Rx only. PHOTOFRIN (porfimer sodium) INJECTION Initial U.S. Approval: 1995

Transcription

1 Rx only HIGHLIGHTS OF PRESCRIBIG IFORMATIO These highlights do not include ll the informtion needed to use PHOTOFRI sfely nd effectively. See full prescriing informtion for PHOTOFRI. PHOTOFRI (porfimer sodium) IJECTIO Initil U.S. Approvl: 1995 RECET MAJOR CHAGES Wrnings nd Precutions (5.1, 5.2, 5.5, 5.8, 5.9, 5.11) 06/2011 IDICATIOS AD USAGE PHOTOFRI is photodynmic therpy drug indicted for: Esophgel Cncer (1.1) Pllition of ptients with completely ostructing esophgel cncer, or of ptients with prtilly ostructing esophgel cncer who, in the opinion of their physicin, cnnot e stisfctorily treted with d:yag lser therpy Endoronchil Cncer (1.2) Tretment of microinvsive endoronchil non-smll-cell lung cncer (SCLC) in ptients for whom surgery nd rdiotherpy re not indicted Reduction of ostruction nd pllition of symptoms in ptients with completely or prtilly ostructing endoronchil SCLC High-Grde Dysplsi in Brrett s Esophgus (1.3) Altion of high-grde dysplsi (HGD) in Brrett s esophgus (BE) ptients who do not undergo esophgectomy DOSAGE AD ADMIISTRATIO PHOTOFRI (2.1) PHOTOFRI dministrtion: 2 mg/kg intrvenous Photoctivtion (2.2) Esophgel Cncer Lser light dose of 300 J/cm of fier optic diffuser length hours following injection with PHOTOFRI; repeted, if needed, hours fter initil injection Endoronchil Cncer Lser light dose of 200 J/cm of fier optic diffuser length hours following injection with PHOTOFRI; repeted, if needed, fter gentle deridement of residul tumor hours fter initil injection High-Grde Dysplsi in Brrett s Esophgus Lser light dose of 130 J/cm of fier optic diffuser length hours following injection with PHOTOFRI; repeted, if needed, with light dose of 50 J/cm of fier optic diffuser length hours fter initil injection 75 mg vil (3) DOSAGE FORMS AD STREGTHS COTRAIDICATIOS Porphyri (4) Existing trcheoesophgel or ronchoesophgel fistul (4, 5.1) Tumors eroding into mjor lood vessel (4, 5.2) Emergency tretment of ptients with severe cute respirtory distress cused y n ostructing endoronchil lesion ecuse 40 to 50 hours re required etween injection of PHOTOFRI nd lser light tretment (4) Esophgel or gstric vrices or esophgel ulcers >1 cm in dimeter (4) WARIGS AD PRECAUTIOS Trcheoesophgel or ronchoesophgel fistul cn occur if esophgel tumor is eroding into trche or ronchil tree (5.1) Gstrointestinl perfortion cn occur (5.1) High risk of leeding in ptients with esophgel vrices (5.2) High risk for ftl mssive hemoptysis with endoronchil tumors tht re: lrge, centrlly locted; cvitting; extensive, extrinsic to the ronchus (5.2) After tretment of HGD in BE, monitor endoscopic iopsy every three months, until four consecutive negtive evlutions for HGD hve een recorded (5.3) Photosensitivity cn e expected; oculr sensitivity is possile (5.4, 5.5) Allow 2-4 weeks etween PDT nd susequent rdiotherpy (5.6) Susternl chest pin my occur fter tretment (5.7) Tretment induced inflmmtion cn cuse irwy ostruction. Administer with cution to ptients with tumors in loctions where tretment-induced inflmmtion cn ostruct the min irwy (5.8) Esophgel stenosis occurs frequently fter tretment of HGD in BE (5.9) Ptients with heptic or renl impirment my need longer precutionry mesures for photosensitivity (5.10) Thromoemolic events cn occur following photodynmic therpy with PHOTOFRI (5.11) ADVERSE REACTIOS Most common dverse rections reported during clinicl trils (>10% of ptients) re (6.2): Esophgel Cncer: Anemi, pleurl effusion, pyrexi, constiption, nuse, chest pin, pin, dominl pin, dyspnoe, photosensitivity rection, pneumoni, vomiting, insomni, ck pin, phryngitis Ostructing Endoronchil Cncer: Dyspnoe, photosensitivity rection, hemoptysis, pyrexi, cough, pneumoni Superficil Endoronchil Tumors: Exudte, photosensitivity rection, ronchil ostruction, edem, ronchostenosis High-Grde Dysplsi in Brrett s Esophgus: Photosensitivity rection, esophgel stenosis, vomiting, chest pin, nuse, pyrexi, constiption, dysphgi, dominl pin, pleurl effusion, dehydrtion To report SUSPECTED ADVERSE REACTIOS, contct Pinncle Biologics, Inc. t or FDA t FDA-1088 or DRUG ITERACTIOS Other photosensitizing gents: My increse the risk of photosensitivity rection (7.1) Concomitnt therpy: My decrese the efficcy of PDT (7.2) See 17 for PATIET COUSELIG IFORMATIO. Revised: 03/2015 FULL PRESCRIBIG IFORMATIO: COTETS* 1 IDICATIOS AD USAGE 1.1 Esophgel Cncer 1.2 Endoronchil Cncer 1.3 High-Grde Dysplsi in Brrett s Esophgus 2 DOSAGE AD ADMIISTRATIO 2.1 PHOTOFRI 2.2 Photoctivtion 3 DOSAGE FORMS AD STREGTHS 4 COTRAIDICATIOS 5 WARIGS AD PRECAUTIOS 5.1 Gstroesophgel Fistul nd Perfortion 5.2 Pulmonry nd Gstroesophgel Hemorrhge 5.3 High-Grde Dysplsi (HGD) in Brrett s Esophgus (BE) 5.4 Photosensitivity 5.5 Oculr Sensitivity 5.6 Use Before or After Rdiotherpy 5.7 Chest Pin 5.8 Airwy Ostruction nd Respirtory Distress 5.9 Esophgel Strictures 5.10 Heptic nd Renl Impirment 5.11 Thromoemolism 6 ADVERSE REACTIOS 6.1 Overll Adverse Rection Profile 6.2 Adverse Rections in Clinicl Trils 6.3 Postmrketing Experience 7 DRUG ITERACTIOS 7.1 Other Photosensitizing Agents 7.2 Concomitnt Therpy 8 USE I SPECIFIC POPULATIOS 8.1 Pregnncy 8.3 ursing Mothers 8.4 Peditric Use 8.5 Geritric Use 10 OVERDOSAGE 10.1 PHOTOFRI Overdose 10.2 Overdose of Lser Light Following PHOTOFRI Injection 11 DESCRIPTIO

2 12 CLIICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 OCLIICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLIICAL STUDIES 14.1 Esophgel Cncer 14.2 Endoronchil Cncer 14.3 High-Grde Dysplsi in Brrett s Esophgus 16 HOW SUPPLIED/STORAGE AD HADLIG 17 PATIET COUSELIG IFORMATIO 17.1 Photosensitivity 17.2 Common Adverse Rections *Sections or susections omitted from the full prescriing informtion re not listed. FULL PRESCRIBIG IFORMATIO 1 IDICATIOS AD USAGE 1.1 Esophgel Cncer PHOTOFRI is indicted for the pllition of ptients with completely ostructing esophgel cncer, or of ptients with prtilly ostructing esophgel cncer who, in the opinion of their physicin, cnnot e stisfctorily treted with d:yag lser therpy. 1.2 Endoronchil Cncer PHOTOFRI is indicted for the tretment of microinvsive endoronchil non-smll-cell lung cncer (SCLC) in ptients for whom surgery nd rdiotherpy re not indicted. PHOTOFRI is indicted for the reduction of ostruction nd pllition of symptoms in ptients with completely or prtilly ostructing endoronchil SCLC. 1.3 High-Grde Dysplsi in Brrett s Esophgus PHOTOFRI is indicted for the ltion of high-grde dysplsi in Brrett s esophgus ptients who do not undergo esophgectomy. 