PRODUCT INFORMATION. XIAFLEX (collagenase clostridium histolyticum) Lyophilised powder for injection 900 micrograms/vial NAME OF THE MEDICINE

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1 PRODUCT INFORMATION (ollgense lostridium histolytium) Lyophilised powder for injetion 900 mirogrms/vil NAME OF THE MEDICINE Ative: ollgense lostridium histolytium CAS: Clostridium histolytium gene olg isoenzyme AUX-I: CAS: Clostridium histolytium gene olh isoenzyme AUX-II: Phrmotherpeuti group: Other Drugs for Disorders of the Musulo- Skeletl System Enzymes DESCRIPTION is lyophilised produt for intrlesionl dministrtion. ontins purified ollgense lostridium histolytium, onsisting of two miroil ollgenses in defined mss rtio, Collgense AUX-I nd Collgense AUX-II, whih re isolted nd purified from the fermenttion of Clostridium histolytium teri. A ollgense is n enzyme tht reognises nd inds to ollgen in its ntive onformtion nd leves the peptide onds resulting in ollgen rekdown. Collgense AUX-I is single polypeptide hin onsisting of pproximtely 1000 mino ids of known sequene. It hs n oserved moleulr weight of 114 kilodltons (kd). It elongs to the lss I Clostridium histolytium ollgenses. Collgense AUX-II is single polypeptide hin onsisting of pproximtely 1000 mino ids of known sequene. It hs n oserved moleulr weight of 113 kd. It elongs to the lss II Clostridium histolytium ollgenses. is supplied in single-use, glss vils ontining 0.9 mg of ollgense lostridium histolytium s sterile, lyophilised powder for reonstitution. Eh vil lso ontins pproximtely 0.5 mg of hydrohlori id, 18.5 mg of surose, nd 1.1mg of trometmol. The reonstituted drug produt hs ph of Sterile diluent for reonstitution is provided in the pkge in single-use glss vil ontining 3 ml of 0.3 mg/ml lium hloride dihydrte in 0.9% sodium hloride. PHARMACOLOGY Phrmodynmi Properties Mehnism of Ation Collgenses re proteinses tht hydrolyse ollgen in its ntive triple-helil onformtion under physiologil onditions, resulting in lysis of ollgen deposits. Injetion of into Dupuytren s ord, whih is omprised mostly of ollgen, my result in enzymti disruption of the ord. The signs nd symptoms of Peyronie s disese re used y ollgen plque. Injetion of into Peyronie s plque, whih is omprised mostly of ollgen, my result in enzymti disruption of the plque. Following this disruption of the plque, penile urvture deformity nd ptient other used y Peyronie s disese re redued. Results of in vitro studies, inluding those of explnt tissues ontining Peyronie s plques, suggest tht disrupts the predominnt ollgen found in plques (Types I nd III). At higher doses nd longer inution times, non-firillr Type IV ollgen ws ffeted using ollgen lysis in smll veins, ut did not use struturl dmge to rteries, nerves or lrge veins whih ontin Type IV ollgen in in vitro or in vivo studies. Results of in vitro studies suggest tht the ollgenses (AUX-I nd AUX- II) worked synergistilly to provide hydrolysing tivity towrds ollgen. However, there re no linil dt regrding the reltive ontriutions of the individul ollgenses (AUX-I or AUX-II) to the effiy of in the tretment of Dupuytren s ontrture or Peyronie s disese. Collgen frgments generted from lostridil ollgense hve een shown to generte inresed vsulr permeility, inflmmtory responses, nd regenertive hnges. However, the effets of the formtion of the ollgen frgments derived from the ollgen plque re unknown. Phrmokinetis Asorption nd Distriution Dupuytren s Contrture Following dministrtion of single dose of 0.58 mg of into ord in ptients with Dupuytren s ontrture, or two onurrent injetions of 0.58 mg of into Dupuytren s ords in the sme hnd of ptients with Dupuytren s ontrture, no quntifile levels of were deteted in plsm up to 30 dys post injetion. Peyronie s Disese Following eh of two intrlesionl dministrtions, seprted y 24 hours, of 0.58 mg into the penile plque of 19 ptients with Peyronie s disese, plsm levels of AUX-I nd AUX-II in ptients with quntifile levels (79% nd 40% for AUX-I nd AUX-II, respetively) were miniml nd short-lived. The mximl plsm onentrtions of AUX-I nd AUX-II were <29 ng/ml nd <71 ng/ml, respetively, nd were oserved pproximtely within 10 minutes fter injetion. All plsm levels were elow the limits of quntifition within 30 minutes following dosing. There ws no evidene of umultion following two sequentil injetions of dministered 24 hours prt. No ptients hd quntifile plsm levels 15 minutes fter modeling of plque on Dy 3 (i.e., 24 hours fter Injetion 2 on Dy 2). Biotrnsformtion nd Elimintion Beuse is not sustrte for ytohrome P450 or other mediinl produt metolising enzyme pthwys, nd euse no tive metolites re expeted, no metolism studies hve een performed. Beuse there is no quntifile systemi exposure following single injetion of in ptients with Dupuytren s ontrture nd miniml nd shortlived systemi exposure in ptients with Peyronie s disese, no forml studies on elimintion hve een performed. Produt Informtion (ollgense lostridium histolytium) 1

2 CLINICAL TRIALS Dupuytren s Contrture The effiy of 0.58 mg ws evluted in two pivotl rndomised, doule-lind, pleo-ontrolled studies, CORD-I (AUX-CC-857), nd CORD-II (AUX-CC-859), in dult ptients with Dupuytren s ontrture. At study entry, ptients in the linil studies hd: (1) finger flexion ontrture with plple ord of t lest one finger (other thn the thum) of 20 to 100 in MP joint, or 20 to 80 in PIP joint, nd (2) positive tletop test defined s the inility to simultneously ple the ffeted finger(s) nd plm flt ginst tle top. The ord ffeting seleted primry joint reeived up to 3 injetions of 0.58 mg of or pleo. A finger extension proedure ws performed if needed, pproximtely 24 hours fter injetion to filitte disruption of the ord. Eh injetion ws seprted y pproximtely 4 weeks. The primry endpoint of eh study ws to evlute the proportion of ptients who hieved redution in ontrture of the seleted primry joint (MP or PIP) to 5 or less, pproximtely 4 weeks fter the lst injetion of tht joint. Other endpoints inluded 50% redution from seline in degree of ontrture, perent hnge from seline in degree of ontrture, hnge from seline in rnge of motion, sujet glol ssessment of tretment stisftion nd physiin glol ssessment of severity. demonstrted linilly signifint enefit ompred to pleo in the proportion of ptients hieving the primry endpoint of redution in the ontrture of ll joints treted to 5 or less, pproximtely 4 weeks fter the lst injetion (MP plus PIP, MP only, PIP only). The men numer of injetions required ws 1.5. See Tle 1 for the seline disese hrteristis of ptients with Dupuytren s ontrture in CORD-I nd CORD-II. Tle 1: Demogrphi nd Bseline Chrteristis Phse 3 doule-lind, pleo-ontrolled studies (CORD-I, CORD-II) Vrile (n=249) Pleo (n=125) Age (yers) men Age tegory (yers), n (%) <45 9 (3.6) 5 (4.0) (13.2) 17 (13.6) (41.4) 44 (35.2) (33.0) 40 (32.0) (8.8) 19 (15.2) Gender, n (%) Mle 210 (84.3) 91 (72.8) Femle 39 (15.7) 34 (27.2) Fmily History of Dupuytren s Disese, n (%) Yes 107 (43.0) 62 (49.6) No 142 (57.0) 63 (50.4) Physiin Rting of Severity t Bseline Mild 38 (15.4%) 21 (16.8%) Moderte 148 (59.9%) 71 (56.8%) Severe 61 (24.7%) 33 (26.4%) Missing 1 2 (0.8%) Note: Inludes ll ptients who reeived t lest 1 injetion of doule-lind study mediinl produt ( 0.58 mg or pleo). 