T max (hr) 1.5 ± ± ± 0.6 AUC (0-10) (ng hr/ml)

Transcription

1 Progesterone Cpsules (progesterone, USP), 100 mg nd 200 mg WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER nd PROBABLE DEMENTIA FOR ESTROGEN PLUS PROGESTIN THERAPY Crdiovsculr Disorders nd Probble Dementi Estrogens plus progestin therpy should not be used for the prevention crdiovsculr disese or dementi (see CLINICAL STUDIES nd WARNINGS, Crdiovsculr disorders nd Probble dementi). The Women s Helth Inititive (WHI) estrogen plus progestin substudy reported incresed risks deep vein thrombosis, pulmonry embolism, stroke nd myocrdil infrction in postmenopusl women (50 to 79 yers ge) during 5.6 yers tretment with dily orl conjugted estrogens (CE) [0.625 mg] combined with medroxyprogesterone cette (MPA) [2.5 mg], reltive to plcebo (see CLINICAL STUDIES nd WARNINGS, Crdiovsculr disorders). The WHI Memory Study (WHIMS) estrogen plus progestin ncillry study the WHI reported n incresed risk developing probble dementi in postmenopusl women 65 yers ge or older during 4 yers tretment with dily CE (0.625 mg) combined with MPA (2.5 mg), reltive to plcebo. It is unknown whether this finding pplies to younger postmenopusl women (see CLINICAL STUDIES nd WARNINGS, Probble dementi nd PRECAUTIONS, Geritric Use). Brest Cncer The WHI estrogen plus progestin substudy lso demonstrted n incresed risk invsive brest cncer (see CLINICAL STUDIES nd WARNINGS, Mlignnt neoplsms, Brest Cncer). In the bsence comprble dt, these risks should be ssumed to be similr for other doses CE nd MPA, nd other combintions nd dosge forms estrogens nd progestins. Progestins with estrogens should be prescribed t the lowest effective doses nd for the shortest durtion consistent with tretment gols nd risks for the individul womn. DESCRIPTION Progesterone cpsules contin progesterone, USP for orl dministrtion. Progesterone, USP hs moleculr weight nd moleculr formul C 21H 30O 2. Progesterone, USP (pregn-4-ene-3, 20-dione) is white or cremy white, odorless, crystlline powder prcticlly insoluble in wter, soluble in lcohol, cetone nd dioxne nd springly soluble in vegetble oils, stble in ir, melting between 126 nd 131 C. The structurl formul is: A. Absorption After orl dministrtion progesterone s st-geltin cpsule formultion, mximum serum concentrtions were ttined within 3 hours. The bsolute biovilbility progesterone is not known. Tble 1 summrizes the men phrmcokinetic prmeters in postmenopusl women fter five orl dily doses progesterone cpsules 100 mg s st-geltin cpsule formultion. TABLE 1. Phrmcokinetic Prmeters Progesterone Cpsules Progesterone Cpsules Dily Dose Prmeter 100 mg 200 mg 300 mg C mx (ng/ml) 17.3 ± ± ± 72.5 T mx (hr) 1.5 ± ± ± 0.6 AUC (0-10) (ng hr/ml) ± 43.3 ± ± Men ± S.D. Serum progesterone concentrtions ppered liner nd dose proportionl following multiple dose dministrtion progesterone cpsules 100 mg over the dose rnge 100 mg per dy to 300 mg per dy in postmenopusl women. Although doses greter thn 300 mg per dy were not studied in femles, serum concentrtions from study in mle volunteers ppered liner nd dose proportionl between 100 mg per dy nd 400 mg per dy. The phrmcokinetic prmeters in mle volunteers were generlly consistent with those seen in postmenopusl women. B. Distribution Progesterone is pproximtely 96 percent to 99 percent bound to serum proteins, primrily to serum lbumin (50 to 54 percent) nd trnscortin (43 to 48 percent). C. Metbolism Progesterone is metbolized primrily by the liver lrgely to pregnnediols nd pregnnolones. Pregnnediols nd pregnnolones re conjugted in the liver to glucuronide nd sulfte metbolites. Progesterone metbolites which re excreted in the bile my be deconjugted nd my be further metbolized in the intestine vi reduction, dehydroxyltion nd epimeriztion. D. Excretion The glucuronide nd sulfte conjugtes pregnnediol nd pregnnolone re excreted in the bile nd urine. Progesterone metbolites re eliminted minly by the kidneys. Progesterone metbolites which re excreted in the bile my undergo enteroheptic recycling or my be excreted in the feces. E. Specil Popultions The phrmcokinetics progesterone cpsules hve not been ssessed in low body weight or obese. Heptic Insufficiency: The effect