2 DOSAGE AD ADMIISTRATIO Photodynmic therpy (PDT) with PHOTOFRI is two-stge process requiring dministrtion of oth drug nd light. The first stge of PDT is the intrvenous injection of PHOTOFRI t 2 mg/kg. Illumintion with lser light hours following injection with PHOTOFRI constitutes the second stge of therpy. A second lser light ppliction my e given hours fter injection [see Dosge nd Administrtion (2.2)]. In clinicl studies on endoronchil cncer, deridement vi endoscopy ws required 2-3 dys fter the initil light ppliction. Stndrd endoscopic techniques re used for light dministrtion nd deridement. Prctitioners should e fully fmilir with the ptient s condition nd trined in the sfe nd efficcious tretment of esophgel or endoronchil cncer, or high-grde dysplsi (HGD) in Brrett s esophgus (BE) using PDT with PHOTOFRI nd ssocited light delivery devices. PDT with PHOTOFRI should e pplied only in those fcilities properly equipped for the procedure. The lser system must e pproved for delivery of stle power output t wvelength of 630 ± 3 nm. Light is delivered to the tumor y cylindricl OPTIGUIDE fier optic diffusers pssed through the operting chnnel of n endoscope/ronchoscope. Instructions for use of the fier optic nd the selected lser system should e red crefully efore use. OPTIGUIDE cylindricl diffusers re ville in severl lengths. The choice of diffuser tip length depends on the length of the tumor or Brrett s mucos to e treted. Diffuser length should e sized to void exposure of nonmlignnt tissue to light nd to prevent overlpping of previously treted mlignnt tissue. Refer to the OPTIGUIDE instructions for use for complete instructions concerning the fier optic diffuser. 2.1 PHOTOFRI PHOTOFRI should e dministered s single slow intrvenous injection over 3 to 5 minutes t 2 mg/kg of ody weight. Reconstitute ech vil of PHOTOFRI with 31.8 ml of either 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), resulting in finl concentrtion of 2.5 mg/ml. Shke well until dissolved. Do not mix PHOTOFRI with other drugs in the sme solution. PHOTOFRI, reconstituted with 5% Dextrose Injection (USP) or with 0.9% Sodium Chloride Injection (USP), hs ph in the rnge of 7 to 8. PHOTOFRI hs een formulted with n overge to deliver the 75 mg leled quntity. The reconstituted product should e protected from right light nd used immeditely. Reconstituted PHOTOFRI is n opque solution, in which detection of prticulte mtter y visul inspection is extremely difficult. Reconstituted PHOTOFRI, however, like ll prenterl drug products, should e inspected visully for prticulte mtter nd discolortion prior to dministrtion whenever solution nd continer permit. Precutions should e tken to prevent extrvstion t the injection site. If extrvstion occurs, cre must e tken to protect the re from light. There is no known enefit from injecting the extrvstion site with nother sustnce. 2.2 Photoctivtion Esophgel Cncer Initite 630 nm wvelength lser light delivery to the ptient hours following injection with PHOTOFRI. A second lser light tretment my e given s erly s 96 hours or s lte s 120 hours fter the initil injection with PHOTOFRI. o further injection of PHOTOFRI should e given for such retretment with lser light. Before providing second lser light tretment, the residul tumor my e derided. The deridement is optionl since the residu will e removed nturlly y peristltic ction of the esophgus. Vigorous deridement my cuse tumor leeding. Photoctivtion of PHOTOFRI is controlled y the totl light dose delivered. In the tretment of esophgel cncer, light dose of 300 Joules/cm (J/cm) of diffuser length should e delivered. The totl power output t the fier tip is set to deliver the pproprite light dose using exposure times of 12 minutes nd 30 seconds. For the tretment of esophgel cncer, ptients my receive second course of PDT minimum of 30 dys fter the initil therpy; up to three courses of PDT (ech seprted y minimum of 30 dys) cn e given. Before ech course of tretment, ptients with esophgel cncer should e evluted for the presence of trcheoesophgel or ronchoesophgel fistul [see Contrindictions (4)]. All ptients should e evluted for the possiility tht the tumor my e eroding into mjor lood vessel [see Contrindictions (4)]. Endoronchil Cncer Initite 630 nm wvelength lser light delivery to the ptient hours following injection with PHOTOFRI. A second lser light tretment my e given s erly s 96 hours or s lte s 120 hours fter the initil injection with PHOTOFRI. o further injection of PHOTOFRI should e given for such retretment with lser light. Before providing second lser light tretment, the residul tumor should e derided. Vigorous deridement my cuse tumor leeding. For endoronchil tumors, deridement of necrotic tissue should e discontinued when the volume of leeding increses, s this my indicte tht deridement hs gone eyond the zone of the PDT effect. Photoctivtion of PHOTOFRI is controlled y the totl light dose delivered. In the tretment of endoronchil cncer, light dose of 200 J/cm of diffuser length should e delivered. The totl power output t the fier tip is set to deliver the pproprite light dose using exposure times of 8 minutes nd 20 seconds. For noncircumferentil endoronchil tumors tht re soft enough to penetrte, interstitil fier plcement is preferred to intrluminl ctivtion, since this method produces etter efficcy nd results in less exposure of the norml ronchil mucos to light. It is importnt to perform deridement 2 to 3 dys fter ech light dministrtion to minimize the potentil for ostruction cused y necrotic deris [see Wrnings nd Precutions (5.8)]. For the tretment of endoronchil cncer, ptients my receive second course of PDT minimum of 30 dys fter the initil therpy; up to three courses of PDT (ech seprted y minimum of 30 dys) cn e given. In ptients with endoronchil lesions who hve recently undergone rdiotherpy, sufficient time (pproximtely 4 weeks) should e llowed etween the therpies to ensure tht the cute inflmmtion produced y rdiotherpy hs susided prior to PDT [see Wrnings nd Precutions (5.6)]. All ptients should e evluted for the possiility tht the tumor my e eroding into mjor lood vessel [see Contrindictions (4)]. High-Grde Dysplsi (HGD) in Brrett s Esophgus (BE) Prior to inititing tretment with PHOTOFRI PDT, the dignosis of HGD in BE should e confirmed y n expert GI pthologist. Approximtely hours fter PHOTOFRI dministrtion light should e delivered y X-Cell Photodynmic Therpy (PDT) Blloon with Fier Optic Diffuser. The choice of fier optic/lloon diffuser comintion will depend on the length of Brrett s mucos to e treted (Tle 1). TABLE 1. Fier Optic Diffuser/Blloon Comintion Treted Brrett s Fier Optic Mucos Length (cm) Diffuser Length (cm) Blloon Window Length (cm) Whenever possile, the BE segment selected for tretment should include norml tissue mrgins of few millimeters t the proximl nd distl ends. Photoctivtion is controlled y the totl light dose delivered. The ojective is to expose nd tret ll res of HGD nd the entire length of BE. The light dose dministered will e 130 J/cm of diffuser length using centering lloon. Bsed on the rndomized clinicl study, cceptle light intensity for the lloon/diffuser comintions rnge from mw/cm of diffuser length. To clculte the light dose, the following specific light dosimetry eqution pplies for ll fier optic diffusers: Light Dose (J/cm) = Power Output From Diffuser (W) x Tretment Time (s) Diffuser Length (cm) Tle 2 provides the settings tht will e used to deliver the dose within the shortest time (light intensity of 270 mw/cm). A second option (light intensity of 200 mw/cm) hs lso een included where necessry to ccommodte lsers with totl cpcity tht does not exceed 2.5 W. TABLE 2. Fier Optic Power Outputs nd Tretment Times Required to Deliver 130 J/cm of Diffuser Length Using the Centering Blloon Blloon Window Length (cm) Fier Optic Diffuser Length (cm) Light Intensity (mw/cm) Required Power Output from Diffuser (mw) Tretment Time (sec) (min:sec) : : : :50 As mesured y immersing the diffuser into the cuvet in the power meter nd slowly incresing the lser power.

