg/day OSPHENA A (0.8% to 4% the humaan exposure baseed on surface areea mg/m2), had a n significcantly prolonged and difficult gesstation, increased post-implantation loss, inncreased number of dead pups at birth, b and an increeased incidence off postnattal loss. OSPHEN NA did not inducce adverse effectss in the surviving g offspriing of pregnant ratts at drug exposurees up to 4% the hum man exposure. 8.3 Nu ursing Mothers It is noot known whether OSPHENA O is excrreted in human breeast milk. In a noonclinical study, ospemifene o was excreted e in rat millk and detected att concenntrations higher thaan that in maternall plasma. 8.4 Ped diatric Use OSPHE ENA is not indicatted in children. Clinical studies havee not been conduccted in the pediatriic population. hemical structuree Figure 1: Ch The chemical dessignation is 1Z-2-[4-(4-chloro--1,2-diphenylbut-1 mpirical formula C24H23ClO2, which enyl)pphenoxy]ethanol, and has the em corressponds to a moleccular weight of 3778.9. Ospemifenee is a white to offfwhite crystalline powdeer that is insoluble in water and solubble in ethanol. Each OSPHENA tablett contains 60 mg of ospemifene. Innactive ingredientts e, includde colloidal siliccon dioxide, hyypromellose, lacttose monohydrate magneesium stearate, maannitol, microcrysttalline cellulose, ppolyethylene glycol, povidoone, pregelatinizeed starch, sodium m starch glycolate,, titanium dioxide e, and triiacetin. 12. C CLINICAL PHA ARMACOLOGY 12.1 M Mechanism of Acttion OSPH HENA is an estroggen agonist/antagoonist with tissue selective effects. Itts biologgical actions are m mediated through binding to estroggen receptors. Thiis bindinng results in activaation of estrogenicc pathways in som me tissues (agonism m) and bllockade of estrogeenic pathways in otthers (antagonism)). 12.3 P Pharmacokineticss 8.5 Geeriatric Use Absorp rption Of the 1892 OSPHENA--treated women en nrolled in the nine phase 2/3 trials off ENA, >19 percen nt were 65 yearss of age or oldeer. No clinically y OSPHE meaninngful differences in safety or effectiv veness were obserrved between thesee womenn and younger wom men less than 65 years y of age. Follow wing a single orral administrationn of OSPHENA 60 mg tablet in postm menopausal womeen under fastedd condition, peaak median serum m concenntrations was reacched at approxim mately 2 hours (rannge: 1 to 8 hourss) post-ddose (see Figure 2). Mean ospem mifene Cmax and A AUC0-inf were 533 ng/mL L and 4165 ng•hr/m mL, respectively. After a single oraal administration of o OSPH HENA 60 mg tabblet in postmenoppausal women wiith a high fat/high caloriee (860 kcal) meal, Cmax was reachedd at approximately 2.5 hours (range: 1 to 6 hoours) post-dose. M Mean ospemifene Cmax and AUC0-innf were 1198 ng/mL L and 75521 ng•hr/mL, resspectively. The abbsolute bioavailability of ospemifen ne was not evaluated. Ospemifene exhhibits less than dose-proportiona al macokinetics from 25 to 200 mg w with ospemifene caapsule formulation n. pharm Accum mulation of ospem mifene with respeect to AUC0-inf waas approximately 2 after tw welve weeks of daaily administrationn. Steady-state wass reached after nin ne days oof ospemifene adm ministration. 8.6 Reenal Impairment w with severee renal impairmentt The phharmacokinetics off ospemifene in women (CrCL <30 mL/min) was w similar to th hose in women with w normal renall harmacology (12.3 3)]. functioon [see Clinical Ph No doose adjustment of o OSPHENA iss required in women with renall impairm ment. 4 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) Figuree 2: Mean serum concentration c proffile of ospemifene following f a singlee oral addministration of OSPHENA O 60 mg ta ablet in postmenop pausal women under ffed (N=28) and fa asted (N=91) conditions men with moderatte compaared to women wiith normal hepaticc function. In wom hepatiic impairment (C Child-Pugh Classs B), the Cmax and AUC0-inf fo or ospem mifene following a single 60 mg doose administered w with a high fat/hig gh caloriee meal were