heptic impirment on the phrmcokinetics progesterone cpsules hs not been studied. Renl Insufficiency: The effect renl impirment on the phrmcokinetics progesterone cpsules hs not been studied. F. Food Drug Interction Concomitnt food ingestion incresed the biovilbility progesterone cpsules reltive to fsting stte when dministered to postmenopusl women t dose 200 mg. Progesterone, USP is synthesized from strting mteril from plnt source nd is chemiclly identicl to progesterone humn ovrin origin. Progesterone cpsules re vilble in multiple strengths to fford dosge flexibility for optimum mngement. Progesterone cpsules contin either 100 mg or 200 mg progesterone, USP. The inctive ingredients for progesterone cpsules 100 mg nd 200 mg include: rchis oil, D&C Yellow No. 10 luminum lke, FD&C Yellow No. 6 luminum lke, geltin, glycerin, purified wter, soy lecithin nd titnium dioxide. CLINICAL PHARMACOLOGY Progesterone cpsules re n orl dosge form progesterone which is chemiclly identicl to progesterone ovrin origin. G. Drug Interctions The metbolism progesterone by humn liver microsomes ws inhibited by ketoconzole (IC 50 <0.1 μm). Ketoconzole is known inhibitor cytochrome P450 3A4, hence these dt suggest tht ketoconzole or other known inhibitors this enzyme my increse the biovilbility progesterone. The clinicl relevnce the in vitro findings is unknown. Co-dministrtion conjugted estrogens nd progesterone cpsules to 29 postmenopusl women over 12-dy period resulted in n increse in totl estrone concentrtions (C mx 3.68 ng/ml to 4.93 ng/ml) nd totl equilin concentrtions (C mx 2.27 ng/ml to 3.22 ng/ml) nd decrese in circulting 17β estrdiol concentrtions (C mx ng/ml to ng/ml). The hlf-life the conjugted estrogens ws similr with codministrtion progesterone cpsules. Tble 2 summrizes the phrmcokinetic prmeters. Phrmcokinetics

2 TABLE 2. Men (± S.D.) Phrmcokinetic Prmeters for Estrdiol, Estrone nd Equilin Following Co-dministrtion Conjugted Estrogens mg nd Progesterone Cpsules 200 mg for 12 Dys to Postmenopusl Women Conjugted Estrogens plus Conjugted Estrogens Progesterone Cpsules C mx T mx AUC (0-24h) C mx T mx AUC (0-24h) Drug (ng/ml) (hr) (ng h/ml) (ng/ml) (hr) (ng h/ml) Estrdiol ± ± ± ± ± 1.21 ± Estrone Totl ± 1.55 ± ± ± 2.07 ± 3.8 ± Equilin Totl ± 0.95 ± 4 ± 13 ± 1.13 ± 2.6 ± 20.2 Totl estrogens is the sum conjugted nd unconjugted estrogen. CLINICAL STUDIES Effects on the endometrium In rndomized, double-blind clinicl tril, 358 postmenopusl women, ech with n intct uterus, received tretment for up to 36 months. The tretment groups were: progesterone cpsules t the dose 200 mg per dy for 12 dys per 28-dy cycle in combintion with conjugted estrogens mg per dy (n=120); conjugted estrogens mg per dy only (n=119); or plcebo (n=119). The subjects in ll three tretment groups were primrily Cucsin women (87 percent or more ech group). The results for the incidence endometril in women receiving up to 3 yers tretment re shown in Tble 3. A comprison the progesterone cpsules plus conjugted estrogens tretment group to the conjugted estrogens only group showed significntly lower rte (6 percent combintion product versus 64 percent estrogen lone) in the progesterone cpsules plus conjugted estrogens tretment group throughout 36 months tretment. TABLE 3. Incidence Endometril Hyperplsi in Women Receiving 3 Yers Tretment Endometril Dignosis Conjugted Estrogens mg + Progesterone Cpsules 200 mg (cyclicl) Tretment Group Conjugted Estrogens mg (lone) n=117 n=115 n=116 HYPERPLASIA Adenocrcinom Atypicl Complex Simple Most dvnced result to lest dvnced result: Adenocrcinom > typicl > complex > simple The times to dignosis endometril over 36 months tretment re shown in Figure 1. This figure illustrtes grphiclly tht the proportion with ws significntly greter for the conjugted estrogens group (64 percent) compred to the conjugted estrogens plus progesterone cpsules group (6 percent). Figure 1. Time to Hyperplsi in Women Receiving up to 36 Months Tretment The discontinution rtes due to over the 36 months tretment re s shown in Tble 4. For ny degree, the discontinution rte for who received conjugted estrogens plus progesterone cpsules ws similr to tht the plcebo only group, while the discontinution