3 ote: o more thn 1.5 times the required diffuser power output should e needed from the lser. If more thn this is required, the system should e checked. Short fier diffusers ( 2.5 cm) re to e used to pretret nodules with 50 J/cm of diffuser length prior to regulr lloon tretment in the first lser light session or for the tretment of skip res (i.e., n re tht does not show sufficient mucosl response) fter the first light session. For this tretment, the fier optic diffuser is used without centering lloon, nd light intensity of 400 mw/cm should e used. For nodule pretretment nd tretment of skipped res, cre should e tken to minimize exposure to norml tissue s it is lso sensitized. Tle 3 lists pproprite fier optic power outputs nd tretment times using light intensity of 400 mw/cm. TABLE 3. Short Fier Optic Diffusers to e Used Without Centering Blloon to Deliver 50 J/cm of Diffuser Length t Light Intensity of 400 mw/cm Fier Optic Diffuser Length (cm) Required Power Output From Diffuser (mw) Tretment Time (sec) Tretment Time (min:sec) : : : :05 As mesured y immersing the diffuser into the cuvet in the power meter nd slowly incresing the lser power. ote: o more thn 1.5 times the required diffuser power output should e needed from the lser. If more thn this is required, the system should e checked. A mximum of 7 cm of esophgel mucos is treted t the first light session using n pproprite size of centering lloon nd fier optic diffuser (Tle 1). Whenever possile, the segment selected for the first light ppliction should contin ll the res of HGD. Also, whenever possile, the BE segment selected for the first light ppliction should include norml tissue mrgin of few millimeters t the proximl nd distl ends. odules re to e pretreted t light dose of 50 J/cm of diffuser length with short ( 2.5 cm) fier optic diffuser plced directly ginst the nodule followed y stndrd lloon ppliction s descried ove. Repet Light Appliction A second lser light ppliction my e given to previously treted segment tht shows skip re, using short, 2.5 cm, fier optic diffuser without centering lloon t the light dose of 50 J/cm of the diffuser length. Ptients with BE >7 cm, should hve the remining untreted length of Brrett s epithelium treted with second PDT course t lest 90 dys lter. The tretment regimen is summrized in Tle 4. TABLE 4. High-Grde Dysplsi in Brrett s Esophgus Procedure Study Dy Light Delivery Devices Tretment Intent PHOTOFRI Injection Dy 1 A Uptke of photosensitizer 3, 5 or 7 cm lloon Lser Light Appliction Dy 3 (130 J/cm) Photoctivtion Lser Light Appliction (Optionl) Dy 5 Short ( 2.5 cm) fier optic diffuser (50 J/cm) Tretment of skip res only Discrete nodules will receive n initil light ppliction of 50 J/cm (using short fier optic diffuser without lloon) efore the lloon light ppliction. A: ot Applicle For the ltion of HGD in BE, ptients my receive n dditionl course of PDT t minimum of 90 dys fter the initil therpy; up to three courses of PDT (ech injection seprted y minimum of 90 dys) cn e given to previously treted segment which still shows HGD, low-grde dysplsi, or Brrett s metplsi, or to new segment if the initil Brrett s segment ws >7 cm in length. Both residul nd dditionl segments my e treted in the sme light session(s) provided tht the totl length of the segments treted with the lloon/ diffuser comintion is not greter thn 7 cm. In the cse of previously treted esophgel segment, if it hs not sufficiently heled nd/or histologicl ssessment of iopsies is not cler, the susequent course of PDT my e delyed for n dditionl 1-2 months. 3 DOSAGE FORMS AD STREGTHS 75 mg vil 4 COTRAIDICATIOS PHOTOFRI is contrindicted in ptients with porphyri. Photodynmic therpy (PDT) is contrindicted in ptients with n existing trcheoesophgel or ronchoesophgel fistul. PDT is contrindicted in ptients with tumors eroding into mjor lood vessel. PDT is not suitle for emergency tretment of ptients with severe cute respirtory distress cused y n ostructing endoronchil lesion ecuse 40 to 50 hours re required etween injection with PHOTOFRI nd lser light tretment. PDT is not suitle for ptients with esophgel or gstric vrices, or ptients with esophgel ulcers >1 cm in dimeter. 5 WARIGS AD PRECAUTIOS 5.1 Gstroesophgel Fistul nd Perfortion Do not initite PHOTOFRI with PDT in ptients with esophgel tumors eroding into the trche or ronchil tree or ronchil wll ecuse of the high likelihood of trcheoesophgel or ronchoesophgel fistul. Serious nd sometimes ftl gstrointestinl nd esophgel necrosis nd perfortion cn occur following tretment with PHOTOFRI with PDT. 5.2 Pulmonry nd Gstroesophgel Hemorrhge Assess ptients for tumors eroding into pulmonry lood vessel [see Contrindictions (4)] nd esophgel vrices. Ptients t high risk for ftl mssive hemoptysis (FMH) include those with lrge, centrlly locted tumors, cvitting tumors, or extensive tumors extrinsic to the ronchus. Do not dminister light directly to n re with esophgel vrices ecuse of the high risk of hemorrhge. 5.3 High-Grde Dysplsi (HGD) in Brrett s Esophgus (BE) The long-term effect of PDT on HGD in BE is unknown. There is lwys risk of cncer or norml epithelium tht is invisile to the endoscopist eneth the new squmous cell epithelium; these fcts emphsize the risk of overlooking cncer in such ptients nd the need for rigorous continuing surveillnce despite the endoscopic ppernce of complete squmous cell reepitheliliztion. It is recommended tht endoscopic iopsy surveillnce e conducted every three months, until four consecutive negtive evlutions for HGD hve een recorded; further follow-up my e scheduled every 6 to 12 months, s per judgment of physicins. The follow-up period of the rndomized study t the time of nlysis ws minimum of two yers (rnging from 2 to 5.6 yers). 5.4 Photosensitivity All ptients who receive PHOTOFRI will e photosensitive nd must oserve precutions to void exposure of skin nd eyes to direct sunlight or right indoor light (from exmintion lmps, including dentl lmps, operting room lmps, unshded light uls t close proximity, etc.) for t lest 30 dys. Some ptients my remin photosensitive for up to 90 dys or more. The photosensitivity is due to residul drug, which will e present in ll prts of the skin. Exposure of the skin to mient indoor light is, however, eneficil ecuse the remining drug will e inctivted grdully nd sfely through photoleching rection. Therefore, ptients should not sty in drkened room during this period nd should e encourged to expose their skin to mient indoor light. The level of photosensitivity will vry for different res of the ody, depending on the extent of previous exposure to light. Before exposing ny re of skin to direct sunlight or right indoor light, the ptient should test it for residul photosensitivity. A smll re of skin should e exposed to sunlight for 10 minutes. If no photosensitivity rection (erythem, edem, listering) occurs within 24 hours, the ptient cn grdully resume norml outdoor ctivities, initilly continuing to exercise cution nd grdully llowing incresed exposure. If some photosensitivity rection occurs with the limited skin test, the ptient should continue precutions for nother 2 weeks efore retesting. The tissue round the eyes my e more sensitive, nd therefore, it is not recommended tht the fce e used for testing. If ptients trvel to different geogrphicl re with greter sunshine, they should retest their level of photosensitivity. Conventionl ultrviolet (UV) sunscreens will only protect ginst UV light-relted photosensitivity nd will e of no vlue in protecting ginst induced photosensitivity rections cused y visile light. 