higheer by 1% and 29% %, respectively, coompared to women with nnormal hepatic funnction. The effect of severe hepatic impairment on th he pharm macokinetics of osspemifene has nott been evaluated [[see Warnings and Precauutions (5.3), and U Use in Specific Poppulations (8.7)]. Drug IInteractions Ospem mifene is metabollized primarily byy CYP3A4 and CYP2C9. CYP2C19 and otther pathways conntribute to the meetabolism of ospem mifene. In order of o decreaasing potency, osspemifene was suuggested to be a weak inhibitor fo or CYP22B6, CYP2C9, CY YP2C19, CYP2C88, CYP2D6 and C CYP3A4 in in vitrro i studie s. Ospemifene is nnot a significant P--glycoprotein subsstrate in vitro; no in was conducted. vivo trransporter study w Effect of Co-Administerred Drugs on the P Pharmacokinetics oof Ospemifene Food E Effect In geneeral, food increaseed the bioavailabillity of ospemifene by approximately y 2-3 folld. In a cross-stud dy comparison, sin ngle dose OSPHE ENA 60 mg tablett adminiistered with a high h fat/high calorie meal (860 kcal) in i postmenopausall womenn increased Cmax and AUC0-inf by y 2.3- and 1.7-ffold, respectively, compaared to fasted con ndition. Eliminatio on half-life and time t to maximum m concenntration (Tmax) weere unchanged in the presence of food. f In two food d effect studies in healthy males using diffeerent ospemifene tablet t formulationss d 1.8-fold, respecttively, with a low w Cmax annd AUC0-inf increeased by 2.3- and fat/low w calorie meal (300 ( kcal) and increased by 3..6- and 2.7-fold, respecttively, with a high h fat/high calorie meal m (860 kcal), compared c to fasted d conditiion. OSPHENA A should be tak ken with food [see [ Dosage and d Administration (2.1)]. Distribbution OSPHE ENA is highly (> >99 percent) boun nd to serum proteeins. The apparentt volumee of distribution iss 448 L. Metaboolism In vitroo experiments witth human liver microsomes indicateed that ospemifenee primarrily undergoes mettabolism via CYP P3A4, CYP2C9 an nd CYP2C19. Thee major metabolite was 4-hydroxyospem mifene. The apparent total body y a clearannce is 9.16 L/hr using a population approach. Excretion h of ospem mifene in postmeno opausal women iss The appparent terminal half-life approxximately 26 hourss. Following an oral administratio on of ospemifene, approxximately 75% and d 7% of the dosee was excreted in n feces and urine, respecttively. Less than 0.2% 0 of the ospem mifene dose was ex xcreted unchanged d in urine. ons Use in Specific Populatio Pediatrric The pharmacokinetics of ospemifene in n pediatric patien nts has not been n pecific Populationss (8.4)]. evaluatted [see Use in Sp Geriatrric No diffferences in ospem mifene pharmacokiinetics were deteccted with regard to o age (raange 40 to 80 yearss) [see Use in Speccific Populations (8.5)]. ( Race harmacokinetics. Race ddid not have clinicaally relevant effectt on ospemifene ph Renal IImpairment In wom men with severe renal r impairment (CrCL <30 mL/m min), the Cmax and d AUC0-inf for ospemifenee following a sing gle 60 mg dose ad dministered with a high ffat/high calorie meal m were loweer by 21% and higher by 20%, respecttively [see Use in Specific Populatio ons (8.6)]. Hepatiic Impairment In wom men with mild hep patic impairment (Child-Pugh Classs A), the Cmax and d AUC0-inf for ospemifenee following a sing gle 60 mg dose ad dministered with a high ffat/high calorie meal m were lower by 21% and 9..1%, respectively, Fluconnazole (CYP3A4/C CYP2C9/CYP2C199 Inhibitor) Fluconnazole (a moderaate CYP3A / stroong CYP2C9 / m moderate CYP2C19 inhibittor) 400 mg was given on Day 1 ffollowed by 200 m mg on Days 2 to 5 under fasted condition. On Day 5 approoximately one houur after fluconazolle es adminnistration, ospemiffene 60 mg was addministered after brreakfast (two slice of breead with ham, cheeese, a few slicess of cucumber and/or tomatoes, and juice).. Fluconazole 2000 mg was taken fo for three additionall days under fasted condittion. Multiple dosses of fluconazole in fourteen postm