Photofrin

1 INDICATIONS AND USAGE PHOTOFRIN is a photoactivated radical generator indicated for: Esophageal Cancer ( 1.1 ) Palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their physician, cannot be satisfactorily treated with Nd:YAG laser therapy Endobronchial Cancer ( 1.2 ) Treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC High-Grade Dysplasia in Barrett’s Esophagus ( 1.3 ) Ablation of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) patients who do not undergo esophagectomy 1.1 Esophageal Cancer PHOTOFRIN ® is indicated for the palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their healthcare provider, cannot be satisfactorily treated with Nd:YAG laser therapy. 1.2 Endobronchial Cancer PHOTOFRIN is indicated for the treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated. PHOTOFRIN is indicated for the reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC. 1.3 High-Grade Dysplasia in Barrett’s Esophagus PHOTOFRIN is indicated for the ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo esophagectomy.

2 DOSAGE AND ADMINISTRATION PHOTOFRIN ( 2.1 ) PHOTOFRIN administration: 2 mg/kg intravenous Photoactivation ( 2.2 ) Esophageal Cancer Laser light dose of 300 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, 96-120 hours after initial injection Endobronchial Cancer Laser light dose of 200 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, after gentle debridement of residual tumor 96-120 hours after initial injection High-Grade Dysplasia in Barrett’s Esophagus Laser light dose of 130 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, with a light dose of 50 J/cm of fiber optic diffuser length 96-120 hours after initial injection 2.1 Important Administration Instructions Photodynamic therapy (PDT) with PHOTOFRIN is a two-stage process requiring administration of both drug and light. The first stage of PDT is the intravenous injection of PHOTOFRIN at 2 mg/kg. Illumination with laser light 40–50 hours following injection with PHOTOFRIN constitutes the second stage of therapy. A second laser light application may be given 96-120 hours after injection [ see Dosage and Administration ( 2.2 )] . In clinical studies on endobronchial cancer, debridement via endoscopy was required 2-3 days after the initial light application. Standard endoscopic techniques are used for light administration and debridement. Healthcare providers should be fully familiar with the patient’s condition and trained in the safe and efficacious treatment of esophageal or endobronchial cancer, or high-grade dysplasia (HGD) in Barrett’s esophagus (BE) using PDT with PHOTOFRIN and associated light delivery devices. PDT with PHOTOFRIN should be applied only in those facilities properly equipped for the procedure. The laser system must be approved for delivery of a stable power output at a wavelength of 630 ± 3 nm. Light is delivered to the tumor by cylindrical OPTIGUIDE™ fiber optic diffusers passed through the operating channel of an endoscope/bronchoscope. Instructions for use of the fiber optic and the selected laser system should be read carefully before use. OPTIGUIDE™ cylindrical diffusers are available in several lengths. The choice of diffuser tip length depends on the length of the tumor or Barrett’s mucosa to be treated. Diffuser length should be sized to avoid exposure of nonmalignant tissue to light and to prevent overlapping of previously treated malignant tissue. Refer to the OPTIGUIDE™ instructions for use for complete instructions concerning the fiber optic diffuser. 2.2 PHOTOFRIN Recommended Dosage The recommended dosage of PHOTOFRIN is 2 mg/kg of body weight administered as a single slow intravenous injection over 3 to 5 minutes. Preparation and Administration Reconstitute each vial of PHOTOFRIN with 31.8 mL of either 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), resulting in a final concentration of 2.5 mg/mL. Shake well until dissolved. Do not mix PHOTOFRIN with other drugs in the same solution. Discard unused portion. PHOTOFRIN reconstituted with 5% Dextrose Injection (USP) or with 0.9% Sodium Chloride Injection (USP), has a pH in the range of 7 to 8. PHOTOFRIN has been formulated with an overage to deliver the 75 mg labeled quantity. The reconstituted product should be protected from bright light and used immediately. Reconstituted PHOTOFRIN is an opaque solution, in which detection of particulate matter by visual inspection is extremely difficult. Reconstituted PHOTOFRIN however, like all parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Management of Extravasation Precautions should be taken to present extravasation at the injection site. If extravasation occurs, care must be taken to protect the area from light. There is no known benefit from injecting the extravasation site with another substance. 