rte for who received conjugted estrogens lone ws significntly higher. Women who permnently discontinued tretment due to were similr in demogrphics to the overll study popultion. TABLE 4. Discontinution Rte Due to Hyperplsi Over 36 Months Tretment Most Advnced Biopsy Result Through 36 Months Tretment Conjugted Estrogens + Progesterone Cpsules (cyclicl) Tretment Group Conjugted Estrogens (lone) n=120 n=119 n=119 Adenocrcinom Atypicl Complex Simple Effects on secondry menorrhe In single-center, rndomized, double-blind clinicl study tht included premenopusl women with secondry menorrhe for t lest 90 dys, dministrtion 10 dys progesterone cpsules therpy resulted in 80 percent women experiencing withdrwl bleeding within 7 dys the lst dose progesterone cpsules, 300 mg per dy (n=20), compred to 10 percent women experiencing withdrwl bleeding in the plcebo group (n=21). In multicenter, prllel-group, open lbel, postmrketing dosing study tht included premenopusl women with secondry menorrhe for t lest 90 dys, dministrtion 10 dys progesterone cpsules during two 28-dy tretment cycles, 300 mg per dy (n=107) or 400 mg per dy (n=99), resulted in 73.8 percent nd 76.8 percent women, respectively, experiencing withdrwl bleeding. The rte secretory trnsformtion ws evluted in multicenter, rndomized, double-blind clinicl study in estrogen-primed postmenopusl women. Progesterone cpsules dministered orlly for 10 dys t 400 mg per dy (n=22)

3 induced complete secretory chnges in the endometrium in 45 percent women compred to 0 percent in the plcebo group (n=23). A second multicenter, prllel-group, open lbel postmrketing dosing study in premenopusl women with secondry menorrhe for t lest 90 dys lso evluted the rte secretory trnsformtion. All subjects received dily orl conjugted estrogens over 3 consecutive 28-dy tretment cycles nd progesterone cpsules, 300 mg per dy (n=107) or 400 mg per dy (n=99) for 10 dys ech tretment cycle. The rte complete secretory trnsformtion ws 21.5 percent nd 28.3 percent, respectively. Women s Helth Inititive Studies The Women s Helth Inititive (WHI) enrolled pproximtely 27,000 predominntly helthy postmenopusl women in two substudies to ssess the risks nd benefits dily orl conjugted estrogens (CE) [0.625 mg]-lone or in combintion with medroxyprogesterone cette (MPA) [2.5 mg] compred to plcebo in the prevention certin chronic diseses. The primry endpoint ws the incidence coronry hert disese [(CHD) defined s nonftl myocrdil infrction (MI), silent MI nd CHD deth], with invsive brest cncer s the primry dverse outcome. A globl index included the erliest occurrence CHD, invsive brest cncer, stroke, pulmonry embolism (PE), endometril cncer (only in the CE plus MPA substudy), colorectl cncer, hip frcture, or deth due to other cuse. These sub studies did not evlute the effects CElone or CE plus MPA on menopusl symptoms. WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy ws stopped erly. According to the predefined stopping rule, fter n verge follow-up 5.6 yers tretment, the incresed risk brest cncer nd crdiovsculr events exceeded the specified benefits included in the globl index. The bsolute excess risk events in the globl index ws 19 per 10,000 women-yers. For those outcomes included in the WHI globl index tht reched sttisticl significnce fter 5.6 yers follow-up, the bsolute excess risks per 10,000 women-yers in the group treted with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs nd 8 more invsive brest cncers, while the bsolute risk reductions per 10,000 women-yers were 6 fewer colorectl cncers nd 5 fewer hip frctures. Results the estrogen plus progestin substudy, which included 16,608 women (verge 63 yers ge, rnge 50 to 79; 83.9 percent White, 6.8 percent Blck, 5.4 percent Hispnic, 3.9 percent Other) re presented in Tble 5. These results reflect centrlly djudicted dt fter n verge follow-up 5.6 yers. TABLE 5. Reltive nd Absolute Risk Seen in the Estrogen Plus Progestin Substudy WHI t n Averge 5.6 Yers, b Event CHD events Non-ftl MI CHD deth Reltive Risk CE/MPA versus (95% nci c ) 1.23 (0.99 to 1.53) 1.28 (1 to 1.63) CE/MPA n = 8,506 n = 8,102 Absolute Risk per 10,000 Women-Yers (0.70 to 1.75) All stroke 1.31 (1.03 to 1.88) Ischemic