menopausal women increaased the Cmax annd AUC0-inf of oospemifene by 11.7- and 2.7-fold d, respecctively [see Drug IInteractions (7.2)]]. Rifamppin (CYP3A4/CYP P2C9/CYP2C19 Innducer) Rifam mpin 600 mg was ggiven once daily ffor 5 consecutive ddays (given at leasst one hoour before or twoo hours after a meeal) in the late aft fternoon. On Day 6 after aan overnight fast, ospemifene 60 m mg was administerred in the mornin ng after uunder fed conditionn (two slices of brread with ham, cheeese, a few slices of o cucum mber and/or tomatooes, and juice). M Multiple doses of rrifampin 600 mg in twelvee postmenopausal women reduced Cmax and AUC0-inff of ospemifene by 51% aand 58%, respecttively. Rifampin aand other inducerrs of CYP3A4 arre expectted to decrease the systemic exxposure of ospem mifene [see Drug Interaactions (7.3)]. Ketocoonazole (CYP3A4 Inhibitor) Ketoc onazole 400 mg was given once daily for 4 conssecutive days afte er breakffast. On Day 5 after an overnighht fast, ketoconaazole 400 mg an nd ospem mifene 60 mg werre co-administeredd under fed condiition (two slices of o bread with ham, cheese,, a few slices of cuucumber and/or toomatoes, and juice). ys Ketoc onazole administrration once daily continued for ann additional 3 day nd (Days 6 to 8). Co-admiinistration of a sinngle 60 mg dose of ospemifene an multipple doses of ketocconazole in twelvve postmenopausall women increased Cmax aand AUC0-inf by 11.5- and 1.4-fold, respectively [see Drug Interaction ns (7.4)].. Omeprrazole (CYP2C19 Inhibitor) Omepprazole (a moderatte CYP2C19 inhiibitor) 40 mg wass given for 5 dayss. Day 5, approxim mately one hourr after omeprazoole administration n, On D ospem mifene 60 mg was administered afteer breakfast (two sslices of bread witth ham, ccheese, a few slicces of cucumber aand/or tomatoes, aand juice). Multiplle doses of omeprazole inn fourteen postmennopausal women increased Cmax an nd AUC00-inf by 1.20- and 1..17-fold, respectivvely. Effect of Ospemifene onn the Pharmacokinnetics of the Co-Addministered Drug Warfaarin Ospem mifene 60 mg wass given after a lighht breakfast (two sslices of bread witth ham aand cheese and juiice) once daily forr 12 days in sixteen postmenopausa al womeen who were deetermined to bee rapid metaboliizers of CYP2C9 P2C9*1/*2). On Daay 8, a single dosee of warfarin 10 mg m (CYP22C9*1/*1 or CYP and viitamin K 10 mg w were administered one hour after a llight breakfast. Th he geomeetric mean ratio (990% CI) for S-waarfarin with and w without ospemifen ne for Cmmax and AUC0-inf weere 0.97 (0.92-1.022) and 0.96 (0.91--1.02), respectively y. Multipple doses of ospem mifene did not signnificantly affect the pharmacokinetic cs of a siingle dose of warrfarin. No study w was conducted withh multiple doses of o warfarrin. 5 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) Omeprrazole Ospem mifene 60 mg was administered oncee daily for 7 days after a light meall in the late afternoon in fourteen postmenopausal women. On O Day 8 after an n o was ad dministered in thee overnigght fast, a single 20 mg dose of omeprazole morninng of at least 10 hrrs; ospemifene wass not given on Day y 8. The geometricc mean rratios for the metabolic index (omep prazole/5-hydroxyo omeprazole) at thee concenntration at the 3 hr time point and for AUC0-8hr was w 0.97 with and d withouut ospemifene. It is unclear if ospemifene will affect thee pharmaacokinetics of dru ugs metabolized by b CYP2C19 due to the significantt time gaap between ospem mifene and omeprazzole administration n. postm menopausal womenn between 41 to 811 years of age (meean 59 years of age e) who aat baseline had ≤5 percent superficiaal cells on a vaginnal smear, a vagina al pH >55.0, and who identtified at least one moderate to severre vaginal symptom m that w was considered the most bothersomee to her (vaginal drryness, pain durin ng intercoourse [dyspareuniia], or vaginal irrritation/itching). Treatment group ps includded 30 mg OSPHE ENA (n=282), 60 m mg OSPHENA (n= =276), and placebo (n=26 8). All women weere assessed for im mprovement in thee mean change from m Baseliine to Week 122 for the co-priimary efficacy vvariables of: mosst botherrsome symptom ((MBS) of vulvar and vaginal atropphy (defined as th he individdual moderate to severe symptom tthat was identifiedd by the woman as a most bbothersome at baseline), percentagge of vaginal supeerficial and vagina al parabaasal cells on a vagginal smear, and vvaginal pH. Follow wing completion of o 12-weeeks, women withh an intact uterus w were allowed to eenroll in a 40-week doublee-blind extensionn study, and wom men without an iintact uterus werre alloweed to enroll in a 522-week open-labell extension study. Buproppion Ospem mifene 60 mg was administered oncce daily for seven n consecutive dayss after thhe evening meal in sixteen postmeenopausal women (not homozygouss for CY YP2B6*6). On thee Day 8 after overrnight fast, a singlle 150 mg dose off sustainned release bupro opion was admin nistered in morn ning under fasted d conditiion. The geometricc mean ratio (90% % CI) for bupropion n with and withoutt ospemiifene for Cmax and d AUC0-inf were 0.8 82 (0.75-0.91) and d 0.81 (0.77-0.86), respecttively. The geomeetric mean ratio (90% CI) for hydrroxybupropion, an n active metabolite formed d via CYP2B6, wiith and without osspemifene for Cmaxx UC0-inf were 1.16 (1.09-1.24) and 0.9 98 (0.92-1.04), resp pectively. and AU 13. N NONCLINICAL TOXICOLOGY T 13.1 C Carcinogenesis, Mutagenesis, M Impa airment of Fertilitty Carcinnogenesis In a 2--year carcinogeniccity study in femaale mice, ospemifeene administration n of 1000, 400 or 1500 mg/kg/day was well tolerated. No N evaluation forr carcinoogenicity was cond ducted in male micce. There was sign nificant increase in n adrenaal subcapsular cell adenomas at 4 and d 5 times the hum man exposure based d on AU UC, and adrenal co ortical tumors at 5 times the human n exposure. In thee ovary, an increase in sex cord/stromal tumors, tubullostromal tumors, a luteomas weree also seen. These findings occurred d granuloosa cell tumors, and at dosees 2 to 5 times th he human exposurre based on AUC, and are probably y relatedd to estrogenic/antiiestrogenic effect of o ospemifene in mice. m In a 2--year carcinogenicity study in rats, ospemifene o adminiistration of 10, 50, w tolerated. A siignificant increasee in thymomas wass or 300 mg/kg/day was well hymomas for femaales at all ospemiffene dose levels, orr recordeed for males and th 0.3 to 1.2 times the hum man exposure baseed on AUC. In thee liver, an increasee in hepaatocellular tumorss were recorded att for females at all ospemifene dosee levels. Mutaggenesis The seecond clinical triaal was a 12-week, randomized, douuble-blind, placebo ocontroolled, parallel-grooup study that enrolled 919 generally health hy postm menopausal womenn between 41 to 799 years of age (meean 59 years of age e) who aat baseline had ≤5 percent superficiaal cells on a vaginnal smear, a vagina al pH > 5.0, and who iddentified either m moderate to severre vaginal drynesss a (dryneess cohort) or mooderate to severe ddyspareunia (dysppareunia cohort) as most bothersome to hher at baseline. T Treatment groupss included 60 mg m HENA (n=463) an and placebo (n=4456). Primary enddpoints and stud dy OSPH conduuct were similar to those in Trial 1. The thhird clinical trial was a 52-week, randomized, doubble-blind, placebo ocontroolled, long-term safety study thaat enrolled 426 generally healthy postm menopausal womenn between 49 to 799 years of age (meean 62 years of age e) with aan intact uterus. T Treatment groups iincluded 60 mg O OSPHENA (n=363 3) and pllacebo (n=63). Effectss on Dyspareunia In thee 1st and 2nd clinnical trial, the moodified intent-to-ttreat population of o womeen treated with OS SPHENA when coompared to placebbo, demonstrated a ne statistiically significant iimprovement (leasst square mean chaange from Baselin to Weeek 12) in the modderate to severe m most bothersome ssymptom (MBS) of