2.3 Photoactivation Esophageal Cancer Initiate 630 nm wavelength laser light delivery to the patient 40-50 hours following injection with PHOTOFRIN. A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN. No further injection of PHOTOFRIN should be given for such retreatment with laser light. Before providing a second laser light treatment, the residual tumor may be debrided. The debridement is optional since the residua will be removed naturally by peristaltic action of the esophagus. Vigorous debridement may cause tumor bleeding. Photoactivation of PHOTOFRIN is controlled by the total light dose delivered. In the treatment of esophageal cancer, a light dose of 300 Joules/cm (J/cm) of diffuser length should be delivered. The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 12 minutes and 30 seconds. For the treatment of esophageal cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of PDT (each separated by a minimum of 30 days) can be given. Before each course of treatment, patients with esophageal cancer should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula [see Contraindications ( 4 )] . All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications ( 4 ) ]. Endobronchial Cancer Initiate 630 nm wavelength laser light delivery to the patient 4050 hours following injection with PHOTOFRIN. A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN. No further injection of PHOTOFRIN should be given for such retreatment with laser light. Before providing a second laser light treatment, the residual tumor should be debrided. Vigorous debridement may cause tumor bleeding. For endobronchial tumors, debridement of necrotic tissue should be discontinued when the volume of bleeding increases, as this may indicate that debridement has gone beyond the zone of the PDT effect. Photoactivation of PHOTOFRIN is controlled by the total light dose delivered. In the treatment of endobronchial cancer, a light dose of 200 J/cm of diffuser length should be delivered. The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 8 minutes and 20 seconds. For noncircumferential endobronchial tumors that are soft enough to penetrate, interstitial fiber placement is preferred to intraluminal activation, since this method produces better efficacy and results in less exposure of the normal bronchial mucosa to light. It is important to perform a debridement 2 to 3 days after each light administration to minimize the potential for obstruction caused by necrotic debris [see Warnings and Precautions ( 5.8 ) ]. For the treatment of endobronchial cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of PDT (each separated by a minimum of 30 days) can be given. In patients with endobronchial lesions who have recently undergone radiotherapy, sufficient time (approximately 4 weeks) should be allowed between the therapies to ensure that the acute inflammation produced by radiotherapy has subsided prior to PDT [see Warnings and Precautions ( 5.6 )] . All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications ( 4 ) ] . High-Grade Dysplasia (HGD) in Barretts Esophagus (BE) Prior to initiating treatment with PHOTOFRIN PDT, the diagnosis of HGD in BE should be confirmed by an expert GI pathologist. Approximately 40-50 hours after PHOTOFRIN administration light should be delivered by a X-Cell Photodynamic Therapy (PDT) Balloon with Fiber Optic Diffuser. The choice of fiber optic/balloon diffuser combination will depend on the length of Barretts mucosa to be treated ( Table 1 ). *Whenever possible, the BE segment selected for treatment should include normal tissue margins of a few millimeters at the proximal and distal ends. TABLE 1 . Fiber Optic Diffuser/Balloon Combination* Treated Barrett's Mucosa Length (cm) Fiber Optic Diffuser Length (cm) Balloon Window Length (cm) 6-7 9 7 4-5 7 5 1-3 5 3 Photoactivation is controlled by the total light dose delivered. The objective is to expose and treat all areas of HGD and the entire length of BE. The light dose administered will be 130 J/cm of diffuser length using a centering balloon. Based on the randomized clinical study, acceptable light intensity for the balloon/diffuser combinations range from 200-270 mW/cm of diffuser length. To calculate the light dose, the following specific light dosimetry equation applies for all fiber optic diffusers: Light Dose (J/cm) = Power Output From Diffuser (W) x Treatment Time (s ) Diffuser Length (cm) Table 2 provides