1 Not used to lulte physiin rting of severity t seline perentge tul denomintor of N=247 used. Tle 2: Perentge of Ptients who Ahieved Redution in Contrture to 5 or Less (lst injetion) Treted CORD-I CORD-II Primry Joints Pleo Pleo n=203 n=103 n=45 n=21 All joints 64.0% 6.8% 44.4% 4.8% Differene (CI d ) 57% (47%, 67%) 40% (14%, 62%) n=133 n=69 n=20 n=11 MP Joints 76.7% 7.2% 65.0% 9.1% Differene (CI d ) 69% (57%, 79%) 56% (19%, 83%) n=70 n=34 n=25 n=10 PIP Joints 40.0% 5.9% 28.0% 0.0% Differene (CI d ) 34% (14%, 52%) 28% (-10%, 61%) Metrpophlngel joint Proximl interphlngel joint Two (2) primry joints were exluded from the effiy nlysis (1 joint from the pleo group ws not evluted nd 1 joint from the -treted group hd seline ontrture of 0 degrees efore tretment) d 95% onfidene intervls. Tle 3: Men Inrese in Rnge of Motion from Bseline (Lst Injetion) CORD-I CORD-II Treted Primry Joints Pleo Pleo All Joints n=197 n=102 n=45 n=21 Men Bseline (SD) 43.9 (20.1) 45.3 (18.7) 40.3 (15.2) 44.0 (16.5) Men Finl (SD) 80.7 (19.0) 49.5 (22.1) 75.8 (17.7) 51.7 (19.6) Men Inrese (SD) 36.7 (21.0) 4.0 (14.8) 35.4 (17.8) 7.6 (14.9) MP Joints n=130 n=68 n=20 n=11 Men Bseline (SD) 42.6 (20.0) 45.7 (19.2) 39.5 (11.8) 41.4 (20.8) Men Finl (SD) 83.7 (15.7) 49.7 (21.1) 79.5 (11.1) 50.0 (21.5) Men Inrese (SD) 40.6 (20.0) 3.7 (12.6) 40.0 (13.5) 8.6 (14.7) PIP Joints n=67 n=34 n=25 n=10 Men Bseline (SD) 46.4 (20.4) 44.4 (17.9) 41.0 (17.7) 47.0 (10.3) Men Finl (SD) 74.9 (23.1) 49.1 (24.4) 72.8 (21.3) 53.5 (18.3) Men Inrese (SD) 29.0 (20.9) 4.7 (18.5) 31.8 (20.1) 6.5 (15.8) Metrpophlngel joint Proximl interphlngel joint Two (2) primry joints were exluded from the effiy nlysis (1 joint from the pleo group ws not evluted nd 1 joint from the - treted group hd seline ontrture of 0 degrees efore tretment). All p-vlues < for ll omprisons etween nd pleo, exept for PIP joints in Study CORD-II whih ws not eligile for sttistil testing due to hierrhil testing proedure. Physiin-rted hnge in ontrture severity ws reported s very muh improved or muh improved in 86% nd 80% of the sujets in the group ompred to 3% nd 5% of sujets in the pleo group for the CORD-I nd CORD-II studies, respetively (p<0.001). Bsed on the Ptient Glol Assessment of Tretment Stisftion, more thn 85% of sujets in the CORD-I nd CORD-II studies reported either eing quite stisfied or very stisfied with their tretment with versus pproximtely 30% treted with pleo (p<0.001). Greter ptient stisftion ws orrelted with improved rnge of motion (r=0.51, p<0.001). 2 (ollgense lostridium histolytium) Produt Informtion

3 Tretment of two onurrent injetions An open-lel, historilly-ontrolled study (AUX-CC-867) ws onduted in 715 ptients to ssess the sfety nd effiy of two onurrent injetions of into one hnd in dults with multiple Dupuytren s ontrtures with plple ords. Two onurrent injetions were dministered into ords ffeting MP nd/or PIP joints on the sme or different fingers in the seleted hnd. The primry effiy endpoint ws fixed flexion ontrture in the treted joint pir sugroup. A signifint men improvement (74.4%) from seline to Dy 31 ws oserved overll in fixed flexion ontrture following dministrtion of two onurrent injetions of 0.58 mg (one injetion per joint) in the sme hnd, see Tle 4. Improvement ws oserved regrdless of joint type or finger involvement (rnge: 60.5% to 83.9%). Improvement of the totl fixed flexion ontrture ws lso oserved irrespetively of the time of finger extension, 24, 48 or 72 hours fter injetion, with men improvement t Dy 31 of 75.2%, 74.8% nd 72.4% respetively. An improvement from seline ws lso seen in rnge of motion t Dy 31 for ll the treted joint pir sugroups, see Tle 4. Tle 4: Totl fixed flexion ontrture nd rnge of motion following dministrtion of two onurrent injetions of 0.58 mg in the sme hnd, mitt popultion, study AUX-CC-867 (first tretment yle) Sme Finger, 1 MP, 1 PIP (n=350) Different Fingers, Both MPs (n=244) Different Fingers, Both PIPs (n=72) Different Fingers, 1 MP, 1 PIP (n=58) Totl (n=724) Totl FFC ( ) Bseline, men (SD) 102 (31) 89 (31) 109 (37) 96 (28) 98 (32) Dy 31, men (SD) 30 (27) 17 (28) 47 (39) 31 (29) 27 (30) Chnge, men (SD) 72 (29) 72 (29) 62 (32) 65 (34) 70 (30) % Chnge, men (SD) 72 (22) 84 (23) 60 (29) 68 (27) 74 (25) Totl ROM ( ) Bseline, men (SD) 87 (31) 92 (34) 93 (36) 92 (29) 90 (33) Dy 31, men (SD) 154 (29) 163 (30) 148 (42) 155 (31) 156 (31) Chnge, men (SD) 67 (30) 71 (34) 55 (28) 63 (37) 67 (32) FFC = Fixed flexion ontrture ROM = Rnge of motion Clinil suess ( redution of ontrture to 5 within 30 dys) fter two onurrent injetions of (one per joint) in the sme hnd ws hieved for the mjority of MP joints (64.6%) ompred with 28.6% of PIP joints following single injetion per ffeted joint. Time of finger extension fter injetion hd no impt on the rte of linil suess for either MP or PIP joints. Clinilly meningful improvement in hnd funtion s determined y the URAM (Unité Rhumtologique des Affetions de l Min) sore ws oserved t Dy 31 (-11.3) nd Dy 61 (-12.3). Long-term effiy nd sfety A long term, non-tretment, Yer 2 to Yer 5 follow-up study (AUX-CC-860) ws undertken to evlute reurrene of ontrture in sujets who reeived up to 8 single injetions of 0.58mg in previous Phse 3 open-lel or doule-lind with open-lel extension study. Reurrene ws ssessed in suessfully treted joints (i.e., sujets hd redution in ontrture to 5 or less t the Dy 30 evlution fter the lst injetion of in previous study) nd ws defined s n inrese in joint ontrture y t lest 20 in the presene of plple ord, or the joint underwent medil or surgil intervention primrily to orret new or worsening Dupuytren s ontrture in tht joint. Dt on the long term reurrene rtes following suessful tretment with re provided in Tle 5. Retretment of Reurrent Contrtures Clinil effiy in Study AUX-CC-862 ws similr to tht reported in studies CORD-I nd CORD-II. In Study AUX-CC-862, 64.5% of reurrent MP joints nd 45.0% of reurrent PIP joints hieved linil suess fter