5.5 Oculr Sensitivity Sensitivity to sun, right lights, or cr hedlights, cusing oculr discomfort, cn occur in ptients who receive PHOTOFRI. For t lest 30 dys nd until oculr sensitivity resolves, instruct ptients when outdoors to wer drk sunglsses which hve n verge white light trnsmittnce of <4%. 5.6 Use Before or After Rdiotherpy If PDT is to e used efore or fter rdiotherpy, sufficient time should e llotted etween the two therpies to ensure tht the inflmmtory response produced y the first tretment hs susided efore commencing the second tretment. The inflmmtory response from PDT will depend on tumor size nd extent of surrounding norml tissue tht receives light. It is recommended tht 2 to 4 weeks e llowed fter PDT efore commencing rdiotherpy. Similrly, if PDT is to e given fter rdiotherpy, the cute inflmmtory rection from rdiotherpy usully susides within 4 weeks fter completing rdiotherpy, fter which PDT my e given. 5.7 Chest Pin As result of PDT tretment, ptients my complin of susternl chest pin ecuse of inflmmtory responses within the re of tretment. Such pin my e of sufficient intensity to wrrnt the short-term prescription of opite nlgesics. 5.8 Airwy Ostruction nd Respirtory Distress PHOTOFRI followed y PDT cn cuse tretment-induced inflmmtion nd ostruct the min irwy. Administer with cution to ptients with endoronchil tumors in loctions where tretment-induced inflmmtion cn ostruct the min irwy, e.g., long or circumferentil tumors of the trche, tumors of the crin tht involve oth minstem ronchi circumferentilly, or circumferentil tumors in the minstem ronchus in ptients with prior pneumonectomy. Monitor ptients closely etween the lser light therpy nd the mndtory deridement ronchoscopy for ny evidence of respirtory distress. Inflmmtion, mucositis, nd necrotic deris my cuse ostruction of the irwy. If respirtory distress occurs, the physicin should e prepred to crry out immedite ronchoscopy to remove secretions nd deris to open the irwy. 5.9 Esophgel Strictures Esophgel strictures occurred in 122 of 318 (38%) ptients enrolled in three clinicl studies of ptients who received PHOTOFRI with PDT to the esophgus. odule pretretment nd re-treting the sme mucosl segment more thn once my influence the risk of developing n esophgel stricture. A totl of 49% of ptients who developed stricture received nodule pretretment nd 82% who developed stricture

4 hd mucosl segment treted twice. Overll, esophgel strictures occurred within six months following PHOTOFRI with PDT. Multiple diltions of esophgel strictures my e required, s shown in Tle Heptic nd Renl Impirment Heptic or Renl impirment will likely prolong the elimintion of porfimer sodium leding to higher rtes of toxicity. Ptients with severe renl impirment or mild to severe heptic impirment should e clerly informed tht the period requiring the precutionry mesures for photosensitivity my e longer thn 90 dys. TABLE 5. Esophgel Diltions in Ptients with Tretment-Relted Strictures umer of Diltions umer of Ptients Percentge of Ptients with Strictures =114 with Strictures 1 2 Diltions 32 28% 3 5 Diltions 32 28% 6 10 Diltions 24 21% >10 Diltions 26 23% 5.11 Thromoemolism Thromoemolic events cn occur following photodynmic therpy with PHOTOFRI. Most reported events occurred in ptients with other risk fctors for thromoemolism including dvnced cncer, following mjor surgery, prolonged immoiliztion, or crdiovsculr disese. 6 ADVERSE REACTIOS 6.1 Overll Adverse Rection Profile Systemiclly induced effects of photodynmic therpy (PDT) with PHOTOFRI consist of photosensitivity nd mild constiption. All ptients who receive PHOTOFRI will e photosensitive nd must oserve precutions to void sunlight nd right indoor light [see Wrnings nd Precutions (5.4)]. Photosensitivity rections occurred in pproximtely 20% of cncer ptients nd in 69% of high-grde dysplsi (HGD) in Brrett s esophgus (BE) ptients treted with PHOTOFRI. Typiclly these rections were mostly mild to moderte erythem ut they lso included swelling, pruritus, urning senstion, feeling hot, or listers. In single study of 24 helthy sujects, some evidence of photosensitivity rections occurred in ll sujects. Other less common skin mnifesttions were lso reported in res where photosensitivity rections hd occurred, such s incresed hir growth, skin discolortion, skin nodule, skin wrinkling nd incresed skin frgility. These mnifesttions my e ttriutle to pseudoporphyri stte (temporry drug-induced cutneous porphyri). Most toxicities of this therpy re locl effects seen in the region of illumintion nd occsionlly in surrounding tissues. The locl dverse rections re chrcteristic of n inflmmtory response induced y the photodynmic effect. A few cses of fluid imlnce hve een reported in ptients treted with PHOTOFRI PDT for overtly disseminted intrperitonel mlignncies. Fluid imlnce is n expected PDT-relted event. A cse of ctrcts hs een reported in 51 yer-old oese mn treted with PHOTOFRI PDT for HGD in BE. The ptient suffered from PDT response with development of deep esophgel ulcer. Within two months post PDT, the ptient noted difficulty with his distnt vision. A thorough eye exmintion reveled chnge in the refrctive error tht lter progressed to ctrcts in oth eyes. Both of his prents hd history of ctrcts in their 70s. Whether PHOTOFRI directly cused or ccelerted fmilil underlying condition is unknown. 6.2 Adverse Rections in Clinicl Trils Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes oserved in the clinicl trils of drug cnnot e directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes oserved in prctice. Esophgel Crcinom The following dverse rections were reported over the entire follow-up period in t lest 5% of ptients treted with PHOTOFRI PDT, who hd completely or prtilly ostructing esophgel cncer. Tle 6 presents dt from 88 ptients who received the currently mrketed formultion. The reltionship of mny of these dverse rections to PDT with PHOTOFRI is uncertin. TABLE 6. Adverse Rections Reported in 5% or More of Ptients with Ostructing Esophgel Cncer SYSTEM ORGA CLASS/ Adverse Rection =88 Ptients with t Lest One Adverse Rection 84 (95) BLOOD nd LYMPHATIC SYSTEM DISORDERS Anemi 28 (32) CARDIAC DISORDERS Atril firilltion 9 (10) Crdic filure 6 (7) Tchycrdi 5 (6) GASTROITESTIAL DISORDERS Constiption 21 (24) use 21 (24) Adominl pin 18 (20) Vomiting 15 (17) Dysphgi 9 (10) Esophgel edem 7 (8) Hemtemesis 7 (8) Dyspepsi 5 (6) Esophgel stenosis 5 (6) Dirrhe 4 (5) Esophgitis 4 (5) Eructtion 