the settings that will be used to deliver the dose within the shortest time (light intensity of 270 mW/cm). A second option (light intensity of 200 mW/cm) has also been included where necessary to accommodate lasers with a total capacity that does not exceed 2.5 W. TABLE 2 . Fiber Optic Power Outputs and Treatment Times Required to Deliver 130 J/cm of Diffuser Length Using the Centering Balloon Balloon Window Length (cm) Fiber Optic Diffuser Length (cm) Light Intensity (mW/cm) Required Power output from Diffuser As measured by immersing the diffuser into the cuvet in the power meter and slowly increasing the laser power. (mW) Treatment Time (sec) (min:sec) 3 5 270 1 350 480 8:00 5 7 270 1 900 480 8:00 7 9 270 2 440 480 8:00 200 1 800 480 10:50 Note: No more than 1.5 times the required diffuser power output should be needed from the laser. If more than this is required, the system should be checked. Short fiber diffusers (2.5 cm) are to be used to pretreat nodules with 50 J/cm of diffuser length prior to regular balloon treatment in the first laser light session or for the treatment of skip areas (i.e., an area that does not show sufficient mucosal response) after the first light session. For this treatment, the fiber optic diffuser is used without a centering balloon, and a light intensity of 400 mW/cm should be used. For nodule pretreatment and treatment of skipped areas, care should be taken to minimize exposure to normal tissue as it is also sensitized. Table 3 lists appropriate fiber optic power outputs and treatment times using a light intensity of 400 mW/cm. TABLE 3 .Short Fiber Optic Diffusers to be Used Without a Centering Balloon to Deliver 50 J/cm of Diffuser Length at a Light Intensity of 400 mW/cm Fiber Optic Diffuser Length (cm) Required Power Output From Diffuser As measured by immersing the diffuser into the cuvet in the power meter and slowly increasing the laser power. (mw) Treatment Time (sec) Treatment Time (min:sec) 1.0 400 125 2:05 1.5 600 125 2:05 2.0 800 125 2:05 2.5 1000 125 2:05 Note: No more than 1.5 times the required diffuser power output should be needed from the laser. If more than this is required, the system should be checked. A maximum of 7 cm of esophageal mucosa is treated at the first light session using an appropriate size of centering balloon and fiber optic diffuser ( Table 1 ). Whenever possible, the segment selected for the first light application should contain all the areas of HGD. Also, whenever possible, the BE segment selected for the first light application should include normal tissue margin of a few millimeters at the proximal and distal ends. Nodules are to be pretreated at a light dose of 50 J/cm of diffuser length with a short (2.5 cm) fiber optic diffuser placed directly against the nodule followed by standard balloon application as described above. Repeat Light Application A second laser light application may be given to a previously treated segment that shows a skip area, using a short, 2.5 cm, fiber optic diffuser without centering balloon at the light dose of 50 J/cm of the diffuser length. Patients with BE >7 cm, should have the remaining untreated length of Barretts epithelium treated with a second PDT course at least 90 days later. The treatment regimen is summarized in Table 4 . TABLE 4. High-Grade Dysplasia in Barretts Esophagus Procedure Study Day Light Delivery Devices Treatment Intent PHOTOFRIN Day 1 NA Uptake of photosensitizer Laser Light Application Day 3 Discrete nodule will receive an initial light application of 50 J/cm (using a short fiber optic diffuser without balloon) before the balloon light application. 3, 5 or 7 cm balloon (130 J/cm) Photoactivation Laser Light Application (Optional) Day 5 Short (2.5 cm) fiber optic diffuser (50 J/cm) Treatment of "skip" areas only NA: Not Applicable For the ablation of HGD in BE, patients may receive an additional course of PDT at a minimum of 90 days after the initial therapy; up to three courses of PDT (each injection separated by a minimum of 90 days) can be given to a previously treated segment which still shows HGD, low-grade dysplasia, or Barretts metaplasia, or to a new segment if the initial Barretts segment was >7 cm in length. Both residual and additional segments may be treated in the same light session(s) provided that the total length of the segments treated with the balloon/ diffuser combination is not greater than 7 cm. In the case of a previously treated esophageal segment, if it has not sufficiently healed and/or histological assessment of biopsies is not clear, the subsequent course of PDT may be delayed for an additional 1-2 months.