stroke 1.44 (1.09 to 1.90) Deep vein thrombosis d 1.95 (1.43 to 2.67) Pulmonry embolism 2.13 (1.45 to 3.11) 18 8 Invsive brest cncer e 1.24 (1.01 to 1.54) Colorectl cncer 0.61 (0.42 to 0.87) Endometril cncer d 0.81 (0.48 to 1.36) 6 7 Cervicl cncer d 1.44 (0.47 to 4.42) 2 1 Hip frcture 0.67 (0.47 to 0.96) Vertebrl frctures d 0.65 (0.46 to 0.92) Lower rm/wrist frctures d 0.71 (0.59 to 0.85) Totl frctures d 0.76 (0.69 to 0.83) Overll mortlity f 1 (0.83 to 1.19) Globl Index g 1.13 (1.02 to 1.25) Adpted from numerous WHI publictions. WHI publictions cn be viewed t b Results re bsed on centrlly djudicted dt. c Nominl confidence intervls undjusted for multiple looks nd multiple comprisons. d Not included in Globl Index. e Includes metsttic nd non-metsttic brest cncer with the exception in situ brest cncer. f All deths, except from brest or colorectl cncer, definite or probble CHD, PE or cerebrovsculr disese. g A subset the events ws combined in globl index defined s the erliest occurrence CHD events, invsive brest cncer, stroke, pulmonry embolism, endometril cncer, colorectl cncer, hip frcture, or deth due to other cuses. Timing the initition estrogen plus progestin therpy reltive to the strt menopuse my ffect the overll risk benefit prile. The WHI estrogen plus progestin substudy strtified for ge showed in women 50 to 59 yers ge non-significnt trend towrd reducing risk overll mortlity [hzrd rtio (HR) 0.69 (95 percent CI, 0.44 to 1.07)]. Women s Helth Inititive Memory Study The estrogen plus progestin Women s Helth Inititive Memory Study (WHIMS), n ncillry study WHI, enrolled 4,532 predominntly helthy postmenopusl women 65 yers ge nd older (47 percent were 65 to 69 yers ge; 35 percent were 70 to 74 yers ge; nd 18 percent were 75 yers ge nd older) to evlute the effects dily CE (0.625 mg) plus MPA (2.5 mg) on the incidence probble dementi (primry outcome) compred to plcebo. After n verge follow-up 4 yers, the reltive risk probble dementi for CE plus MPA versus plcebo ws 2.05 (95 percent CI, 1.21 to 3.48). The bsolute risk probble dementi for CE plus MPA versus plcebo ws 45 versus 22 per 10,000 women-yers. Probble dementi s defined in this study included Alzheimer s disese (AD), vsculr dementi (VD) nd mixed type (hving fetures both AD nd VD). The most common clssifiction probble dementi in the tretment group nd the plcebo group ws AD. Since the ncillry study ws conducted in women 65 to 79 yers ge, it is unknown whether these findings pply to younger postmenopusl women (see WARNINGS, Probble dementi nd PRECAUTIONS, Geritric Use). INDICATIONS AND USAGE Progesterone cpsules re indicted for use in the prevention endometril in nonhysterectomized postmenopusl women who re receiving conjugted estrogens tblets. They re lso indicted for use in secondry menorrhe. CONTRAINDICATIONS Progesterone cpsules should not be used in women with ny the following conditions: 1. Progesterone cpsules should not be used in with known hypersensitivity to its ingredients. Progesterone cpsules contin penut oil nd should never be used by llergic to penuts. 2. Undignosed bnorml genitl bleeding. 3. Known, suspected, or history brest cncer. 4. Active deep vein thrombosis, pulmonry embolism or history these conditions. 5. Active rteril thromboembolic disese (for exmple, stroke nd myocrdil infrction), or history these conditions. 6. Known liver dysfunction or disese. 7. Known or suspected pregnncy. WARNINGS See BOXED WARNING. 1. Crdiovsculr disorders An incresed risk pulmonry embolism, deep vein thrombosis (DVT), stroke nd myocrdil infrction hs been reported with estrogen plus progestin therpy. Should ny these occur or be suspected, estrogen with progestin therpy should be discontinued immeditely. Risk fctors for rteril vsculr disese (for exmple, hypertension, dibetes mellitus, tobcco use, hypercholesterolemi nd obesity) nd/or venous thromboembolism (for exmple, personl history or fmily history venous thromboembolism [VTE], obesity nd systemic lupus erythemtosus) should be mnged ppropritely.. Stroke In the Women s Helth Inititive (WHI) estrogen plus progestin substudy, sttisticlly significnt incresed risk stroke ws reported in women 50 to 79 yers ge receiving dily CE (0.625 mg) plus MPA (2.5 mg) compred to women in the sme ge group receiving plcebo (33 versus 25 per 10,000