o dysparreunia (1st trial p= =0.0012, 2nd trial p< <0.0001). See Tabble 2. A statistically signifi ficant increase in tthe proportion of ssuperficial cells annd a correspondin ng statistiically significant decrease in the proportion of paarabasal cells on a vaginaal smear was allso demonstratedd (p<0.0001 for both). The mea an reducttion in vaginal pH H between baselinee and Week 12 w was also statisticallly signifi ficant (p<0.0001). mifene was not genotoxic g in vitro o in the Ames test t in strains off Ospem Salmonnella typhimurium m or at the thym midine kinase (tk)) locus of mousee lymphooma L5178Y cellls in the absence and in the presen nce of a metabolicc activattor system. In in vivo testing, ospemifene was no ot genotoxic in a standarrd mouse bone maarrow micronucleu us test or in a deterrmination of DNA A adductts in the liver of ratts. Impairrment of Fertility The eff ffect of ospemifenee on fertility was not n directly evaluatted. In female ratss and m monkeys, decreasess in ovarian and uterine weights, decreased d corporaa lutea nnumber, increased ovarian cysts, utterine atrophy, and d disrupted cycless were oobserved when giv ven repeated daily oral doses. In maale rats, atrophy off the proostate and seminaal vesicles was noted. The effectts on reproductivee organs observed in anim mals are consistentt with the estrogen n receptor activity y ntial for impairmen nt of fertility. of ospeemifene and poten 14. C CLINICAL STUD DIES The efffectiveness and saafety of OSPHENA on moderate to o severe symptomss of vulvvar and vaginal atrophy in postmen nopausal women were examined in n three pplacebo-controlled d clinical trials (tw wo 12-week efficaacy trials and onee 52-weeek long-term safetty trial). In the thrree placebo-contro olled trials, a totall of 787 women received placebo p and 1102 women received 60 6 mg OSPHENA.. w a 12-week, randomized, r doub ble-blind, placebo-The first clinical trial was oup study that enrolled 826 generally g healthy y controllled, parallel-gro 6 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) Table 2: Vaginal Bleeding 17.2 V Week 12 Effects on Dy yspareunia (the Woman’s Self-me Moderate to Severe Symptom m Identified Most Bothersom of Vulvar and Vaginal Atrrophy at Baselinee). Mean Changee in Severitty at Week 12 with Last Obseervation Carried d Forward (LOCF), ( Modified Intent-to-Treatt Populationa Inform m postmenopausaal women of thee importance of reporting unusua al vaginaal bleeding to thheir healthcare pproviders as soonn as possible [se ee Warniings and Precautioons (5.2)]. 1st Clinical Trial Resullts Most B Bothersome Moderrate to Severee Symptom at Baseeline OSPHEN NA 60 mg Placebo (N=110) (N=113) Dyspareeunia Baseeline Mean (SD) LS M Mean Change from Baseline B (SE) p-value vs. placebo 2.7 (0 0.44) 2.7 2 (0.45) -1.39 (0.11) ( -0 0.89 (0.11) 0.001 12 ---- 2nd Clinical Trial Results Most Boothersome Moderatee to Severe Symptom at Baselinee OSPHEN NA 60 mg Placebo (N=3 301) (N=297) Dyspareeunia Baseline Mean (SD) Mean Change from LS M Baseline (SE) pp-value vs. placebo a. 2.7 (0.47) 2.7 (0.47) -1.55 (0 0.06) -1.29 (0.07) <0.000 01 --- T The modified inten nt-to-treat populatiion (mITT) includ ded only women in n thhe ITT population who at baselin ne met the inclusiion criteria of ≤5 5 ppercent superficial cells on a vaginal smear, a vaginal pH p > 5.0, and who o iddentified moderatte or severe dyspareunia as her most bothersomee vvaginal symptom. Definittions: LOCF = lastt observation carriied forward; SD = standard deviatiion; SE = standard d error; LS = least square 16. H HOW SUPPLIED D/STORAGE AND D HANDLING 16.1 H How Supplied OSPHE ENA tablets are white w to off-white,, oval, biconvex, film f coated tabletss containning 60 mg of osp pemifene and eng graved with “60” on o one side. They y are avaailable as follows: NDC 559630-580-10 Bottle off 100 tablets NDC 559630-580-30 Blister pack of 30 tablets containing c 2 blisterr cards of 15 tablets each 16.2 Sttorage and Handling Store aat 20º to 25ºC (68ºº to 77ºF); excursiions permitted to 15º 1 to 30ºC (59º to o 86ºF) [[see USP Controlleed Room Temperaature]. 