4 CONTRAINDICATIONS PHOTOFRIN is contraindicated in patients with porphyria. Photodynamic therapy (PDT) is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula. PDT is contraindicated in patients with tumors eroding into a major blood vessel. PDT is not suitable for emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection with PHOTOFRIN and laser light treatment. PDT is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter. Porphyria ( 4 ) Existing tracheoesophageal or bronchoesophageal fistula ( 4 , 5.1 ) Tumors eroding into a major blood vessel ( 4 , 5.2 ) Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection of PHOTOFRIN and laser light treatment ( 4 ) Esophageal or gastric varices or esophageal ulcers >1 cm in diameter ( 4 )

5 WARNINGS AND PRECAUTIONS Gastroesophageal Fistula and Perforation : Do not initiate PHOTOFRIN with photodynamic therapy (PDT) in patients with esophageal tumors eroding into the trachea or bronchial tree or bronchial wall. ( 5.1 ) Pulmonary and Gastroesophageal Hemorrhage : Assess patients for tumors eroding into a pulmonary blood vessel and esophageal varices. Do not administer light directly to an area with esophageal varices. ( 5.2 ) High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE) : After treatment of HGD in BE, conduct endoscopic biopsy surveillance every 3 months, until 4 consecutive negative evaluations for HGD have been recorded. ( 5.3 ) Photosensitivity and Ocular Photosensitivity : Observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light for at least 30 days. Instruct patients when outdoors to wear dark sunglasses which have an average light transmittance of <4% for at least 30 days and until ocular sensitivity resolves. ( 5.4 , 5.5 ) Use Before or After Radiotherapy : Allow 2-4 weeks between PDT and subsequent radiotherapy. ( 5.6 ) Chest Pain : Substernal chest pain can occur ( 5.7 ) Airway Obstruction and Respiratory Distress : Administer with caution to patients with tumors in locations where treatment- induced inflammation can obstruct the main airway. Monitor patients closely between the laser light therapy and the mandatory debridement bronchoscopy for any evidence of respiratory distress. ( 5.8 ) Esophageal Strictures : Esophageal strictures can occur ( 5.9 ) Hepatic and Renal Impairment : Patients with hepatic or renal impairment may need longer precautionary measures for photosensitivity. ( 5.10 ) Thromboembolism : Thromboembolic events can occur. ( 5.11 ) Embryo-Fetal Toxicity : May cause embryo-fetal toxicity. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.12 , 8.1 ) 5.1 Gastroesophageal Fistula and Perforation Serious and sometimes fatal gastrointestinal and esophageal necrosis and perforation can occur following treatment with PHOTOFRIN with PDT. Do not initiate PHOTOFRIN with PDT in patients with esophageal tumors eroding into the trachea or bronchial tree or bronchial wall because of the high likelihood of tracheoesophageal or bronchoesophageal fistula. 5.2 Pulmonary and Gastroesophageal Hemorrhage Patients with large, centrally located tumors, cavitating tumors, or extensive tumors extrinsic to the bronchus are at high risk for fatal massive hemoptysis. Assess patients for tumors eroding into a pulmonary blood vessel [ see Contraindications ( 4 )] and esophageal varices. Do not administer light directly to an area with esophageal varices because of the high risk of hemorrhage. 5.3 High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE) The long-term effect of PDT on HGD in BE is unknown. There is always a risk of cancer or abnormal epithelium that is invisible to the endoscopist beneath the new squamous cell epithelium; these facts emphasize the risk of overlooking cancer in such patients and the need for rigorous continuing surveillance despite the endoscopic appearance of complete squamous cell reepithelialization. Conduct endoscopic biopsy surveillance every 3 months, until 4 consecutive negative evaluations for HGD have been recorded; further follow-up may be scheduled every 6 to 12 months, as per judgment of healthcare providers. The follow-up period of the randomized study at the time of analysis was a minimum of 2 years (range 2 to 5.6 years). 5.4 Photosensitivity All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental lamps, operating room lamps, unshaded light bulbs at close proximity, etc.) for at least 30 days. Some patients may remain photosensitive for up to 90 days or more. The photosensitivity is due to residual drug, which will be present in all parts of the skin. Exposure of the skin to ambient indoor light is, however, beneficial because the remaining drug will be inactivated gradually and safely through a photobleaching reaction. Therefore, patients should not stay in a darkened room during this period and should be encouraged to expose their skin to ambient indoor light. The level of photosensitivity will vary for different areas of the body, depending on the extent of previous exposure to light. Before exposing any area of skin to direct sunlight or bright indoor light, the patient should test it for residual photosensitivity. A small area