4 women-yers). The increse in risk ws demonstrted fter the first yer nd persisted (see CLINICAL STUDIES). Should stroke occur or be suspected, estrogen plus progestin therpy should be discontinued immeditely. b. Coronry Hert Disese In the WHI estrogen plus progestin substudy, there ws sttisticlly nonsignificnt incresed risk coronry hert disese (CHD) events (defined s nonftl myocrdil infrction [MI], silent MI, or CHD deth) reported in women receiving dily CE (0.625 mg) plus MPA (2.5 mg) compred to women receiving plcebo (41 versus 34 per 10,000 women-yers). An increse in reltive risk ws demonstrted in yer 1 nd trend towrd decresing reltive risk ws reported in yers 2 through 5 (see CLINICAL STUDIES). In postmenopusl women with documented hert disese (n = 2,763, verge ge 66.7 yers), in controlled clinicl tril secondry prevention crdiovsculr disese (Hert nd Estrogen/Progestin Replcement Study [HERS]), tretment with dily CE (0.625 mg) plus MPA (2.5 mg) demonstrted no crdiovsculr benefit. During n verge follow-up 4.1 yers, tretment with CE plus MPA did not reduce the overll rte CHD events in postmenopusl women with estblished coronry hert disese. There were more CHD events in the CE plus MPA-treted group thn in the plcebo group in yer 1, but not during the subsequent yers. Two thousnd, three hundred nd twenty-one (2,321) women from the originl HERS tril greed to prticipte in n open-lbel extension HERS, HERS II. Averge follow-up in HERS II ws n dditionl 2.7 yers, for totl 6.8 yers overll. Rtes CHD events were comprble mong women in the CE plus MPA group nd the plcebo group in HERS, HERS II nd overll. c. Venous Thromboembolism In the WHI estrogen plus progestin substudy, sttisticlly significnt 2-fold greter rte VTE (DVT nd pulmonry embolism [PE]) ws reported in women receiving dily CE (0.625 mg) plus MPA (2.5 mg) compred to women receiving plcebo (35 versus 17 per 10,000 women-yers). Sttisticlly significnt increses in risk for both DVT (26 versus 13 per 10,000 womenyers) nd PE (18 versus 8 per 10,000 women-yers) were lso demonstrted. The increse in VTE risk ws demonstrted during the first yer nd persisted (see CLINICAL STUDIES). Should VTE occur or be suspected, estrogen plus progestin therpy should be discontinued immeditely. If fesible, estrogens with progestins should be discontinued t lest 4 to 6 weeks before surgery the type ssocited with n incresed risk thromboembolism, or during periods prolonged immobiliztion. 2. Mlignnt neoplsms. Brest Cncer The most importnt rndomized clinicl tril providing informtion bout brest cncer in estrogen plus progestin users is the Women s Helth Inititive (WHI) substudy dily CE (0.625 mg) plus MPA (2.5 mg). After men follow-up 5.6 yers, the estrogen plus progestin substudy reported n incresed risk invsive brest cncer in women who took dily CE plus MPA. In this substudy, prior use estrogen-lone or estrogen plus progestin therpy ws reported by 26 percent the women. The reltive risk invsive brest cncer ws 1.24 (95 percent nci, 1.01 to 1.54), nd the bsolute risk ws 41 versus 33 cses per 10,000 women-yers, for CE plus MPA compred with plcebo. Among women who reported prior use hormone therpy, the reltive risk invsive brest cncer ws 1.86, nd the bsolute risk ws 46 versus 25 cses per 10,000 women-yers, for estrogen plus progestin compred with plcebo. Among women who reported no prior use hormone therpy, the reltive risk invsive brest cncer ws 1.09, nd the bsolute risk ws 40 versus 36 cses per 10,000 women-yers for CE plus MPA compred with plcebo. In the sme substudy, invsive brest cncers were lrger, were more likely to be node positive, nd were dignosed t more dvnced stge in the CE (0.625 mg) plus MPA (2.5 mg) group compred with the plcebo group. Metsttic disese ws rre, with no pprent difference between the two groups. Other prognostic fctors such s histologic subtype, grde nd hormone receptor sttus did not differ between the groups (see CLINICAL STUDIES). Consistent with the WHI clinicl trils, observtionl studies hve lso reported n incresed risk brest cncer for estrogen plus progestin therpy, nd smller incresed risk