retretment with up to three injetions of. Tle 5: Long Term Reurrene Rtes for Joints Treted Suessfully with Follow-up Intervl (dys) N (%) of Joints in Eh Intervl N (%) of Reurrent Joints in Eh Intervl Cumultive Nominl Reurrene y Joint Type (%) Cumultive Nominl Reurrene Rte (%) Nominl Chnge in Reurrene Rte vs Previous Yer (%) MP PIP (3.2) 19 (6.3) (18.3) 103 (33.9) (20.1) 97 (31.9) (13.6) 45 (14.8) (27.1) 27 (8.9) > (17.7) 13 (4.3) MP=Metrpophlngel joint; PIP= Proximl interphlngel joint A joint ws onsidered in n intervl if the durtion of ssessment flls in the intervl. The durtion of ssessment strted t the dy of suess (visit fter the lst injetion where the 0 to 5 mesurement ws first reorded). The durtion of ssessment ended t the lst ville mesurement or t the dy of medil intervention for joints tht did not reur nd the reurrene dy for reurrent joints. A reurrent joint ws joint evluted y the investigtor s hving worsening Dupuytren s ontrture due to plple ord. The reurrene dy ws the visit where the reurrene ws reported or the dy of intervention if joint ws treted for worsening Dupuytren s ontrture. For joints reported s reurring in previous study, the dy of reurrene ws the first visit with fixed flexion ontrture mesurement of 20 or greter following the report of reurrene. The nominl rte of reurrene ws the totl numer of reurrenes ourring prior to the lst dy of the intervl divided y the totl numer of joints ( 100). Peyronie s Disese The effiy of ws evluted in two rndomised, doule-lind, pleo-ontrolled studies, Study 1 (AUX-CC-803) nd Study 2 (AUX-CC-804), in dult mles with Peyronie s disese. At study entry, ptients must hve hd penile urvture deformity of t lest 30 degrees nd hd disese present for t lest 12 months prior to enrolment. Ptients were exluded if they hd penile urvture greter thn 90, ventrl urvture deformity, n isolted hourglss deformity or lified plque tht ould hve interfered with the injetion tehnique. At seline, penile pin ws either not present or ws mild in most (98%) ptients. In these studies, ptients were given up to 4 tretment yles of or pleo (weeks 0, 6, 12, 18), nd were followed in non-tretment follow-up period (weeks 24-52). In eh tretment yle, two injetions of or two injetions of pleo were dministered 1 to 3 dys prt. A penile modeling proedure ws performed on ptients t the study site 1 to 3 dys fter the seond injetion of the yle. The tretment yle ws repeted t pproximtely six-week intervls for up to three dditionl times, for mximum of 8 totl injetion proedures nd 4 totl modeling proedures. In ddition, ptients were instruted to perform penile modeling t home for six weeks fter eh tretment yle. In Studies 1 nd 2, the o-primry endpoints were: the perent hnge from seline to Week 52 in penile urvture deformity nd the hnge from seline to Week 52 in the Bother domin of the Peyronie s Disese Questionnire (PDQ) The Bother domin sore is omposite of the following ptient-reported items: onern out eretion pin, eretion pperne, nd the impt of Peyronie s disese on interourse nd on frequeny of interourse. tretment signifintly improved penile urvture deformity in ptients with Peyronie s disese ompred with pleo (Tle 7). The perentge improvement in urvture deformity ws numerilly similr mong ptients with seline deformity from 30 to 60 degrees nd those with urvture deformity from 61 to 90 degrees. signifintly redued ptient-reported other ssoited with Peyronie s disese ompred with pleo (Tle 8). The redution in the Bother domin sore ws numerilly similr etween ptient groups strtified y degree of seline urvture deformity (30 to 60 degrees nd 61 to 90 degrees). Tle 6 provides the seline disese hrteristis for the study popultion nd Tles 7-8 provide the results of the o-primry effiy endpoints mesured in the 2 doule-lind pleo-ontrolled studies 1 nd 2. Produt Informtion (ollgense lostridium histolytium) 3

4 Tle 6: Bseline disese hrteristis of ptients with Peyronie s Disese (PD) Study 1 Study 2 n=277 Pleo n=140 n=274 Pleo n=141 Men ge (yers) (Min-Mx) (28-79) (30-81) (23-84) (33-78) Men durtion of PD (yers) (Min-Mx) ( ) ( ) ( ) ( ) Men Penile Curvture Deformity (degrees) (Min-Mx) (30-90) (30-89) (30-90) (30-85) Peyronie s Disese Questionnire (PDQ), Men Ptient- Reported PD Bother Domin Sore (rnge: 0-16) History of Eretile Dysfuntion N (%) 128 (46.2) 75 (53.6) 134 (48.9) 76 (53.9) Sujets were from ITT popultion nd reeived t lest one dose of study drug in Study 1 or 2 Eh PDQ ssessment required sujets to hve hd vginl interourse in the 3 months prior to ompletion Higher sores represent worse symptoms Tle 7: Men perent hnge in penile urvture deformity from seline to week 52 Studies 1 nd 2 Study 1 Study 2 n=199 Pleo n=104 n=202 Pleo n=107 Bseline Men (degrees) Men Perent Chnge -35.0% -17.8% -33.2% -21.8% Tretment Differene (95% CI) -17.2% (-26.7%, -7.6%) -11.4% (-19.5%, -3.3%) Men perent hnge, tretment differene, 95% CI, nd p-vlue were sed on n ANOVA model with ftors for tretment, strtum of seline penile urvture, nd their intertion nd using lst oservtion rried forwrd (LOCF) in the modified intent-to-tret (mitt) popultion. The mitt popultion ws defined s ll rndomised sujets who hd oth penile urvture deformity mesurement nd PDQ ssessment t seline nd t one or more susequent time points. p-vlue < 0.01 Tle 8: Men Chnge in Peyronie s Disese Bother Domin Sore from Bseline to Week 52 - Studies 1 nd 2 n=199 Study 1 Study 2 Pleo n=104 n=202 Pleo n=107 Bseline Men Men Chnge Tretment Differene (95% CI) -1.2 (-2.4, -0.03) -1.1 (-2.1, ) Men hnge, tretment differene, 95% CI, nd p-vlue ll sed on n ANOVA model with ftors for tretment, strtum of seline penile urvture, nd their intertion nd using lst oservtion rried forwrd (LOCF) in the modified intent-to-tret (mitt) popultion. The mitt popultion ws defined s ll rndomised sujets who hd oth penile urvture deformity mesurement nd PDQ ssessment t seline nd t one or more susequent time points. p-vlue < There were no linilly meningful differenes in the men perent improvement in urvture deformity or men redution in the Bother domin sore following tretment with sed on the severity of seline eretile dysfuntion or onomitnt phosphodiesterse type 5 (PDE5) inhiitor use. INDICATIONS is indited for: The tretment of Dupuytren s ontrture in dult ptients with plple ord. The tretment of dult men with Peyronie s disese with plple plque nd urvture deformity of t lest 30 degrees t the strt of therpy. CONTRAINDICATIONS Do not use in ptients with hypersensitivity to the tive sustne or to ny of the exipients. Do not use for the tretment of Peyronie s plques tht involve the penile urethr due to potentil risk to