of skin should be exposed to sunlight for 10 minutes. If no photosensitivity reaction (erythema, edema, blistering) occurs within 24 hours, the patient can gradually resume normal outdoor activities, initially continuing to exercise caution and gradually allowing increased exposure. If some photosensitivity reaction occurs with the limited skin test, the patient should continue precautions for another 2 weeks before retesting. The tissue around the eyes may be more sensitive, and therefore, it is not recommended that the face be used for testing. If patients travel to a different geographical area with greater sunshine, they should retest their level of photosensitivity. Conventional ultraviolet (UV) sunscreens will only protect against UV light-related photosensitivity and will be of no value in protecting against induced photosensitivity reactions caused by visible light. 5.5 Ocular Sensitivity Sensitivity to sun, bright lights, or car headlights, causing ocular discomfort, can occur in patients who receive PHOTOFRIN. For at least 30 days and until ocular sensitivity resolves, instruct patients when outdoors to wear dark sunglasses which have an average white light transmittance of <4%. 5.6 Use Before or After Radiotherapy If PDT is to be used before or after radiotherapy, allot sufficient time between the two therapies to ensure that the inflammatory response produced by the first treatment has subsided before commencing the second treatment. The inflammatory response from PDT will depend on tumor size and extent of surrounding normal tissue that receives light. Allow 2 to 4 weeks after PDT before commencing radiotherapy. The acute inflammatory reaction from radiotherapy usually subsides within 4 weeks after completing radiotherapy. Allow 4 weeks after completing radiotherapy before commencing PDT. 5.7 Chest Pain As a result of PDT treatment, patients may complain of substernal chest pain because of inflammatory responses within the area of treatment. Such pain may be of sufficient intensity to warrant the short-term prescription of opiate analgesics. 5.8 Airway Obstruction and Respiratory Distress PHOTOFRIN followed by PDT can cause treatment-induced inflammation and obstruct the main airway. Administer with caution to patients with endobronchial tumors in locations where treatment-induced inflammation can obstruct the main airway, e.g., long or circumferential tumors of the trachea, tumors of the carina that involve both mainstem bronchi circumferentially, or circumferential tumors in the mainstem bronchus in patients with prior pneumonectomy. Monitor patients closely between the laser light therapy and the mandatory debridement bronchoscopy for any evidence of respiratory distress. Inflammation, mucositis, and necrotic debris may cause obstruction of the airway. If respiratory distress occurs, the physician should be prepared to carry out immediate bronchoscopy to remove secretions and debris to open the airway. 5.9 Esophageal Strictures Esophageal strictures occurred in 122 of 318 (38%) patients enrolled in three clinical studies of patients who received PHOTOFRIN with PDT to the esophagus. Nodule pretreatment and re-treating the same mucosal segment more than once may influence the risk of developing an esophageal stricture. A total of 49% of patients who developed a stricture received nodule pretreatment and 82% who developed a stricture had a mucosal segment treated twice. Overall, esophageal strictures occurred within six months following PHOTOFRIN with PDT. Multiple dilations of esophageal strictures may be required, as shown in Table 5 TABLE 5 . Esophageal Dilations in Patients with Treatment – Related Strictures Number of Dilations Number of Patients With Strictures N=114 Percentage of Patients with Strictures 1 – 2 Dilations 32 28% 3 – 5 Dilations 32 28% 6 - 10 24 21% >10 Dilations 26 23% 5.10 Risk of Prolonged Duration of Photosensitivity in Patients with Hepatic and Renal Impairment Hepatic or renal impairment will likely prolong the elimination of porfimer sodium leading to higher rates of toxicity. Inform patients with severe renal impairment or mild to severe hepatic impairment that the period requiring the precautionary measures for photosensitivity may be longer than 90 days. 5.11 Thromboembolism Thromboembolic events can occur following photodynamic therapy with PHOTOFRIN. Most reported events occurred in patients with other risk factors for thromboembolism including advanced cancer, following major surgery, prolonged immobilization, or cardiovascular disease. 5.12 Embryo-Fetal Toxicity Based on animal studies, PHOTOFRIN may cause embryo-fetal toxicity when administered to a pregnant woman. Intravenous administration of porfimer sodium to pregnant rats and rabbits during the period of organogenesis at dose levels approximately 0.64 times the recommended human dose of PHOTOFRIN based on body surface area (BSA) resulted in increased fetal resorptions, decreased litter size, and reduced fetal weight but did not cause fetal malformations. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with PHOTOFRIN and for 5 months after the final dose.