for estrogen-lone therpy, fter severl yers use. The risk incresed with durtion use, nd ppered to return to bseline over bout 5 yers fter stopping tretment (only the observtionl studies hve substntil dt on risk fter stopping). Observtionl studies lso suggest tht the risk brest cncer ws greter, nd becme pprent erlier, with estrogen plus progestin therpy s compred to estrogen-lone therpy. However, these studies hve not generlly found significnt vrition in the risk brest cncer mong different estrogen plus progestin combintions, doses, or routes dministrtion. The use estrogen plus progestin hs been reported to result in n increse in bnorml mmmogrms requiring further evlution. All women should receive yerly brest exmintions by helthcre provider nd perform monthly brest self-exmintions. In ddition, mmmogrphy exmintions should be scheduled bsed on ptient ge, risk fctors nd prior mmmogrm results. b. Endometril Cncer An incresed risk endometril cncer hs been reported with the use unopposed estrogen therpy in womn with uterus. The reported endometril cncer risk mong unopposed estrogen users is bout 2 to 12 times greter thn in non-users, nd ppers dependent on durtion tretment nd on estrogen dose. Most studies show no significnt incresed risk ssocited with the use estrogens for less thn 1 yer. The gretest risk ppers ssocited with prolonged use, with incresed risks 15- to 24-fold for 5 to 10 yers or more nd this risk hs been shown to persist for t lest 8 to 15 yers fter estrogen therpy is discontinued. Clinicl surveillnce ll women using estrogen plus progestin therpy is importnt. Adequte dignostic mesures, including directed or rndom endometril smpling when indicted, should be undertken to rule out mlignncy in ll cses undignosed persistent or recurring bnorml genitl bleeding. There is no evidence tht the use nturl estrogens results in different endometril risk prile thn synthetic estrogens equivlent estrogen dose. Adding progestin to estrogen therpy in postmenopusl women hs been shown to reduce the risk endometril, which my be precursor to endometril cncer. c. Ovrin Cncer The WHI estrogen plus progestin substudy reported sttisticlly non-significnt incresed risk ovrin cncer. After n verge follow-up 5.6 yers, the reltive risk for ovrin cncer for CE plus MPA versus plcebo ws 1.58 (95 percent nci, 0.77 to 3.24). The bsolute risk for CE plus MPA versus plcebo ws 4 versus 3 cses per 10,000 women-yers. In some epidemiologic studies, the use estrogen plus progestin nd estrogen-only products, in prticulr for 5 or more yers, hs been ssocited with n incresed risk ovrin cncer. However, the durtion exposure ssocited with incresed risk is not consistent cross ll epidemiologic studies nd some report no ssocition. 3. Probble dementi In the estrogen plus progestin Women s Helth Inititive Memory Study (WHIMS), n ncillry study WHI, popultion 4,532 postmenopusl women 65 to 79 yers ge ws rndomized to dily CE (0.625 mg) plus MPA (2.5 mg) or plcebo. In the WHIMS estrogen plus progestin ncillry study, fter n verge followup 4 yers, 40 women in the CE plus MPA group nd 21 women in the plcebo group were dignosed with probble dementi. The reltive risk probble dementi for estrogen plus progestin versus plcebo ws 2.05 (95 percent CI, 1.21 to 3.48). The bsolute risk probble dementi for CE plus MPA versus plcebo ws 45 versus 22 cses per 10,000 womenyers. It is unknown whether these findings pply to younger postmenopusl women (see CLINICAL STUDIES nd PRECAUTIONS, Geritric Use). 4. Vision bnormlities Retinl vsculr thrombosis hs been reported in receiving estrogen. Discontinue estrogen plus progestin therpy pending exmintion if there is sudden prtil or complete loss vision, or if there is sudden onset proptosis, diplopi or migrine. If exmintion revels ppilledem or retinl vsculr lesions, estrogen plus progestin therpy should be permnently discontinued. PRECAUTIONS A. Generl 1. Addition progestin when womn hs not hd hysterectomy Studies the ddition progestin for 10 or more dys cycle estrogen dministrtion, or dily with estrogen in continuous regimen, hve reported lowered incidence endometril thn would be induced by estrogen tretment lone. Endometril my be precursor to endometril cncer.