4 (5) Melen 4 (5) GEERAL DISORDERS nd ADMIISTRATIO SITE CODITIOS Pyrexi 27 (31) Chest pin 19 (22) Pin 19 (22) Edem peripherl 6 (7) Astheni 5 (6) Chest pin (susternl) 4 (5) Edem generlized 4 (5) IFECTIOS nd IFESTATIOS Cndidisis 8 (9) Urinry trct infection 6 (7) IJURY, POISOIG nd PROCEDURAL COMPLICATIOS Post procedurl compliction 4 (5) IVESTIGATIOS Weight decresed 8 (9) METABOLISM AD UTRITIO DISORDERS Anorexi 7 (8) Dehydrtion 6 (7) MUSCULOSKELETAL nd COECTIVE TISSUE DISORDERS Bck pin 10 (11) EOPLASMS BEIG, MALIGAT nd USPECIFIED Tumor hemorrhge 7 (8) PSYCHIATRIC DISORDERS Insomni 12 (14) Confusionl stte 7 (8) Anxiety 6 (7) RESPIRATORY, THORACIC nd MEDIASTIAL DISORDERS Pleurl effusion 28 (32) Dyspnoe 18 (20) Pneumoni 16 (18) Phryngitis 10 (11) Respirtory insufficiency 9 (10) Cough 6 (7) Trcheoesophgel fistul 5 (6) SKI nd SUBCUTAEOUS TISSUE DISORDERS Photosensitivity rection 17 (19) VASCULAR DISORDERS Hypotension 6 (7) Hypertension 5 (6) Bsed on dverse rections reported t ny time during the entire period of follow-up. Loction of the tumor ws prognostic fctor for three dverse rections: upper-third of the esophgus (esophgel edem), middle-third (tril firilltion), nd lower-third, the most vsculr region (nemi). Also, ptients with lrge tumors (>10 cm) were more likely to experience nemi. Two of 17 ptients with complete esophgel ostruction from tumor experienced esophgel perfortions, which were considered to e possily tretment-ssocited; these perfortions occurred during susequent endoscopies. Serious nd other notle dverse rections oserved in less thn 5% of PDT-treted ptients with ostructing esophgel cncer in the clinicl studies include the following; their reltionship to therpy is uncertin. In the gstrointestinl system, esophgel perfortion, gstric ulcer, ileus, jundice, nd peritonitis hve occurred. Sepsis hs een reported occsionlly. Crdiovsculr rections hve included ngin pectoris, rdycrdi, myocrdil infrction, sick sinus syndrome, nd suprventriculr tchycrdi. Respirtory rections of ronchitis, ronchospsm, lryngotrchel edem, pneumonitis, pulmonry hemorrhge, pulmonry edem, respirtory filure, nd stridor hve occurred. The temporl reltionship of some gstrointestinl, crdiovsculr nd respirtory rections to the dministrtion of light ws suggestive of medistinl inflmmtion in some ptients. Vision-relted rections of norml vision, diplopi, eye pin nd photophoi hve een reported. Ostructing Endoronchil Cncer Tle 7 presents dverse rections tht were reported over the entire follow-up period in t lest 5% of ptients with ostructing endoronchil cncer treted with PHOTOFRI PDT or d:yag. These dt re sed

5 on the 86 ptients who received the currently mrketed formultion. Since it seems likely tht most dverse rections cused y these cute cting therpies would occur within 30 dys of tretment, Tle 7 presents those rections occurring within 30 dys of tretment procedure, s well s those occurring over the entire follow-up period. It should e noted tht follow-up ws 33% longer for the PDT group thn for the d:yag group, therey introducing is ginst PDT when dverse rection rtes re compred for the entire followup period. The extent of follow-up in the 30-dy period following tretment ws comprle etween groups (only 9% more for PDT). Trnsient inflmmtory rections in PDT-treted ptients occur in out 10% of ptients nd mnifest s pyrexi, ronchitis, chest pin, nd dyspnoe. The incidences of ronchitis nd dyspnoe were higher with PDT thn with d:yag. Most cses of ronchitis occurred within 1 week of tretment nd ll ut one were mild or moderte in intensity. The rections usully resolved within 10 dys with ntiiotic therpy. Tretment-relted worsening of dyspnoe is generlly trnsient nd self-limiting. Deridement of the treted re is mndtory to remove exudte nd necrotic tissue. Life-thretening respirtory insufficiency likely due to therpy occurred in 3% of PDT-treted ptients nd 2% of d:yag-treted ptients [see Wrnings nd Precutions (5.8)]. There ws trend towrd higher rte of ftl mssive hemoptysis (FMH) occurring on the PDT rm (10%) versus the d:yag rm (5%), however, the rte of FMH occurring within 30 dys of tretment ws the sme for PDT nd d:yag (4% totl events, 3% tretment-ssocited events). Ptients who hve received rdition therpy hve higher incidence of FMH fter tretment with PDT nd fter other forms of locl therpy thn ptients who hve not received rdition therpy, ut nlyses suggest tht this incresed risk my e due to ssocited prognostic fctors such s hving centrlly locted tumor. The incidence of FMH in ptients previously treted with rdiotherpy ws 21% (6/29) in the PDT group nd 10% (3/29) in the d:yag group. In ptients with no prior rdiotherpy, the overll incidence of FMH ws less thn 1%. Chrcteristics of ptients t high risk for FMH re descried in Contrindictions (4) nd Wrnings nd Precutions (5.2). Other serious or notle dverse rections were oserved in less thn 5% of PDT-treted ptients with endoronchil cncer; their reltionship to therpy is uncertin. In the respirtory system, pulmonry thromosis, pulmonry emolism, nd lung scess hve occurred. Crdic filure, sepsis, nd possile cererovsculr ccident hve lso een reported in one ptient ech. TABLE 7. Adverse Rections Reported in 5% or More of Ptients with Ostructing Endoronchil Cncer SYSTEM ORGA umer (%) of Ptients CLASS/ Within 30 Dys of Tretment Entire Follow-up Period Adverse Rection PDT d:yag PDT d:yag =86 =86 =86 =86 Ptients with t Lest One Adverse Rection 43 (50) 33 (38) 62 (72) 48 (56) GASTROITESTIAL DISORDERS Dyspepsi 1 (1) 4 (5) 2 (2) 5 (6) Constiption 4 (5) 1 (1) 4 (5) 2 (2) GEERAL DISORDERS nd ADMIISTRATIO SITE CODITIOS Pyrexi 7 (8) 7 (8) 14 (16) 8 (9) Chest pin 6 (7) 6 (7) 7 (8) 8 (9) Pin 1 (1) 4 (5) 4 (5) 8 (9) Edem peripherl 3 (3) 3 (3) 4 (5) 3 (3) MUSCULOSKELETAL nd COECTIVE TISSUE DISORDERS Bck pin 3 (3) 1(1) 3 (3) 5 (6) ERVOUS SYSTEM DISORDERS Dysphoni 3 (3) 2 (2) 4 (5) 2 (2) PSYCHIATRIC DISORDERS Insomni 4 (5) 2 (2) 4 (5) 3 (4) Anxiety 3 (3) 0 (0) 5 (6) 0 (0) RESPIRATORY, THORACIC nd MEDIASTIAL DISORDERS Dyspnoe 15 (17) 7 (8) 26 (30) 13 (15) Cough 5 (6) 8 (9) 13 (15) 11 (13) Hemoptysis 6 (7) 5 (6) 14 (16) 7 (8) Pneumoni 5 (6) 4 (5) 10 (12) 5 (6) Bronchitis 9 (10) 2 (2) 9 (10) 2 (2) Productive cough 4 (5) 5 (6) 7 (8) 6 (7) Respirtory insufficiency 0 (0) 0 (0) 5 (6) 1 (1) Pleurl effusion 0 (0) 0 (0) 4 (5) 1 (1) Pneumothorx 0 (0) 0 (0) 0 (0) 4 (5) SKI nd SUBCUTAEOUS TISSUE DISORDERS Photosensitivity rection 16 (19) 0 (0) 18 (21) 0 (0) Follow-up ws 33% longer for the PDT group thn for the d:yag group, introducing is ginst PDT when dverse rections re compred for the entire follow-up period. Superficil Endoronchil Tumors The following dverse rections were reported over the entire follow-up period in t lest 5% of ptients with superficil tumors (microinvsive or crcinom in situ) who received the currently mrketed formultion. TABLE 8. Adverse Rections Reported in 5% or More of Ptients with Superficil Endoronchil Tumors =90 Adverse Rection Ptients with t Lest One Adverse Rection 44 (49) RESPIRATORY, THORACIC nd MEDIASTIAL