7 DRUG INTERACTIONS Other Photosensitizing Agents : May increase the risk of photosensitivity reaction ( 7.1 ) 7.1 Use with Other Photosensitizing Agents PHOTOFRIN can cause photosensitivity. The concomitant use of PHOTOFRIN with other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and fluoroquinolones) may increase the risk of a photosensitivity reaction. Avoid the concomitant use of PHOTOFRIN with other products known to cause photosensitivity.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Gastroesophageal Fistula and Perforation [see Warnings and Precautions ( 5.1 )] Pulmonary and Gastroesophageal Hemorrhage [see Warnings and Precautions ( 5.2 )] High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE) [see Warnings and Precautions ( 5.3 )] Photosensitivity [see Warnings and Precautions ( 5.4 )] Ocular Sensitivity [see Warnings and Precautions ( 5.5 )] Use Before or After Radiotherapy [see Warnings and Precautions ( 5.6 )] Chest Pain [see Warnings and Precautions ( 5.7 )] Airway Obstruction and Respiratory Distress [see Warnings and Precautions ( 5.8 )] Esophageal Strictures [see Warnings and Precautions ( 5.9 )] Thromboembolism [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (>10%) are Esophageal Cancer : Anemia, pleural effusion, pyrexia, constipation, nausea, chest pain, pain, abdominal pain, dyspnea, photosensitivity reaction, pneumonia, vomiting, insomnia, back pain, pharyngitis ( 6.1 ) Obstructing Endobronchial Cancer : Dyspnea, photosensitivity reaction, hemoptysis, pyrexia, cough, pneumonia ( 6.1 ) Superficial Endobronchial Tumors : Exudate, photosensitivity reaction, bronchial obstruction, edema, bronchostenosis ( 6.1 ) High-Grade Dysplasia in Barrett’s Esophagus : Photosensitivity reaction, esophageal stenosis, vomiting, chest pain, nausea, pyrexia, constipation, dysphagia, abdominal pain, pleural effusion, dehydration ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pinnacle Biologics, Inc. at 1-866-248-2039 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Overall Adverse Reaction Profile Systemically induced effects of photodynamic therapy (PDT) with PHOTOFRIN consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid sunlight and bright indoor light [see Warnings and Precautions ( 5.4 ) ]. Photosensitivity reactions occurred in approximately 20% of cancer patients and in 69% of high-grade dysplasia (HGD) in Barretts esophagus (BE) patients treated with PHOTOFRIN. Typically, these reactions were mostly mild to moderate erythema, but they also included swelling, pruritus, burning sensation, feeling hot, or blisters. In a single study of 24 healthy subjects, some evidence of photosensitivity reactions occurred in all subjects.Other less common skin manifestations were also reported in areas where photosensitivity reactions had occurred, such as increased hair growth, skin discoloration, skin nodule, skin wrinkling and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria). Most toxicities of this therapy are local effects seen in the region of illumination and occasionally in surrounding tissues. The local adverse reactions are characteristic of an inflammatory response induced by the photodynamic effect. A few cases of fluid imbalance have been reported in patients treated with PHOTOFRIN PDT for overtly disseminated intraperitoneal malignancies. Fluid imbalance is an expected PDT-related event. A case of cataracts has been reported in a 51-year-old obese man treated with PHOTOFRIN PDT for HGD in BE. The patient suffered from a PDT response with development of a deep esophageal ulcer. Within two months post PDT, the patient noted difficulty with his distant vision. A thorough eye examination revealed a change in the refractive error that later progressed to cataracts in both eyes. Both of his parents had a history of cataracts in their 70s. Whether PHOTOFRIN directly caused or accelerated a familial underlying condition is unknown. Esophageal Carcinoma The following adverse reactions were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN PDT, who had completely or partially obstructing esophageal cancer. Table 6 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse reactions to PDT with PHOTOFRIN is uncertain. * Based on adverse reactions reported at any time during the entire period of follow-up. TABLE 6 . Adverse Reactions Reported in 5% or More of Patients* with Obstructing Esophageal Cancer SYSTEM ORGAN CLASS (SOC) Adverse Reaction All Grades (%) Patients with at Least One Adverse Reaction 95 RESPIRATORY, THORACIC, and MEDIASTINAL DISORDERS Pleural effusion 32 Dyspnea 20 Pneumonia 18 Pharyngitis 11 Respiratory insufficiency 10 Cough 7 Tracheoesophageal fistula 6 BLOOD and LYMPHATIC SYSTEM DISORDERS Anemia 32 GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS Pyrexia 31 Chest pain 22 Pain 22 Edema Peripheral 7 Asthenia 6 Chest Pain (substernal) 5 Edema generalized 5 GASTROINTESTINAL DISORDERS Constipation 24 Nausea 24 Abdominal