this struture. PRECAUTIONS Allergi retions Dupuytren s Contrture In the ontrolled portions of the linil trils CORD-1 nd CORD-2, greter proportion of -treted ptients (15%) ompred to pleo-treted ptients (1%) hd mild llergi retions (e.g. pruritus) fter up to 3 injetions. The inidene of -ssoited pruritus inresed fter more injetions. Beuse ontins foreign proteins, severe llergi retions to n our. Anphylxis ws reported in post-mrketing linil tril in one ptient who hd previous exposure to for the tretment of Dupuytren s ontrture. Some ptients with Dupuytren s ontrture developed IgE-nti-drug ntiodies in greter proportions nd higher titres with suessive injetions. Physiins must e ppropritely equipped nd prepred to ddress ny severe lol or systemi llergi retions inluding the potentil for nphylxis tht my our following injetion. The ptient should therefore e oserved for t lest 20 minutes following the injetion of for signs of ny severe lol or systemi llergi retions inluding nphylxis. Peyronie s Disese In the doule-lind portion of the two phse 3 pleo-ontrolled linil trils in Peyronie s disese, greter proportion of -treted ptients (4%) ompred to pleo-treted ptients (1%) hd lolised pruritus fter up to 4 tretment yles (involving up to 8 injetions). The inidene of -ssoited pruritus ws similr fter eh injetion regrdless of the numer of injetions dministered. Physiins must e ppropritely equipped nd prepred to ddress ny severe lol or systemi llergi retions inluding the potentil for nphylxis tht my our following injetion. Tendon rupture or other serious injury to the finger/hnd in the tretment of Dupuytren s Contrture must only e injeted into the Dupuytren s ord. In the ontrolled nd unontrolled portions of the linil trils, flexor tendon ruptures ourred fter injetion. should e injeted only into the ollgen ord with MP or PIP joint ontrture. Other -ssoited serious lol dverse retions in the ontrolled nd unontrolled portions of the studies inluded pulley rupture, ligment injury, omplex regionl pin syndrome (CRPS), nd sensory normlity of the hnd. Beuse lyses ollgen, re must e tken to void injeting into tendons, nerves, lood vessels, or other ollgen-ontining strutures of the hnd. Injetion of into ollgen ontining strutures my result in dmge to those strutures, nd possile permnent injury suh s tendon rupture or ligment dmge. When injeting ord ffeting PIP joint of the fifth finger, the needle insertion must not e more thn 2 to 3 mm in depth nd not more thn 4 mm distl to the plmr digitl rese. Ptients should e instruted to promptly ontt their physiin if they hve troule ending the finger fter the swelling hs susided s it my e symptom of tendon rupture. Ptients with Dupuytren s ontrtures tht dhere to the skin my e t higher risk of skin lesions s result of the phrmologil effet of nd the finger extension proedure on the skin overlying the trgeted ord. If this ours, over the re with guze nd pply gentle pressure until leeding stops. Stndrd wound re with regulr dressings should e pplied. Skin lertions requiring skin grfting hve een reported. 4 (ollgense lostridium histolytium) Produt Informtion

5 Corporl rupture (frture of penis) or other serious injury to the penis in the tretment of Peyronie s Disese. Injetion of into ollgen-ontining strutures suh s the orpor vernos of the penis my result in dmge to those strutures nd possile injury suh s orporl rupture (penile frture). Therefore, must e injeted only into the Peyronie s plque nd re should e tken to void injeting into the urethr, nerves, lood vessels, orpor vernos or other ollgen-ontining strutures of the penis. Corporl rupture ws reported s serious dverse event fter injetion in 5 out of 1044 ptients (0.5%) in the ontrolled nd unontrolled linil trils in Peyronie s disese. In other -treted ptients (9 of 1044; 0.9%), omintion of penile ehymoses or hemtom, sudden penile detumesene, nd/or penile popping sound or senstion ws reported, nd in these ses, dignosis of orporl rupture nnot e exluded. These ptients were mnged without surgil intervention, ut the long-term onsequenes re unknown. Severe penile hemtom ws lso reported s n dverse retion in 39 of 1044 ptients (3.7%) in the ontrolled nd unontrolled linil studies in Peyronie s disese. Signs or symptoms tht my reflet serious injury to the penis should e promptly evluted in order to ssess for orporl rupture or severe penile hemtom, whih my require surgil intervention. Physiins should dvise ptients to wit two weeks fter the seond injetion of tretment yle efore resuming sexul tivity, provided pin nd swelling hve susided. Speil penile onditions/diseses not studied in linil trils There is limited informtion on the tretment of ptients with disese of less thn 1 yer durtion. Ptients with penile urvture greter thn 90 were not studied in the linil studies. tretment in ptients hving lified plque tht ould hve interfered with the injetion tehnique, hordee in the presene or sene of hypospdis, thromosis of the dorsl penile rtery nd/or vein, infiltrtion y enign or mlignnt mss resulting in penile urvture, infiltrtion y n infetious gent, suh s in lymphogrnulom venereum, ventrl urvture from ny use nd isolted hourglss deformity of the penis hs not een studied nd tretment in these ptients should e voided. Use in ptients with ogultion disorders must e used with ution in ptients with ogultion disorders or those tking ntiogulnts. In the linil studies 70% nd 38% of - treted ptients reported ehymosis/ontusion nd hemorrhge respetively t the injetion site t signifintly higher rte thn pleo ptients. In the two doule-lind, pleo ontrolled phse 3 studies in Peyronie s disese, 65.5% of -treted ptients developed penile hemtom nd 14.5% developed penile ehymosis. The effiy nd sfety of in ptients reeiving ntiogulnt mediinl produts other thn up to 150 mg etylsliyli id per dy prior to dministrtion is not known. Use of in ptients who hve reeived ntiogulnts (with the exeption of up to 150 mg etylsliyli id dily) within 7 dys prior to reeiving n injetion of is not reommended. Immunogeniity nd Autoimmune disese As with ny non-humn protein mediinl produt, ptients my develop ntiodies to the therpeuti protein. During linil studies, lood smples from ptients with Dupuytren s ontrture were tested t multiple time points for ntiodies to the protein omponents of the mediinl produt (AUX-I nd AUX-II). In the Dupuytren s ontrture linil trils 30 dys fter the first injetion, 92% of ptients hd irulting ntiodies deteted ginst AUX-I, nd 86% of ptients ginst AUX-II. After third or fourth injetion, ll sujets developed positive ntiodies to oth AUX-I nd AUX-II. At five yers fter the initil injetion