DISORDERS Exudte 20 (22) Bronchil mucus plug or ronchil ostruction 19 (21) Edem 16 (18) Bronchostenosis 10 (11) Bronchil ulcertion 8 (9) Cough 8 (9) Dyspnoe 6 (7) SKI nd SUBCUTAEOUS TISSUE DISORDERS Photosensitivity rection 20 (22) Bsed on dverse rections reported t ny time during the entire period of follow-up. In ptients with superficil endoronchil tumors, 44 of 90 ptients (49%) experienced n dverse rection, two-thirds of which were relted to the respirtory system. The most common rection to therpy ws mucositis rection in one-fifth of the ptients, which mnifested s edem, exudte, nd ostruction. The ostruction (mucus plug) is esily removed with suction or forceps. Mucositis cn e minimized y voiding exposure of norml tissue to excessive light [see Wrnings nd Precutions (5.8)]. Three ptients experienced life-thretening dyspnoe: one ws given doule dose of light, one ws treted concurrently in oth minstem ronchi nd the other hd hd prior pneumonectomy nd ws treted in the sole remining min irwy [see Wrnings nd Precutions (5.2)]. Stent plcement ws required in 3% of the ptients due to endoronchil stricture. Ftl mssive hemoptysis occurred within 30 dys of tretment in one ptient with superficil tumors (1%). High-Grde Dysplsi (HGD) in Brrett s Esophgus (BE) Tle 9 presents dverse rections tht were reported over the follow-up period in t lest 5% of ptients with HGD in BE in either controlled or uncontrolled clinicl trils. In the PHOTOFRI PDT + OM group severe dverse rections included chest pin of non-crdic origin, dysphgi, nuse, vomiting, regurgittion, nd herturn. The severity of these symptoms decresed within 4 to 6 weeks following tretment. The mjority of the photosensitivity rections occurred within 90 dys following PHOTOFRI injection nd ws of mild (68%) or moderte (24%) intensity. Fourteen (10%) ptients reported severe rections, ll of which resolved. The typicl rection ws descried s skin disorder, sunurn or rsh, nd ffected mostly the fce, hnds, nd neck. Associted symptoms nd signs were swelling, pruritis, erythem, listers, urning senstion, nd feeling of het. The mjority of esophgel stenosis including strictures reported in the PHOTOFRI PDT + OM group were of mild (57%) or moderte (35%) intensity, while pproximtely 8% were of severe intensity. The mjority of esophgel strictures were reported during Course 2 of tretment. All esophgel strictures were considered to e due to tretment. Most esophgel strictures were mngele through diltions [see Wrnings nd Precutions (5.9)]. TABLE 9. Adverse Rections Reported in 5% of Ptients Treted with PHOTOFRI PDT in the Clinicl Trils on High-Grde Dysplsi in Brrett s Esophgus Tretment Groups SYSTEM ORGA CLASS/ Adverse Rection HGD PHOPDT +OM =219 HGD OM Only =69 Other c PHOPDT +OM =99 Totl PHOPDT +OM =318 Ptients with t Lest One Adverse Rection 206 (94) 9 (13) 97 (98) 303 (95) GASTROITESTIAL DISORDERS 163 (74) 6 (9) 83 (84) 246 (77) use 57 (26) 1 (1) 61 (62) 118 (37) Vomiting 63 (29) 1 (1) 34 (34) 97 (31) Esophgel Stricture d 81 (37) 0 33 (33) 114 (36) Esophgel rrowing e 71 (32) 4 (6) 24 (24) 95 (30) Dysphgi 49 (22) 0 26 (26) 75 (24) Constiption 25 (11) 1 (1) 7 (7) 32 (10) Adominl pin 11 (5) 1 (1) 6 (6) 17 (5) (Upper, lower, OS) Esophgel pin 13 (6) 0 9 (9) 22 (7) Dyspepsi 10 (5) 0 4 (4) 14 (4) Hiccups 16 (7) 0 1 (1) 17 (5)

6 Odynophgi 13 (6) 0 4 (4) 17 (5) GEERAL nd ADMIISTRATIO 110 (50) 0 62 (63) 172 (54) SITE CODITIOS Chest pin 63 (29) 0 37 (37) 100 (31) Pyrexi 41 (19) 0 13 (13) 54 (17) Chest discomfort 13 (6) 0 19 (19) 32 (10) Pin 11 (5) 0 7 (7) 18 (6) IJURY, POISOIG nd 24 (11) 0 19 (19) 43 (14) PROCEDURAL COMPLICATIOS Post procedurl pin 14 (6) 0 14 (14) 28 (9) IVESTIGATIOS 24 (11) 0 11 (11) 35 (11) Weight decresed 15 (7) 0 2 (2) 17 (5) METABOLISM nd UTRITIO 28 (13) 0 16 (16) 44 (14) DISORDERS Dehydrtion 24 (11) 0 8 (8) 32 (10) RESPIRATORY, THORACIC nd 35 (16) 0 18 (18) 53 (17) MEDIASTIAL DISORDERS Pleurl effusion 22 (10) 0 15 (15) 37 (12) SKI nd SUBCUTAEOUS 115 (53) 1 (1) 28 (28) 143 (45) TISSUE DISORDERS Photosensitivity rection 102 (47) 0 16 (16) 118 (37) PHO: PHOTOFRI Includes ll HGD ptients in the Sfety popultion from PHO BAR 02 (=133), TCSC (=44), nd TCSC (=42). Includes ll HGD ptients in the Sfety popultion from PHO BAR 02 (=69). c Includes ptients with Brrett s metplsi, indefinite dysplsi, LGD, nd denocrcinom t seline in the Sfety popultion from TCSC (=55) nd TCSC (=44). d Esophgel stricture ws defined s dilted esophgel stenosis. e Esophgel nrrowing ws defined s n undilted esophgel stenosis. OTE: Adverse rections clssified using MedDRA 5.0 dictionry with the exception of esophgel stricture nd esophgel nrrowing. Lortory Anormlities In ptients with esophgel cncer, PDT with PHOTOFRI my result in nemi due to tumor leeding. o significnt effects were oserved for other prmeters in ptients with endoronchil crcinom or with HGD in BE. 6.3 Postmrketing Experience The following dverse rections hve een identified during post-pprovl use of PHOTOFRI with PDT. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possile to relily estimte their frequency or estlish cusl reltionship to drug exposure. Infusion rections: Infusion rections including urticri, rdycrdi, hypotension, dizziness, nd hypertension 7 DRUG ITERACTIOS 7.1 Other Photosensitizing Agents There hve een no forml interction studies of PHOTOFRI nd ny other drugs. However, it is possile tht concomitnt use of other photosensitizing gents (e.g., tetrcyclines, sulfonmides, phenothizines, sulfonylure hypoglycemic gents, thizide diuretics, griseofulvin, nd fluoroquinolones) could increse the risk of photosensitivity rection. 7.2 Concomitnt Therpy Photodynmic therpy (PDT) with PHOTOFRI cuses direct intrcellulr dmge y inititing rdicl chin rections tht dmge intrcellulr memrnes nd mitochondri. Tissue dmge lso results from ischemi secondry to vsoconstriction, pltelet ctivtion nd ggregtion nd clotting. Reserch in nimls nd in cell culture hs suggested tht mny drugs could influence the effects of PDT, possile exmples of which re descried elow. There re no humn dt tht support or reut these possiilities. Compounds tht quench ctive oxygen species or scvenge rdicls, such s dimethyl sulfoxide, ß-crotene, ethnol, formte nd mnnitol would e expected to decrese PDT ctivity. Preclinicl dt lso suggest tht tissue ischemi, llopurinol, clcium chnnel lockers nd some prostglndin synthesis inhiitors could interfere with PHOTOFRI PDT. Drugs tht decrese clotting, vsoconstriction or pltelet ggregtion, e.g., thromoxne A 2 inhiitors, could decrese the efficcy of PDT. Glucocorticoid hormones given efore or concomitnt with PDT my decrese the efficcy of the tretment. 