17. P PATIENT COUN NSELING INFOR RMATION See FDA-apprroved patient labeling (Patient Information) 17.1 H Hot Flashes or Flu ushes OSPHE ENA may initiate or increase the occcurrence of hot flaashes in some womenn. 7 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) Patient Information and know th he results. Do not take OSPH HENA if the tes st is positive an nd talk to yourr healthcare prrovider. TM OS SPHENA (os s fee’ nah) (ospemiffene) tabletts Read this Patientt Information before you start taking g OSPH HENA and each h time you gett a refill. There e may be new w inform mation. This information does not take the place off talkin ng to your healthcare h pro ovider about your medical condition or your tre eatment. Wha at is the most important in nformation I should kno ow about OSP PHENA ? OSPHENA is a medicine th hat works lik ke estrogen in the lining of the uterus s (womb), but can work differently in n other parts of the body. Taking estro ogen-alone or r OSPHENA may m increase you ur chance of getting g cance er of the lining of the uterus (wom mb). Vaginal bleeding b after menopause may be a warning sign of cancer of the e lining of the e uterus (wom mb). Your healthcare provider p should check any unusual vaginal bleed ding to find out o the cause. Tell your healthcare provider p rightt away if you have any unusual vaginal bleeding while you ar re taking OSPHENA. OSPHENA may increase your y chance of o getting strokes and blood clots. You and your healthcare provider should talk out whether you y still need d regularly abo treatment with w OSPHENA A. at should I telll my healthcare provider before taking g Wha OSPH HENA? Befo ore you take O OSPHENA, telll your health hcare provider if yo ou: have any u nusual vaginal bleeding Vaginal blee eding after me enopause may y be a warning sign of cancer of the lining g of the uterus s (womb). You ur healthcare p provider should d check any u unusual vagina al bleeding to ffind out the cause. have any otther medical conditions Such as seve ere liver proble ems. are going t o have surge ery or will be on bed rest Your healthccare provider w will let you know if you need to stop takin ng OSPHENA. are breast ffeeding It is not kno wn if OSPHENA A can pass into o your breast milk. care providerr about all m medicines you u Tell your healthc take e, including pr escription and d non-prescripttion medicines s, vitam mins, and herrbal suppleme ents. Some m medicines may affecct how OSPHE NA works. OS SPHENA may a also affect how w otherr medicines wo ork. Keep a listt of your medicines and show w it to your healthca are provider an nd pharmacist each time you get a new medicine e. Whatt is OSPHENA A? How w should I tak ke OSPHENA? OSPH HENA is an oral o prescriptio on medicine used to treatt painfu ul intercourse, a symptom off changes in an nd around yourr vagina, due to menopause. Take OSPH HENA exactly h how your healtthcare providerr tells you to take it. Take OSPH HENA by moutth 1 time each day with food.. Who should not ta ake OSPHENA A? You and y our healthcare e provider shou uld talk regularly ((every 3 to 6 m months) about the dose you are taking g and whether or not you stilll need treatment with OSPHENA A. Do no ot start taking OSPHENA if yo ou: have unusual vaginal ble eeding Vagin nal bleeding affter menopause may be a warning w sign off cance er of the lining g of the uteru us (womb). Yo our healthcare e provid der should check any unusual vaginal bleeding to find d out th he cause. currently ha ave or have had h certain ca ancers Estrogen ma ay increase the e chances of getting g certain n types of can ncers, such as cancer of the e lining of the e uterus. If yo ou have or hav ve had cancer, talk with yourr healthcare provider p aboutt whether you u should take e OSPHENA. currently ha ave or have had h blood clotts had a stroke e or heart atttack