Pain 20 Vomiting 17 Dysphagia 10 Esophageal edema 8 Hematemesis 8 Dyspepsia 6 Esophageal stenosis 6 Diarrhea 5 Esophagitis 5 Eructation 5 Melena 5 SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 19 PSYCHIATRIC DISORDERS Insomnia 14 Confusional state 8 Anxiety 7 MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS Back Pain 11 CARDIAC DISORDERS Atrial fibrillation 10 Cardiac failure 7 Tachycardia 6 INFECTIONS and INFESTATIONS Candidiasis 9 Urinary tract infection 7 INVESTIGATIONS Weight decreased 9 METABOLISM and NUTRITION DISORDERS Anorexia 8 Dehydration 7 NEOPLASMS BENIGN, MALIGNANT and UNSPECIFIED Tumor hemorrhage 8 VASCULAR DISORDERS Hypotension 7 Hypertension 6 INJURY, POISONING and PROCEDURAL COMPLICATIONS Post procedural complication 5 Location of the tumor was a prognostic factor for three adverse reactions: upper-third of the esophagus (esophageal edema), middle-third (atrial fibrillation), and lower-third, the most vascular region (anemia). Also, patients with large tumors (>10 cm) were more likely to experience anemia. Two of 17 patients with complete esophageal obstruction from tumor experienced esophageal perforations, which were considered to be possibly treatment-associated; these perforations occurred during subsequent endoscopies. Serious and other notable adverse reactions observed in less than 5% of PDT-treated patients with obstructing esophageal cancer in the clinical studies include the following; their relationship to therapy is uncertain. In the gastrointestinal system, esophageal perforation, gastric ulcer, ileus, jaundice, and peritonitis have occurred. Sepsis has been reported occasionally. Cardiovascular reactions have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia. Respiratory reactions of bronchitis, bronchospasm, laryngotracheal edema, pneumonitis, pulmonary hemorrhage, pulmonary edema, respiratory failure, and stridor have occurred. The temporal relationship of some gastrointestinal, cardiovascular and respiratory reactions to the administration of light was suggestive of mediastinal inflammation in some patients. Vision-related reactions of abnormal vision, diplopia, eye pain and photophobia have been reported. Obstructing Endobronchial Cancer Table 7 presents adverse reactions that were reported over the entire follow-up period in at least 5% of patients with obstructing endobronchial cancer treated with PHOTOFRIN PDT or Nd: YAG. These data are based on the 86 patients who received the currently marketed formulation. Since it seems likely that most adverse reactions caused by these acute acting therapies would occur within 30 days of treatment, Table 7 presents those reactions occurring within 30 days of a treatment procedure, as well as those occurring over the entire follow-up period. It should be noted that follow-up was 33% longer for the PDT group than for the Nd: YAG group, thereby introducing a bias against PDT when adverse reaction rates are compared for the entire follow- up period. The extent of follow-up in the 30-day period following treatment was comparable between groups (only 9% more for PDT). Transient inflammatory reactions in PDT-treated patients occur in about 10% of patients and manifest as pyrexia, bronchitis, chest pain, and dyspnea. The incidences of bronchitis and dyspnea were higher with PDT than with Nd: YAG. Most cases of bronchitis occurred within 1 week of treatment and all but one was mild or moderate in intensity. The reactions usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnea is generally transient and self-limiting. Debridement of the treated area is mandatory to remove exudate and necrotic tissue. Life-threatening respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated patients and 2% of Nd: YAG-treated patients [see Warnings and Precautions ( 5.8 )] . There was a trend toward a higher rate of fatal massive hemoptysis (FMH) occurring on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4% total events, 3% treatment-associated events). Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor. The incidence of FMH in patients previously treated with radiotherapy was 21% (6/29) in the PDT group and 10% (3/29) in the Nd:YAG group. In patients with no prior radiotherapy, the overall incidence of FMH was less than 1%. Characteristics of patients at high risk for FMH are described in Contraindications ( 4 ) and Warnings and Precautions ( 5.2 ). Other serious or notable adverse reactions were observed in less than 5% of PDT-treated patients with endobronchial cancer; their relationship to therapy is uncertain. In the respiratory system, pulmonary thrombosis, pulmonary embolism, and lung abscess have occurred. Cardiac failure, sepsis, and possible cerebrovascular accident have also been reported in one patient each. TABLE 7. Adverse Reactions Reported in 5% or More of Patients with Obstructing Endobronchial Cancer SYSTEM ORGAN CLASS (SOC) Adverse Reaction Within 30 Days of Treatment Entire Follow-up