8 USE I SPECIFIC POPULATIOS 8.1 Pregnncy Pregnncy Ctegory C. Porfimer sodium hs een shown to hve n emryocidl effect in rts nd rits when given in doses 0.64 times the recommended humn dose on mg/m 2 sis. Porfimer sodium given to rt dms during fetl orgnogenesis intrvenously t 0.64 times the clinicl dose on mg/m 2 sis for 10 dys cused no mjor mlformtions or developmentl chnges. This dose cused mternl nd fetl toxicity resulting in incresed resorptions, decresed litter size, delyed ossifiction, nd reduced fetl weight. Porfimer sodium cused no mjor mlformtions when given to rits intrvenously during orgnogenesis t 0.65 times the clinicl dose on mg/m 2 sis for 13 dys. This dose cused mternl toxicity resulting in incresed resorptions, decresed litter size, nd reduced fetl ody weight. Porfimer sodium given to rts during lte pregnncy through lcttion intrvenously t 0.32 times the clinicl dose on mg/m 2 sis for t lest 42 dys cused reversile decrese in growth of offspring. Prturition ws unffected. There re no dequte nd well-controlled studies of PHOTOFRI in pregnnt women. PHOTOFRI should e used during pregnncy only if the potentil enefit justifies the potentil risk to the fetus. 8.3 ursing Mothers It is not known whether PHOTOFRI is excreted in humn milk. Becuse mny drugs re excreted in humn milk nd ecuse of the potentil for serious dverse rections in nursing infnts from PHOTOFRI, decision should e mde whether not to tret or to discontinue restfeeding, tking into ccount the importnce of the drug to the mother. 8.4 Peditric Use Sfety nd effectiveness in children hve not een estlished. 8.5 Geritric Use Approximtely 70% of the ptients treted with PDT using PHOTOFRI in clinicl trils were over 60 yers of ge. There ws no pprent difference in effectiveness or sfety in these ptients compred to younger people. Dose modifiction sed upon ge is not required. 10 OVERDOSAGE 10.1 PHOTOFRI Overdose There is no informtion on overdosge situtions involving PHOTOFRI. Higher thn recommended drug doses of two 2 mg/kg doses given two dys prt (10 ptients) nd three 2 mg/kg doses given within two weeks (one ptient), were tolerted without notle dverse rections. Effects of overdosge on the durtion of photosensitivity re unknown. Lser tretment should not e given if n overdose of PHOTOFRI is dministered. In the event of n overdose, ptients should protect their eyes nd skin from direct sunlight or right indoor lights for 30 dys. At this time, ptients should test for residul photosensitivity [see Wrnings nd Precutions (5.4)]. PHOTOFRI is not dilyzle Overdose of Lser Light Following PHOTOFRI Injection Light doses of two to three times the recommended dose hve een dministered to few ptients with superficil endoronchil tumors. One ptient experienced life-thretening dyspnoe nd the others hd no notle complictions. Incresed symptoms nd dmge to norml tissue might e expected following n overdose of light. There is no informtion on overdose of lser light following PHOTOFRI injection in ptients with esophgel cncer or in ptients with high-grde dysplsi in Brrett s esophgus. 11 DESCRIPTIO PHOTOFRI (porfimer sodium) for Injection is photosensitizing gent used in the photodynmic therpy (PDT) of tumors nd of high-grde dysplsi (HGD) in Brrett s esophgus (BE). Following reconstitution of the freeze-dried product with 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intrvenously. This is followed hours lter y illumintion of the tumor or the esophgel segment with HGD in BE with lser light (630 nm wvelength). PHOTOFRI is not single chemicl entity; it is mixture of oligomers formed y ether nd ester linkges of up to eight porphyrin units. It is drk red to reddish rown cke or powder. Ech vil of PHOTOFRI contins 75 mg of porfimer sodium s sterile freeze-dried cke or powder. Hydrochloric Acid nd/ or Sodium Hydroxide my e dded during mnufcture to djust the ph to within There re no preservtives or other dditives. The structurl formul elow is representtive of the components present in PHOTOFRI. O 2C(CH 2) 2 H 3C R = HO O 2C(CH 2) 2 CH H R Figure 1 Structure of Porfimer Sodium H nd/or CH CH 2 H H 3C O CO(CH 2) 2 R OOC(CH 2) 2 H 12 CLIICAL PHARMACOLOGY 12.1 Mechnism of Action Cellulr dmge cused y photodynmic therpy (PDT) with PHOTOFRI is consequence of the propgtion of rdicl rections. Rdicl initition my occur fter porfimer sodium sors light to form porphyrin excited stte. Spin trnsfer from porfimer sodium to moleculr oxygen my then generte singlet oxygen. Susequent rdicl rections cn form superoxide nd hydroxyl rdicls. Tumor deth lso occurs through ischemic necrosis secondry to vsculr occlusion tht ppers to e prtly medited y thromoxne A 2 relese. As opposed to therml effect, the lser tretment with porfimer sodium induces photochemicl effect. The necrotic rection nd ssocited inflmmtory responses my evolve over severl dys. H H O H 3C n H n = 0-6 H H (CH 2) 2CO 2 R (CH 2) 2CO 2

7 12.2 Phrmcodynmics The cytotoxic nd ntitumor ctions of PHOTOFRI re light nd oxygen dependent. PDT with PHOTOFRI is two-stge process. The first stge is the intrvenous injection of PHOTOFRI. Clernce from vriety of tissues occurs over hours, ut tumors, skin, nd orgns of the reticuloendothelil system (including liver nd spleen) retin PHOTOFRI for longer period. Illumintion with 630 nm wvelength lser light constitutes the second stge of therpy. Tumor selectivity in tretment occurs through comintion of selective retention of PHOTOFRI nd selective delivery of light Phrmcokinetics The phrmcokinetics of PHOTOFRI were studied in 18 cncer ptients who received two doses of PHOTOFRI, 2 mg/kg ech, dministered 30 to 45 dys prt s slow IV injection over 3 to 5 minutes. The men C mx vlues were comprle fter the first nd second dministrtions (43.1±10.5 mcg/ml nd 41.3±8.7 mcg/ml, respectively). However, the men AUC 0-inf of porfimer ws out 34% higher fter the second dministrtion thn tht fter the first dministrtion (3937±1034 mcg.h/ml nd 2937±627 mcg. hour/ml, respectively), indicting some ccumultion upon repeted dministrtion. The elimintion hlflife of porfimer incresed from 410 to 725 hours fter the first nd second dministrtions, respectively. PHOTOFRI ws pproximtely 90% protein ound in humn serum, studied in vitro. The inding ws independent of concentrtion over the concentrtion rnge of mcg/ml. Effect of Gender: The effect of gender ws determined in 18 ptients (8 mles nd 10 femles) who received two dministrtions of PHOTOFRI 2 mg/kg within dys prt s slow IV injection over 3 to 5 minutes. The men C mx nd AUC vlues were comprle etween mles nd femles following either the first or the second dministrtions. Effect of Heptic nd Renl Impirment: The effect of heptic nd renl impirment hs not een studied. 