think you may m be pregna ant OSPHENA is not for pregna ant women. If you think you u may be preg gnant, you should have a pregnancy p testt Wha at are the pos ssible side efffects of OSPH HENA? See ““What is the most importa ant informatio on I should know w about OSPH HENA?” Serio ous, but less common side e effects inclu ude: stroke blood clotss cancer of tthe lining of th he uterus (wom mb) Call your healthc care provider right away iif you get any y of th he following warning sig gns or any o other unusua al symp ptoms that co oncern you: unusual va aginal bleeding g changes in n vision or speech sudden ne ew severe head daches severe paiins in your che est or legs with h or without shortness of breath, wea akness and fatigue 8 OSPH HENATM (OSPEM MIFENE) OSPH HENATM (OSPEM MIFENE) Less serious, but common side e effects inclu ude: For more informa ation, go to www.osphena.com or call nogi Inc. at 1-8 855-OSPHENA A (1-855-677-4 4362). Shion hot flushes s or flashes vaginal dis scharge muscle spa asms increased sweating s These e are not all the t possible side effects of OSPHENA. Forr more information, ask your healthcare provider orr pharm macist. Tell your healthcare provider ab bout any side e effectts that bother you y or does no ot go away. Call y your doctor for medical advice e about side efffects. You may rreport side effe ects to FDA at 1-800-FDA-10 088. Whatt can I do to lower my cha ances of a ser rious side effec ct with OSPHE ENA? Talk with your y healthcare e provider regu ularly about whether yo ou should continue taking OS SPHENA. If you have e a uterus, talk k with your hea althcare provider ab bout whether the t addition of a progestin is right for yo ou. See your healthcare h prov vider right awa ay if you develop va aginal bleeding while taking OSPHENA. O Have a pelvic exam, brea ast exam and mammogram m (breast x-rray) every year unless your healthcare h provider te ells you someth hing else. If memberrs of your familly have had bre east cancer or if you have e ever had brea ast lumps or an abnormal mammogra am (breast x-rray), you may need to have breast exams more often n. If you have e high blood prressure, high cholesterol c (fatt in the blood), diabetes, are a overweight, or use tobacco, yo ou may have a higher chance e of getting heart disea ase. Wha at are the ingrredients in OSPHENA? Activ ve Ingredient: o ospemifene Inacttive ingredientss: colloidal silic con dioxide, hy ypromellose, lacto se monohydra te, magnesium m stearate, ma annitol, ocrystalline celllulose, polyeth hylene glycol, p povidone, micro prege elatinized starcch, sodium starch glycolate, titanium dioxi de, and triacettin. This Patient Inform mation has been n approved by the U.S. Food and D Drug Administrration. Manu ufactured for: Shion nogi Inc. Florh ham Park, NJ 0 07932 Manu ufactured by: Penn n Pharmaceuticcal Services Ltd d. 23-24 4 Tafarnaubacch Industrial Es state Trede egar, Gwent, S South Wales NP22 2 3AA, United K Kingdom Made e in UK OSP--PI-MKT-01 Appro y 2013 oved: February your healthcare e provider for ways w to lower your y chances Ask y of gettting heart dise ease. How should I stor re OSPHENA? ? • Store OSPH HENA at room temperature between b 68°F to 77°F (20°C to 25 5°C). Keep p OSPHENA an nd all medicin nes out of the e reach of children. Gene eral informatiion about the e safe and effe ective use of OSPH HENA. Medic cines are sometimes prescribed for condiitions that are e not m mentioned in patient inform mation leaflets. Do not take e OSPH HENA for condiitions for whic ch it was not prescribed. p Do o not g give OSPHENA A to other peo ople, even if they t have the e same e symptoms you have. It may harm them. This leaflet summarrizes the most important info ormation aboutt OSPH HENA. If you would w like more e information, talk with yourr health hcare provide er or pharmacist. You can c ask yourr health hcare providerr or pharmacistt for more info ormation aboutt OSPH HENA that is wrritten for health professionals s. 9