5 There re, however, possible risks tht my be ssocited with the use progestins with estrogens compred with estrogen-lone regimens. These include n incresed risk brest cncer. 2. Fluid Retention Progesterone my cuse some degree fluid retention. Women with conditions tht might be influenced by this fctor, such s crdic or renl dysfunction, wrrnt creful observtion. 3. Dizziness nd Drowsiness Progesterone cpsules my cuse trnsient dizziness nd drowsiness nd should be used with cution when driving motor vehicle or operting mchinery. Progesterone cpsules should be tken s single dily dose t bedtime. B. Ptient Informtion Generl: This product contins penut oil nd should not be used if you re llergic to penuts. Physicins re dvised to discuss the contents the Ptient Informtion leflet with for whom they prescribe Progesterone cpsules. C. Drug Lbortory Test Interctions The following lbortory results my be ltered by the use estrogen plus progestin therpy: Incresed sulfobromophthlein retention nd other heptic function tests. Cogultion tests: increse in prothrombin fctors VII, VIII, IX nd X. Pregnnediol determintion. Thyroid function: increse in PBI, nd butnol extrctble protein bound iodine nd decrese in T3 uptke vlues. D. Crcinogenesis, Mutgenesis, Impirment Fertility Progesterone hs not been tested for crcinogenicity in nimls by the orl route dministrtion. When implnted into femle mice, progesterone produced mmmry crcinoms, ovrin grnulos cell tumors nd endometril stroml srcoms. In dogs, long-term intrmusculr injections produced nodulr nd benign nd mlignnt mmmry tumors. Subcutneous or intrmusculr injections progesterone decresed the ltency period nd incresed the incidence mmmry tumors in rts previously treted with chemicl crcinogen. Progesterone did not show evidence genotoxicity in in vitro studies for point muttions or for chromosoml dmge. In vivo studies for chromosome dmge hve yielded positive results in mice t orl doses 1000 mg/kg nd 2000 mg/kg. Exogenously dministered progesterone hs been shown to inhibit ovultion in number species nd it is expected tht high doses given for n extended durtion would impir fertility until the cesstion tretment. E. Pregnncy Progesterone cpsules should not be used during pregnncy (see CONTRAINDICATIONS). Pregnncy Ctegory B: Reproductive studies hve been performed in mice t doses up to 9 times the humn orl dose, in rts t doses up to 44 times the humn orl dose, in rbbits t dose 10 mcg/dy delivered loclly within the uterus by n implnted device, in guine pigs t doses pproximtely one-hlf the humn orl dose nd in rhesus monkeys t doses pproximtely the humn dose, ll bsed on body surfce re, nd hve reveled little or no evidence impired fertility or hrm to the fetus due to progesterone. F. Nursing Women Detectble mounts progestin hve been identified in the milk nursing women receiving progestins. Cution should be exercised when progesterone cpsules re dministered to nursing womn. G. Peditric Use Progesterone cpsules re not indicted in children. Clinicl studies hve not been conducted in the peditric popultion. H. Geritric Use There hve not been sufficient numbers geritric women involved in clinicl studies utilizing progesterone cpsules to determine whether those over 65 yers ge differ from younger subjects in their response to progesterone cpsules. The Women s Helth Inititive Study In the Women s Helth Inititive (WHI) estrogen plus progestin substudy (dily CE [0.625 mg] plus MPA [2.5 mg] versus plcebo), there ws higher reltive risk nonftl stroke nd invsive brest cncer in women greter thn 65 yers ge (see CLINICAL STUDIES nd WARNINGS, Crdiovsculr disorders nd Mlignnt neoplsms). The Women s Helth Inititive Memory Study In the Women s Helth Inititive Memory Study (WHIMS) postmenopusl women 65 to 79 yers ge, there ws n incresed risk developing probble dementi in the estrogen plus progestin ncillry study when compred to plcebo (see CLINICAL STUDIES nd WARNINGS, Probble dementi). ADVERSE REACTIONS See BOXED WARNING, WARNINGS nd PRECAUTIONS. Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils drug cnnot be directly compred to rtes in the clinicl trils nother drug nd my not reflect the rtes observed in prctice. In multicenter, rndomized, double-blind, plcebo-controlled clinicl tril, the effects progesterone cpsules on the endometrium ws studied in totl 875 postmenopusl women. Tble 6 lists dverse rections greter thn or equl to 2 percent women who received cyclic progesterone cpsules 200 mg dily (12 dys per clendr month cycle) with mg conjugted estrogens or plcebo. TABLE 6. Adverse Rections ( 2%) Reported in n 875 Ptient - Controlled Tril in Postmenopusl Women Over 3-Yer Period [Percentge (%) Ptients Reporting] Progesterone Cpsules 200 mg with Conjugted Estrogens mg (n=178) (n=174) Hedche Brest Tenderness 27 6 Joint Pin Depression Dizziness 15 9 Abdominl Bloting 12 5 Hot Flshes Urinry Problems 11 9 Abdominl Pin Vginl Dischrge 10 3 Nuse / Vomiting 8 7 Worry 8 4 Chest Pin 7 5 Dirrhe 7 4 Night Swets 7 17 Brest Pin 6 2 Swelling Hnds nd Feet 6 9 Vginl Dryness 6 10 Constiption 3 2 Brest Crcinom 2 <1 Brest Excisionl Biopsy 2 <1 Cholecystectomy 2 <1 Effects on Secondry Amenorrhe In multicenter, rndomized, double-blind, plcebo-controlled clinicl tril, the effects progesterone cpsules on secondry menorrhe ws studied in 49 estrogen-primed postmenopusl women. Tble 7 lists dverse rections greter thn or equl to 5 percent women who received progesterone cpsules or plcebo.