of, 92.8% nd 93.4% of sujets were seropositive for nti-aux-i nd nti-aux-ii respetively. Among ptients in Study AUX-CC-867 who reported no prior exposure to, the umultive immunologil response of two onurrent doses of 0.58 mg (totl dose of 1.16 mg) in the sme hnd ws pproximtely one men log titre unit less thn the umultive immunologil response oserved fter two single sequentil injetions of 0.58 mg dministered 4 weeks prt (umultive totl dose of 1.16 mg). There ws no pprent orreltion of ntiody frequeny, ntiody titres, or neutrlising sttus to linil response or dverse retions. Long-term follow-up of 634 ptients who prtiipted in the Phse 3 studies showed tht pproximtely two yers fter the initil injetion of, 7.7% (49/634) of ptients were serum negtive for AUX-I ntiodies nd 5.0% (32/634) were serum negtive for AUX-II ntiodies. Of the 49 sujets who were serum negtive for AUX-I ntiodies t the Yer 2 follow-up, 44 hd een positive for AUX-I ntiodies during Phse 3. Of the 32 who were serum negtive for AUX-II ntiodies t the Yer 2 follow-up, 29 hd een positive for AUX-II ntiodies during Phse 3. Sine the protein omponents in hve some sequene homology with humn mtrix metlloproteinses (MMPs), nti-produt ntiodies ould theoretilly interfere with humn MMPs. No sfety onerns relted to the inhiition of endogenous MMPs hve een oserved, in prtiulr no dverse events inditing the development or exertion of utoimmune diseses or the development of musuloskeletl syndrome (MSS). Whilst there is no linil evidene from the urrent sfety dt of musuloskeletl syndrome developing following the dministrtion of, the potentil for it to our nnot e exluded. If this syndrome were to develop, it would our progressively nd is hrterised y one or more of the following signs nd symptoms: rthrlgi, mylgi, joint stiffness, stiffness of the shoulders, hnd oedem, plmr firosis nd thikening or nodules forming in the tendons. In the retretment Study AUX-CC-862 in ptients with Dupuytren s ontrture, 150 nti-aux-i ntiody positive smples nd 149 nti-aux-ii ntiody positive smples were ssessed for potentil ross-retivity with humn MMPs-1, -2, -3, -8, nd -13. Results showed no ross-retivity with ny of the five MMPs tested. In the Peyronie s disese linil studies, t 6 weeks fter the first tretment yle of, pproximtely 75% of ptients hd ntiodies ginst AUX-I nd pproximtely 55% of ptients hd ntiodies ginst AUX-II. Six weeks fter the eighth injetion (fourth tretment yle) of >99% of -treted ptients developed high titres of ntiodies to oth AUX-I nd AUX-II. In ptients treted for these two inditions, there ws no pprent orreltion of ntiody frequeny, ntiody titres, or neutrlising sttus to linil response or dverse retions. Effets on Fertility Dupuytren s Contrture Collgense lostridium histolytium did not impir fertility nd erly emryoni development when dministered intrvenously in rts t doses up to 0.13 mg/dose (pproximtely 45 times the humn dose on mg/kg sis). Peyronie s Disese Peyronie s disese ours exlusively in dult mle ptients nd hene there is no relevnt informtion for use in femles. Low levels of were quntifile in the plsm of evlule mle ptients for up to 30 minutes following dministrtion of into the penile plque of ptients with Peyronie s disese (see PHARMACOKINETICS). Use in Pregnny (Ctegory B1) There re no dequte nd well-ontrolled studies of in pregnnt women. Humn phrmokineti studies showed tht levels were not quntifile in the systemi irultion following injetion into Dupuytren s ord. Reprodution studies hve een performed in rts with intrvenous doses up to 0.13 mg (pproximtely 45 times the humn dose of on mg/kg sis, if dministered intrvenously) nd hve reveled no evidene of impired fertility or hrm to the fetus due to ollgense lostridium histolytium. Prturition or postntl development studies in nimls were not onduted sine humn phrmokineti studies show tht levels re not quntifile in the systemi irultion following injetion into Dupuytren s ord. Almost ll ptients develop nti-drug ntiodies (nti- AUX-I nd nti-aux-ii) fter tretment with, the ross-retivity of whih versus endogenous mtrix metlloproteinses involved in pregnny nd lour nnot e exluded. The potentil risk for humns on prturition nd postntl development is unknown. Therefore the use of is not reommended in pregnny nd tretment should e postponed until fter pregnny. Produt Informtion (ollgense lostridium histolytium) 5

6 Use in Lttion It is not known whether ollgense lostridium histolytium is exreted in humn milk. Beuse mny drugs re exreted in humn milk, ution should e exerised when is dministered to nursing womn. Peditri use The sfety nd effetiveness of in peditri ptients less thn 18 yers old hve not een investigted nd therefore not estlished. Use in the Elderly (> 65 yers of ge) No overll differenes in sfety or effetiveness were oserved etween elderly nd younger ptients. Driving/Operting Mhinery my hve mjor influene on the ility to drive nd use mhines due to the swelling nd pin whih my impir the use of the treted hnd. Other minor influenes on the ility to drive nd use mhines inlude dizziness, presthesi, hypoesthesi, nd hedhe tht hve lso een reported following injetion of. Ptients must e instruted to void potentilly hzrdous tsks suh s driving or using mhines until it is sfe to do so or s dvised y the physiin. Genotoxiity Purified ollgense lostridium histolytium ws not mutgeni in Slmonell typhimurium (Ames test) nd ws not lstogeni in oth n in vivo mouse mironuleus ssy nd n in vitro hromosoml errtion ssy in humn lymphoytes. Crinogeniity Long term niml studies to evlute the rinogeni potentil of ollgense lostridium histolytium hve not een onduted. Long-term sfety Long-term sfety of is not fully hrterised. The impt of tretment with on susequent surgery, if needed, is not known. INTERACTIONS WITH OTHER MEDICINES Due to the lk of quntifile systemi exposure of in ptients with Dupuytren s ontrture nd miniml nd short-lived systemi exposure of in ptients with Peyronie s disese, no forml mediinl produt intertion studies with hve een performed. Antiogulnt drugs: should e used with ution in ptients reeiving onomitnt ntiogulnts (exept for low-dose etylsliyli id) [see WARNINGS AND PRECAUTIONS]. Tetryline, nthryline, nd nthrquinone drugs: There is no linil evidene of n intertion etween nd tetryline, nthryline, nthrquinone, or their derivtives. However, suh drugs hve een shown to inhiit mtrix metlloproteinse-medited ollgen degrdtion t suprphrmologil onentrtions in vitro. Therefore, use of in ptients who hve reeived tetryline ntiiotis (e.g., doxyyline) within 14 dys prior to reeiving n injetion of is not reommended. ADVERSE EFFECTS