13 OCLIICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, nd Impirment of Fertility o long-term studies hve een conducted to evlute the crcinogenic potentil of porfimer sodium. In the presence of light, in vitro, porfimer sodium PDT did not cuse muttions in the Ames test, nor did it cuse chromosome errtions or muttions (HGPRT locus) in Chinese hmster ovry (CHO) cells. Porfimer sodium PDT cused <2-fold, ut significnt, increses in sister chromtid exchnge in CHO cells irrdited with visile light nd 3-fold increse in Chinese hmster lung firolsts irrdited with ner UV light. Porfimer sodium PDT cused n increse in thymidine kinse mutnts nd DA-protein cross-links in mouse L5178Y cells, ut not mouse LYR83 cells. Porfimer sodium PDT cused light-dose dependnt increse in DA-strnd reks in mlignnt humn cervicl crcinom cells, ut not in norml cells. In the sence of light, porfimer sodium ws negtive in Chinese hmster ovrin cells (CHO/HGPRT) muttion test. In vivo, porfimer sodium did not cuse chromosoml errtions in the mouse micronucleus test. Porfimer sodium given to mle nd femle rts intrvenously, t 4 mg/kg/d (0.32 times the clinicl dose on mg/m 2 sis) efore conception nd through Dy 7 of pregnncy cused no impirment of fertility. In this study, long-term dosing with porfimer sodium cused discolortion of testes nd ovries nd hypertrophy of the testes. Porfimer sodium lso cused decresed ody weight in the prent rts. 14 CLIICAL STUDIES Clinicl studies of photodynmic therpy (PDT) with PHOTOFRI were conducted in ptients with ostructing esophgel nd endoronchil non-smll-cell lung cncers, in ptients with erly-stge rdiologiclly occult endoronchil cncer, nd in ptients with high-grde dysplsi (HGD) in Brrett s esophgus (BE). In ll clinicl studies, the method of PDT dministrtion ws essentilly identicl. A course of therpy consisted of one injection of PHOTOFRI (2 mg/kg dministered s slow intrvenous injection over 3 5 minutes) followed y up to two non-therml pplictions of 630 nm lser light. Light doses of 300 J/cm of diffuser length were used in esophgel cncer. Light doses of 200 J/cm of diffuser length were used in endoronchil cncer for oth pllition of ostructing cncer nd tretment of superficil lesions. For the ltion of HGD in BE, the light dose dministered ws 130 J/cm of diffuser length using centering lloon for the first ppliction nd 50 J/cm of diffuser length without centering lloon for the second ppliction [see Dosge nd Administrtion (2.2)]. In ll cses, the first ppliction of light occurred hours fter PHOTOFRI injection. For tretment of esophgel cncer deridement of residu vi endoscopy is optionl hours fter injection, fter which ny residul tumor could e retreted with second lser light ppliction t the sme light dose used for the initil tretment. Additionl courses of PDT with PHOTOFRI were llowed fter one month, up to mximum of three courses. For tretment of endoronchil cncer, deridement of residu ws performed vi ronchoscopy hours fter injection, fter which ny residul tumor could e retreted with second lser light ppliction t the sme light dose used for the initil tretment. Additionl courses of PDT with PHOTOFRI were llowed fter one month, up to mximum of three courses. For ltion of HGD in BE, second lser light ppliction of 50 J/cm of diffuser length without centering lloon could e given hours fter the PHOTOFRI injection for untreted res ( skip res). Additionl courses of PDT with PHOTOFRI were llowed fter three months, up to mximum of three courses Esophgel Cncer PDT with PHOTOFRI ws utilized in multicenter, single-rm study in 17 ptients with completely ostructing esophgel crcinom. Assessments were mde t 1 week nd 1 month fter the lst tretment procedure. As shown in Tle 10, fter single course of therpy, 94% of ptients otined n ojective tumor response nd 76% of ptients experienced some pllition of their dysphgi. On verge, efore tretment these ptients hd difficulty swllowing liquids, even sliv. After one course of therpy, there ws sttisticlly significnt improvement in men dysphgi grde (1.5 units, p <0.05) nd 13 of 17 ptients could swllow liquids without difficulty 1 week nd/or 1 month fter tretment. Bsed on ll courses, three ptients chieved complete tumor response (CR). In two of these ptients, the CR ws documented only t s they hd no further ssessments. The third ptient chieved CR fter second course of therpy, which ws supported y negtive histopthology nd mintined for the entire follow-up of 6 months.0 Of the 17 treted ptients, 11 (65%) received cliniclly importnt enefit from PDT. Cliniclly importnt enefit ws defined hierrchiclly s complete tumor response (3 ptients), chievement of norml swllowing (2 ptients went from Grde 5 dysphgi to Grde 1), or chievement of mrked improvement of two or more grdes of dysphgi with miniml dverse rections (6 ptients). The medin durtion of enefit in these ptients ws 69 dys. Durtion of enefit ws clculted only for the period with documented evidence of improvement. All of these ptients were still in response t their lst ssessment nd, therefore, the estimte of 69 dys is conservtive. The medin survivl for these 11 ptients ws 115 dys Endoronchil Cncer Two rndomized multicenter Phse III studies were conducted to compre the sfety nd efficcy of PHOTOFRI PDT versus d:yag lser therpy for reduction of ostruction nd pllition of symptomtic ptients with prtilly or completely ostructing endoronchil non-smll-cell lung cncer. Assessments were mde t 1 week nd t monthly intervls fter tretment. Tle 11 shows the results from ll rndomized ptients in the two studies comined. Ojective tumor response rtes (CR + PR), which demonstrte reduction of ostruction, were 59% for PDT nd 58% for d:yag t. The response rte t 1 month or lter ws 60% for PDT nd 41% for d:yag. Ptient symptoms were evluted using 5- or 6-grde pulmonry symptom severity rting scle for dyspnoe, cough, nd hemoptysis. Ptients with moderte to severe symptoms re those most in need of pllition. Improvements of 2 or more grdes re considered to e cliniclly significnt. Tle 12 shows the percentges of ptients with moderte to severe symptoms t seline who demonstrted 2-grde improvement t ny time during the intervl evluted. TABLE 10. Course 1 Efficcy Results in Ptients with Completely Ostructing Esophgel Cncer EFFICACY PARAMETER PDT =17 OBJECTIVE TUMOR RESPOSE (% of ptients) 82% Month 1 35% Any ssessment c 94% IMPROVEMET d I DYSPHAGIA (% of ptients) Month 1 Any ssessment c MEA DYSPHAGIA GRADE e AT BASELIE (units) MEA IMPROVEMET e I DYSPHAGIA GRADE (units) Month 1 71% 47% 76% MEA UMBER OF LASER APPLICATIOS (units) 1.4 CR+PR, CR = complete response (sence of endoscopiclly visile tumor), PR = prtil response (ppernce of visile lumen). Eight of the 17 treted ptients did not hve ssessments t Month 1. c or Month 1. d Ptients with t lest one-grde improvement in dysphgi grde. e Dysphgi Scle: Grde 1 = norml swllowing; Grde 2 = difficulty swllowing some hrd solids, cn swllow semisolids; Grde 3 = unle to swllow ny solids, cn swllow liquids; Grde 4 = difficulty swllowing liquids; Grde 5 = unle to swllow sliv. TABLE 11. Efficcy Results from Studies in Lte-stge Ostructing Endoronchil Cncer All Rndomized Ptients EFFICACY PARAMETER PDT =102 % Ptients d:yag =109 % Ptients OBJECTIVE TUMOR RESPOSE Month 1 or lter 59% 60% 58% 41% ATELECTASIS IMPROVEMET c n=60 =71 Month 1 or lter 35% 35% 18% 20% Sttisticl comprisons were precluded y the mount of missing dt t Month 1 or lter (e.g., for tumor response, PDT 28% missing, d:yag 38%). CR+PR where CR = complete response (sence of ronchoscopiclly visile tumor) nd PR = prtil response (increse of 50% in the smllest luminl dimeter; or ny ppernce of lumen for completely ostructing tumors). c In ptients with telectsis t seline.