6 TABLE 7. Adverse Rections ( 5%) Reported in Ptients Using 400 mg/dy in -Controlled Tril in Estrogen-Primed Postmenopusl Women Progesterone Cpsules 400 mg Adverse Experience n=25 n=24 Percentge (%) Ptients Ftigue 8 4 Hedche 16 8 Dizziness 24 4 Abdominl Distention (Bloting) 8 8 Abdominl Pin (Crmping) Dirrhe 8 4 Nuse 8 0 Bck Pin 8 8 Musculoskeletl Pin 12 4 Irritbility 8 4 Brest Pin 16 8 Infection Virl 12 0 Coughing 8 0 In multicenter, prllel-group, open lbel postmrketing dosing study consisting three consecutive 28-dy tretment cycles, 220 premenopusl women with secondry menorrhe were rndomized to receive dily conjugted estrogens therpy (0.625 mg conjugted estrogens) nd progesterone cpsules, 300 mg per dy (n=113) or progesterone cpsules, 400 mg per dy (n=107) for 10 dys ech tretment cycle. Overll, the most frequently reported tretmentemergent dverse rections, reported in greter thn or equl to 5 percent subjects, were nuse, ftigue, vginl mycosis, nsophryngitis, upper respirtory trct infection, hedche, dizziness, brest tenderness, bdominl distension, cne, dysmenorrhe, mood swing nd urinry trct infection. Postmrketing Experience: The following dditionl dverse rections hve been reported with progesterone cpsules. Becuse these rections re reported voluntrily from popultion uncertin size, it is not lwys possible to relibly estimte the frequency or estblish cusl reltionship to drug exposure. Genitourinry System: endometril crcinom, hypospdi, intr-uterine deth, menorrhgi, menstrul disorder, metrorrhgi, ovrin cyst, spontneous bortion. Crdiovsculr: circultory collpse, congenitl hert disese (including ventriculr septl defect nd ptent ductus rteriosus), hypertension, hypotension, tchycrdi. Gstrointestinl: cute pncretitis, cholestsis, cholesttic heptitis, dysphgi, heptic filure, heptic necrosis, heptitis, incresed liver function tests (including lnine minotrnsferse incresed, sprtte minotrnsferse incresed, gmm-glutmyl trnsferse incresed), jundice, swollen tongue. OVERDOSAGE No studies on overdosge hve been conducted in humns. In the cse overdosge, progesterone cpsules should be discontinued nd the ptient should be treted symptomticlly. DOSAGE AND ADMINISTRATION Prevention Endometril Hyperplsi Progesterone cpsules should be given s single dily dose t bedtime, 200 mg orlly for 12 dys sequentilly per 28-dy cycle, to postmenopusl womn with uterus who is receiving dily conjugted estrogens tblets. Tretment Secondry Amenorrhe Progesterone cpsules my be given s single dily dose 400 mg t bedtime for 10 dys. Some women my experience difficulty swllowing progesterone cpsules. For these women, progesterone cpsules should be tken with glss wter while in the stnding position. HOW SUPPLIED Progesterone cpsules, 100 mg, re supplied s round, light ornge st geltin cpsules, printed with A87. They re vilble s follows: Bottles 100: NDC Bottles 500: NDC Progesterone cpsules, 200 mg, re supplied s ovl, light ornge st geltin cpsules, printed with A80. They re vilble s follows: Bottles 100: NDC Bottles 500: NDC Store t 20 to 25 C (68 to 77 F); excursions permitted between 15 to 30 C (59 to 86 F) [see USP Controlled Room Temperture]. Protect from excessive moisture. Dispense in tight, light-resistnt continer s defined in USP/NF, ccompnied by Ptient Insert. Keep out rech children. Distributed by: Amnel Phrmceuticls LLC Bridgewter, NJ Rev Skin: lopeci, pruritus, urticri. Eyes: blurred vision, diplopi, visul disturbnce. Centrl Nervous System: ggression, convulsion, depersonliztion, depressed consciousness, disorienttion, dysrthri, loss consciousness, presthesi, sedtion, stupor, syncope (with nd without hypotension), trnsient ischemic ttck, suicidl idetion. During initil therpy, few women hve experienced constelltion mny or ll the following symptoms: extreme dizziness nd/or drowsiness, blurred vision, slurred speech, difficulty wlking, loss consciousness, vertigo, confusion, disorienttion, feeling drunk nd shortness breth. Miscellneous: bnorml git, nphylctic rection, rthrlgi, blood glucose incresed, choking, cleft lip, cleft plte, difficulty wlking, dyspne, fce edem, feeling bnorml, feeling drunk, hypersensitivity, sthm, muscle crmp, throt tightness, tinnitus, vertigo, weight decresed, weight incresed. To report SUSPECTED ADVERSE REACTIONS, contct Amnel Phrmceuticls t or FDA t FDA-1088 or