Dupuytren s Contrture The dt desried elow re sed on two pooled rndomised, doulelind, pleo-ontrolled trils through Dy 90 in ptients with Dupuytren s ontrture (CORD-I nd CORD-II). The doule-lind study popultion ws omprised of 374 sujets of whom 249 reeived 0.58 mg nd 125 reeived pleo. The men ge ws 62.9 yers (rnge 33 to 89 yers), most (80.5%) sujets were men, nd ll sujets were white exept for one sujet who ws Hispni. In these trils, ptients were treted with up to 3 injetions of 0.58 mg of or pleo with pproximtely 4-week intervls etween injetions nd the ptients hd finger extension proedures the dy fter injetion, if needed, to filitte disruption of the ord. The numer of - nd pleo-treted sujets who experiened t lest one dverse event ws 243/249 (97.7%) nd 64/125 (51.2%), respetively. These events were lssed s mild in 35.3% vs 35.2%, moderte in 52.2% vs 14.4%, nd severe in 10.0% vs 1.6% of sujets. Serious dverse events were experiened y 8 (3.2%) sujets treted with nd y 1 (0.8%) sujet treted with pleo. Some ptients developed vsovgl synope fter finger extension proedures. Tle 9: Adverse Events Ourring in 1% of Treted Sujets nd t Greter Inidene thn Pleo Studies CORD-I nd CORD-II N=249 Pleo N=125 N (%) of sujets with t lest one 243 (97.6) 64 (51.2) dverse effet Blood nd Lymphti System Disorders: Lymph node pin 21 (8.4) 0 (0.0) Lymphdenopthy 33 (13.3) 0 (0.0) Gstrointestinl disorders: Nuse 3 (1.2) 1 (0.8) Generl disorders nd Administrtion Site Conditions: Axillry pin 15 (6.0) 0 (0.0) Inflmmtion 8 (3.2) 0 (0.0) Injetion site hemorrhge 95 (38.2) 4 (3.2) Injetion site retion 87 (34.9) 7 (5.6) Injetion site swelling 61 (24.5) 8 (6.4) Injetion site vesiles 6 (2.4) 1 (0.8) Peripherl oedem d 183 (73.5) 6 (4.8) Pruritus e 37 (14.9) 1 (0.8) Swelling 6 (2.4) 0 (0.0) Tenderness 60 (24.1) 0 (0.0) Infetions nd Infesttions: Lower respirtory trt infetion 3 (1.2) 0 (0.0) Injury, Poisoning, nd Proedurl Complitions: Contusion 137 (55.0) 4 (3.2) Skin lertion 22 (8.8) 0 (0.0) Musuloskeletl nd Connetive Tissue Disorders: Arthrlgi 11 (4.4) 1 (0.8) Joint swelling 6 (2.4) 0 (0.0) Mylgi 3 (1.2) 1 (0.8) Pin in extremity 87 (34.9) 5 (4.0) Shoulder pin 3 (1.2) 0 Nervous System Disorders: Burning senstion 3 (1.2) 0 (0.0) Dizziness 4 (1.6) 0 (0.0) Hedhe 6 (2.4) 5 (4.0) Hypoesthesi 6 (2.4) 0 (0.0) Presthesi 7 (2.8) 1 (0.8) Skin nd Suutneous Tissue Disorders: Blister 11 (4.4) 0 (0.0) Blood lister 10 (4.0) 0 (0.0) Ehymosis 51 (20.5) 0 (0.0) Erythem 14 (5.6) 0 (0.0) Hyperhidrosis 3 (1.2) 0 (0.0) Rsh 3 (1.2) 1 (0.8) Inludes the terms: lymphdenopthy nd xillry mss Inludes the terms: injetion site retion, injetion site erythem, injetion site inflmmtion, injetion site irrittion, injetion site pin, nd injetion site wrmth Inludes the terms: injetion site swelling nd injetion site oedem d Most involved swelling of the treted extremity e Inludes the terms: pruritus nd injetion site pruritus Severe AEs: injetion site retion, pin in extremity (2%); peripherl oedem, ontusion (1.6%); injetion site hemorrhge (1.2%); nd tenderness, injetion site ellulitis, ligment injury, skin lertion, tendon rupture, hest wll pin, irritility (<1%). 6 (ollgense lostridium histolytium) Produt Informtion

7 Tle 10 presents dverse retions listed y system orgn lss nd frequeny tegory, using the onvention: unommon ( 1/1,000 to <1/100).Within eh frequeny group, dverse retions re presented in order of deresing seriousness. Adverse retions reported from the linil progrmme re those tht ourred in the Phse 3 doule lind pleo ontrolled studies. The most frequently reported dverse retions during the linil studies were lol injetion-site retions suh s oedem peripherl (lol to the injetion site), ontusion (inluding ehymosis), injetion-site hemorrhge, nd injetion-site pin. Injetion site retions were very ommon, ourring in the vst mjority of ptients, were mostly mild to moderte in severity nd generlly susided within 1-2 weeks post injetion. Lymphngitis ws reported in 1% of sujets (11/1082) who reeived t lest one injetion of nd hs een reported post mrketing. The dverse retion profile ws similr for eh injetion, regrdless of the numer of injetions dministered. However, the inidene of pruritus inresed with more injetions. Serious dverse retions of tendon rupture, tendonitis, other ligment injury nd omplex regionl pin syndrome relted to the mediinl produt were reported Tle 10: Unommon Adverse Retions ( 1/1,000 to <1/100) Listed y System Orgn Clss Studies CORD-I nd CORD-II System orgn lss Infetions nd infesttions Blood nd lymphti system disorders Immune system disorders Psyhitri disorders Nervous system disorders Eye disorders Vsulr disorders Respirtory, thori nd medistinl disorders Gstrointestinl disorders Skin nd suutneous tissue disorders Musuloskeletl nd onnetive tissue disorders Reprodutive system nd rest disorders Generl disorders nd dministrtion site onditions Investigtions Injury, poisoning nd proedurl omplitions Unommon 1/1,000 to <1/100 Injetion site ellulitis, Lymphngitis Thromoytopeni Hypersensitivity Disorienttion, Agittion, Insomni, Irritility, Restlessness Complex regionl pin syndrome, Monoplegi, Synope vsovgl, Tremor Eyelid oedem Hemtom, Hypotension Dyspnoe, Hyperventiltion Dirrhoe, Vomiting, Adominl pin upper Rsh erythemtous, Rsh mulr, Ezem, Swelling fe, Pin of skin, Skin exfolition, Skin lesion, Skin disorder, S, Skin disolourtion, Skin tightness Axillry mss, Chest wll pin, Groin pin, Joint repittion, Joint stiffness, Lim disomfort, Musle spsms, Musulr wekness, Musuloskeletl disomfort, Musuloskeletl stiffness, Nek pin, Shoulder pin Brest tenderness, Hypertrophy rest Pin, Injetion site irrittion, Injetion site retion, lol swelling, Pyrexi, Disomfort, Ftigue, Feeling hot, Influenz like illness, Injetion site nesthesi, Injetion site desqumtion, Injetion site disolourtion, Injetion site nodule, Mlise Lymph node plple, Alnine minotrnsferse inresed, Asprtte minotrnsferse inresed, Body temperture inresed Tendon rupture, Ligment injury, Lim injury, Open wound, Wound, Dehisene Tle 11: Undesirle effets in Post-Mrketing Reports (rre <1/1000; very rre <1/10,000) Blood nd lymphti system disorders Nervous system disorders Eye disorders Er nd lyrinth disorders Crdi disorders Rre: Lymphdenopthy Very rre: Lymphdenitis, Lymph node pin Very rre: Burning senstion, Dizziness, Hypoesthesi, Loss of onsiousness, Presthesi, Presynope, Sleep disorder Very rre: Vision lurred Very rre: Vertigo Very rre: Atril firilltion, Cynosis, Myordil infrtion Vsulr disorders Rre: Hemtom Respirtory, thori Very rre: Dyspnoe, Throt irrittion nd medistinl disorders Gstrointestinl Very rre: Nuse disorders Skin nd suutneous tissue disorders Rre: Blister, Blood lister, Dry skin, Ehymosis, Erythem, Pruritus, Rsh, Rsh pruriti, Sr, Skin disolourtion, Skin exfolition, Skin hemorrhge, Skin lesion, Urtiri Reprodutive system nd rest disorders Very rre Eretile dysfuntion Generl disorders nd dministrtion site onditions Rre: Drug ineffetive, Injetion site hemtom, Injetion site swelling, Oedem peripherl, Swelling Very rre: Administrtion site pin, Astheni, Axillry pin, Chest pin, Condition ggrvted, Disomfort, Drug effet deresed, Ftigue, Injetion site disolourtion, Injetion site hemorrhge, Injetion site pruritus, Injetion site retion, Injetion site vesiles, Lol retion, Mlise, Needle issue, No dverse event, No therpeuti response, Oedem, Pin, Produt reonstitution issue, Pyrexi, Tenderness, Hypersensitivity, Lymphngitis Investigtions Rre: Pin in extremity Very rre: Blood gluose inresed, Intr oulr pressure inresed, Arthrlgi, Dupuytren s ontrture, Musulr wekness, Musuloskeletl stiffness, Mylgi, Tenosynovitis Injury, poisoning Rre: Contusion, Lertion nd proedurl Very rre: Aidentl exposure, Drug omplitions dministrtion error, Fll, Hnd frture, Inpproprite shedule of drug dministrtion, Inorret dose dministered, Injury, Ligment injury, Medition error, Proedurl pin, Tendon injury, Tendon rupture, Wound, Wound hemorrhge, Wrong tehnique in drug usge proess. Surgil nd medil Rre: Skin grft proedures Very rre: Off lel use Produt Informtion (ollgense lostridium histolytium) 7

8 The sfety of two onurrent injetions of into Dupuytren s ords in the sme hnd ws evluted in historilly-ontrolled, open-lel multientre tril in 715 dult ptients with Dupuytren s ontrture (Study AUX- CC-867). In Study AUX-CC-867, finger extension proedures were performed pproximtely 24 to 72 hours fter injetion. Out of 715 ptients who reeived two onurrent injetions of in the sme hnd (1450 injetions) in Study AUX-CC-867, one (0.1%) ptient experiened tendon rupture of the treted finger within 3 dys of the injetion nd one (0.1%) ptient who ws previously treted with in nother study experiened n nphylti retion. The inidene of skin lertion (29.1%) ws higher for sujets treted with two onurrent injetions of in Study AUX-CC-867 ompred with sujets treted with up to three single injetions in the studies CORD-I nd CORD-II (skin lertion [9%]). There were no other linilly relevnt differenes etween two onurrent injetions of in the sme hnd nd up to three single injetions of in the types of dverse events reported (i.e., most dverse events were lol to the treted extremity nd of mild or moderte intensity). Tle 12 shows the inidene of dverse retions tht were reported in -treted ptients fter two onurrent injetions of in the sme hnd through Dy 60 in Study AUX-CC-867. The overll sfety profile ws similr regrdless of the timing of the postinjetion finger extension proedure (i.e., 24 hours, 48 hours, nd 72 hours fter injetion) mong ptients who reeived two onurrent injetions of in Study AUX-CC-867. A study ws onduted (AUX-CC-860) to evlute the long-term sfety profile of. No new sfety signls were identified mong ptients who were followed for 5 yers fter their initil injetion of in previous linil study. The mjority of dverse events reported during the long-term follow-up period were non-serious, mild or moderte in intensity, nd were not relted to the lol dministrtion of. These dt support the long term sfety profile of onfirming tht no new sfety risks were identified during the 5 yer follow-up period. Tle 12 : Adverse Retions Ourring in Sujets who reeived Two Conurrent Injetions of in Study AUX-CC-867 (listed y system orgn lss nd frequeny tegories) System orgn lss Blood nd lymphti system disorders Crdi disorders Eye disorders Very ommon Common Unommon 1/10 1/100 to <1/10 1/1,000 to <1/100 Lymphdenopthy Lymph node pin Lymphdenitis Plpittions Eye pruritus Pigment dispersion syndrome Gstrointestinl disorders Nuse Dirrhoe, Pltl oedem, Vomiting Generl disorders nd dministrtion site onditions Immune system disorders Infetions nd infesttions Injury, poisoning nd proedurl omplitions Investigtions Musuloskeletl nd onnetive tissue disorders Neoplsm enign, mlignnt nd unspeified (inl ysts nd polyps) Injetion site pin, Oedem peripherl Contusion, Skin lertion Pin in extremity Axillry pin, Injetion site hemtom, Injetion site hemorrhge, Injetion site lertion, Injetion site oedem, Injetion site pruritus, Injetion site swelling, Injetion site vesiles, Swelling Proedurl pin Arthrlgi, Joint swelling, Musuloskeletl stiffness Chills, Ftigue, Feeling old, Feeling hot, Inflmmtion, Injetion site disomfort, Lol swelling, Mlise, Mss, Nodule, Pin Anphylti retion Fungl infetion, Gingivl infetion, Infetion, Influenz, Lymphngitis Post proedurl hemorrhge, Tendon rupture, Wound Asprtte minotrnsferse inresed, Blood holesterol inresed, Blood retinine inresed, Blood urine present, Eosinophil ount inresed, Grip strength deresed, Lymph node plple, Monoyte ount inresed, Neutrophil ount inresed, Protein urine present Finger deformity, Joint repittion, Joint rnge of motion deresed, Joint stiffness, Lim disomfort, Musle spsms Musulr wekness, Musuloskeletl hest pin, Musuloskeletl pin, Tenosynovitis stenosns, Trigger finger Pyogeni grnulom Nervous system disorders Presthesi Burning senstion, Crpl tunnel syndrome, Complex regionl pin syndrome, Dizziness, Hedhe, Hyperesthesi, Hypoesthesi, Presynope, Sensory loss Renl nd urinry disorders Polyuri Reprodutive system nd Brest swelling rest disorders Respirtory, thori nd medistinl disorders Epistxis, Pulmonry emolism Skin nd suutneous tissue disorders Blood lister, Pruritus Blister, Ehymosis Dermtitis, Dry skin, Erythem, Hyperhidrosis Pruritus generlized, Rsh, Skin urning senstion, Skin exfolition, Skin hemorrhge, Skin tightness Vsulr disorders Hemtom Deep vein thromosis, Flushing, Peripherl oldness, Rynud s phenomenon, Superfiil vein prominene oedem peripherl inludes injetion site oedem nd oedem 8 (ollgense lostridium histolytium) Produt Informtion

9 Peyronie s Disese ws studied in ptients with Peyronie s disese in two rndomised, doule-lind, pleo ontrolled studies (Studies 1; AUX-CC-803 nd 2; AUX- CC-804). The doule lind study popultion omprised 832 mle ptients of whom 551 ptients reeived nd 281 reeived pleo. The medin ge ws 58 yers (rnge 23 to 84 yers). In the ontrolled nd unontrolled linil studies of in Peyronie s disese, out of 1044 ptients who reeived totl of 7466 injetions, orporl rupture nd other serious penile injury were reported s follows: 5 (0.5%) ptients hd orporl rupture of the penis. 9 (0.9%) ptients hd omintion of penile ehymoses or hemtom, sudden penile detumesene, nd/or penile popping sound or senstion nd in these ses, dignosis of orporl rupture nnot e exluded. 39 (3.7%) ptients hd severe penile hemtom. The mjority of Peyronie s ptients experiened t lest one dverse retion (92% -treted ptients, 61% pleo-treted). Most dverse retions were lol events of the penis nd groin nd the mjority of these events were of mild or moderte severity, nd most (79%) resolved within 14 dys of the injetion. The dverse retion profile ws similr fter eh injetion, regrdless of the numer of injetions dministered. The most frequently reported dverse drug retions (> 25%) during the linil studies were penile hemtom, penile swelling nd penile pin. Tle 13 shows the inidene of dverse retions tht were reported in greter thn or equl to 1% of -treted ptients nd t frequeny greter thn pleo-treted ptients. Tle 13: Adverse Events Ourring in 1% of - Treted Sujets nd t Greter Inidene thn Pleo Studies 1 nd 2. n=551 Pleo n=281 N (%) of sujets with t lest one 508 (92.2) 172 (61.2) dverse effet Gstrointestinl disorders: Dirrhoe 11 (2.0) 5 (1.8) Generl disorders nd Administrtion Site Conditions: Injetion site vesiles 8 (1.5) 0 (0.0) Nodule 8 (1.5) 0 (0.0) Lolised oedem 7 (1.3) 0 (0.0) Injetion site pruritus 6 (1.1) 0 (0.0) Supr pui pin 6 (1.1) 0 (0.0) Infetions nd Infesttions: Nsophryngitis 20 (3.6) 7 (2.5) Sinusitis 15 (2.7) 4 (1.4) Influenz 6 (1.1) 3 (1.1) Injury, Poisoning, nd Proedurl Complitions: Proedurl pin 12 (2.2) 6 (2.1) Skin lertion 8 (1.5) 1 (0.4) Exorition 6 (1.1) 0 (0.0) Musuloskeletl nd Connetive Tissue Disorders: Musuloskeletl pin 14 (2.5) 2 (0.7) Musle spsms 6 (1.1) 1 (0.4) Pin in extremity 6 (1.1) 1 (0.4) Nervous System Disorders: Hedhe 16 (2.9) 6 (2.1) Reprodutive system nd rest disorders: Penile hemtom 388 (70.4) 70 (24.9) Swelling 319 (57.9) 11 (3.9) Pin 268 (48.6) 31 (11.0) Ehymosis d 168 (30.5) 25 (8.9) Penile lister 18 (3.3) 0 (0.0) Penile erythem 18 (3.3) 4 (1.4) Pruritus genitl 18 (3.3) 1 (0.4) Eretile dysfuntion 17 (3.1) 3 (1.1) Pinful eretion 16 (2.9) 1 (0.4) Pripism 10 (1.8) 5 (1.8) Dyspreuni 6 (1.1) 0 (0.0) Respirtory, thori & medistinl disorders: Cough 8 (1.5) 4 (1.4) Skin nd Suutneous Tissue Disorders: Blood lister 26 (4.7) 0 (0.0) Skin disolourtion 10 (1.8) 0 (0.0) Skin hyperpigmenttion 6 (1.1) 0 (0.0) Inludes: injetion site hemtom nd penile hemtom were reported with the vertim term of penile ruising or injetion site ruising in 87% of ptients. Inludes: injetion site swelling, penile oedem, penile swelling, lol swelling, srotl swelling, nd injetion site oedem. Inludes: injetion site pin, penile pin, nd injetion site disomfort. d Inludes: ontusion, ehymosis, penile hemorrhge, nd injetion site hemorrhge. Produt Informtion (ollgense lostridium histolytium) 9

10 Severe penile hemtom or severe injetion site hemtom were reported in 33/551 (6.0%) of -treted ptients nd 0/281 (0%) of pleo-treted ptients, in Studies 1 nd 2 omined. A popping noise or popping senstion in the penis, sometimes desried s snpping or rking, nd sometimes ompnied y detumesene, hemtom nd/or pin, were reported in 73/551 (13.2%) -treted ptients nd 1/281 (0.3%) pleo-treted ptients, in Studies 1 nd 2 omined. Tle 14 presents dverse retions listed y system orgn lss nd frequeny tegories, using the following onvention: very ommon ( 1/10), ommon ( 1/100 to <1/10), nd unommon ( 1/1,000 to <1/100). Within eh frequeny group, dverse retions re presented in order of deresing seriousness. Adverse retions reported from the linil progrmme re those tht ourred in the Phse 3 doule-lind pleo ontrolled studies t n inidene greter thn pleo. There were no linilly meningful differenes in the inidene of dverse events following tretment with sed on the severity of seline eretile dysfuntion or onomitnt phosphodiesterse type 5 (PDE5) inhiitor use. ws not ssoited with shortening of penile length in linil trils in the tretment of Peyronie s disese. Tle 14: Very ommon ( 1/10), ommon ( 1/100 to <1/10), nd unommon ( 1/1,000 to <1/100) Adverse Retions Listed y System Orgn Clss Studies 1 nd 2. System orgn lss Blood nd lymphti system disorders Crdi disorders Er nd lyrinth disorders Gstrointestinl disorders Generl disorders nd dministrtion site onditions Immune system disorders Infetions nd infesttions Injury, poisoning nd proedurl omplitions Investigtions Metolism nd nutrition disorders Musuloskeletl nd onnetive tissue disorders Nervous system disorders Psyhitri disorders Renl nd urinry disorders Reprodutive system nd rest disorders Respirtory, thori nd medistinl disorders Skin nd suutneous tissue disorders Very ommon 1/10 Penile hemtom Penile swelling Penile pin Penile ehymosis d Common 1/100 to <1/10 Injetion site vesiles, Lolised oedem, Injetion site pruritus, Nodule, Suprpui pin Proedurl pin Penile lister, Pruritus genitl, Pinful eretion, Eretile dysfuntion, Dyspreuni, Penile erythem Blood lister, Skin disolourtion Unommon 1/1,000 to <1/100 Lymph node pin, Eosinophili, Lymphdenopthy Thyrdi Tinnitus Adominl distension, Constiption Injetion site retion, Injetion site disolourtion, Pyrexi, Swelling, Astheni, Chills, Cyst, Indurtion, Influenz like illness, Injetion site nodule, Oedem, Seretion dishrge, Tenderness Drug hypersensitivity Fungl skin infetion, Infetion, Upper respirtory infetion Frture of penis, Skin lertion, Open wound, Srotl hemtom, Joint injury, Penis injury Blood gluose inresed, Blood pressure systoli inresed, Body temperture inresed, Eosinophil ount inresed Fluid retention Bk pin, Pui pin, Groin pin, Ligment disorder, Ligment pin, Musuloskeletl disomfort Hedhe, Dizziness, Dysgeusi, Presthesi, Burning senstion, Hyperesthesi, Hypoesthesi Anorml drems, Depression, Sexul inhiition Dysuri, Pollkiuri Penile dhesion, Penis disorder, Peyronie s disese, Sexul dysfuntion, Testiulr pin, Srotl erythem, Genitl disomfort, Genitl hemorrhge, Pelvi pin, Penile size redued, Penile vein thromosis, Srotl oedem, Srotl pin Cough Skin hyperpigmenttion, Erythem, Pigmenttion disorder, Skin nodule, Blister, Grnulom skin, Night swets, Penile ulertion, Rsh erythemtous, Skin disorder, Skin irrittion, Skin oedem Vsulr disorders Hemtom Hemtom, Hypertension, Hemorrhge, Lymphngiopthy, Thromophleitis superfiil Inludes: injetion site hemtom nd penile hemtom were reported with the vertim term of penile ruising or injetion site ruising in 87% of ptients. Inludes: injetion site swelling, penile oedem, penile swelling, lol swelling, srotl swelling, nd injetion site oedem. Inludes: injetion site pin, penile pin, nd injetion site disomfort. d Inludes: ontusion, ehymoses, penile hemorrhge, nd injetion site hemorrhge. 10 (ollgense lostridium histolytium) Produt Informtion