Period Follow-up was 33% longer for the PDT group than for the Nd:YAG group, introducing a bias against PDT when adverse reactions are compared for the entire follow-up period. PDT Nd:YAG PDT Nd:YAG % % % % Patients with at Least One Adverse Reaction 50 38 72 56 RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS Dyspnea 17 8 30 15 Bronchitis 10 2 10 2 Hemoptysis 7 6 16 8 Cough 6 9 15 13 Pneumonia 6 5 12 6 Productive cough 5 6 8 7 Respiratory insufficiency 0 0 6 1 Pleural effusion 0 0 5 1 Pneumothorax 0 0 0 5 SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 9 0 21 0 GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS Pyrexia 8 8 16 9 Chest pain 7 7 8 9 Edema peripheral 3 3 5 3 Pain 1 5 5 9 PSYCHIATRIC DISORDERS Insomnia 5 2 5 4 Anxiety 3 0 6 0 GASTROINTESTINAL DISORDERS Constipation 5 1 5 2 Dyspepsia 1 5 2 6 MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS Back pain 3 1 3 6 NERVOUS SYSTEM DISORDERS Dysphonia 3 2 5 2 Superficial Endobronchial Tumors The following adverse reactions were reported over the entire follow-up period in at least 5% of patients with superficial tumors (microinvasive or carcinoma in situ ) who received the currently marketed formulation. * Based on adverse reactions reported at any time during the entire period of follow-up. TABLE 8 . Adverse Reactions Reported in 5% or More of Patients* with Superficial Endobronchial Tumors SYSTEM ORGAN CLASS (SOC) Adverse Reaction All grades (%) Patients with at Least One Adverse Reaction 49 RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS Exudate 22 Bronchial mucus plug or bronchial obstruction 21 Edema 18 Bronchostenosis 11 Bronchial ulceration 9 Cough 9 Dyspnea 7 SKIN and SUBCUTANEOUS TISSUE DISORDERS Photosensitivity reaction 22 In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse reaction, two-thirds of which were related to the respiratory system. The most common reaction to therapy was a mucositis reaction in one-fifth of the patients, which manifested as edema, exudate, and obstruction. The obstruction (mucus plug) is easily removed with suction or forceps. Mucositis can be minimized by avoiding exposure of normal tissue to excessive light [see Warnings and Precautions ( 5.8 )]. Three patients experienced life-threatening dyspnea: one was given a double dose of light, one was treated concurrently in both mainstem bronchi and the other had had prior pneumonectomy and was treated in the sole remaining main airway [see Warnings and Precautions ( 5.2 )]. Stent placement was required in 3% of the patients due to endobronchial stricture. Fatal massive hemoptysis occurred within 30 days of treatment in one patient with superficial tumors (1%). High-Grade Dysplasia (HGD) in Barretts Esophagus (BE) Table 9 presents adverse reactions that were reported over the follow-up period in at least 5% of patients with HGD in BE in either controlled or uncontrolled clinical trials. In the PHOTOFRIN PDT + omeprazole (OM) group, severe adverse reactions included chest pain of non- cardiac origin, dysphagia, nausea, vomiting, regurgitation, and heartburn. The severity of these symptoms decreased within 4 to 6 weeks following treatment. The majority of the photosensitivity reactions occurred within 90 days following PHOTOFRIN and was of mild (68%) or moderate (24%) intensity. Fourteen (10%) patients reported severe reactions, all of which resolved. The typical reaction was described as skin disorder, sunburn or rash, and affected mostly the face, hands, and neck. Associated symptoms and signs were swelling, pruritis, erythema, blisters, burning sensation, and feeling of heat. The majority of esophageal stenosis including strictures reported in the PHOTOFRIN PDT + OM group were of mild (57%) or moderate (35%) intensity, while approximately 8% were of severe intensity. The majority of esophageal strictures were reported during Course 2 of treatment. All esophageal strictures were considered to be due to treatment. Most esophageal strictures were manageable through dilations [see Warnings and Precautions ( 5.9 )]. TABLE 9. Adverse Reactions Reported in > 5% of Patients Treated with PHOTOFRIN PDT in the Clinical Trials on High-Grade Dysplasia in Barrett's Esophagus SYSTEM ORGAN CLASS (SOC) Adverse Reaction TREATMENT GROUPS HGD Includes all HGD patients in the Safety population from PHO BAR 02 (N=133), TCSC 93-07 (N=44), and TCSC 96-01 (N=42). PHOTOFRIN HGD Includes all HGD patients in the Safety population from PHO BAR 02 (N=69). Omeprazole Other Includes patients with Barretts metaplasia, indefinite dysplasia, LGD, and adenocarcinoma at baseline in the Safety population from TCSC 93-07 (N=55) and TCSC 96-01 (N=44). PHOTOFRIN Total PHOTOFRIN PDT + Omeprazole N (%) Only N (%) PDT + Omeprazole N (%) PDT + Omeprazole N (%) Patients with at Least One Adverse Reaction 94 13 98 95 GASTROINTESTINAL DISORDERS Gastrointestinal 74 9 84 77 Esophageal Stricture Esophageal stricture was defined as a dilated esophageal stenosis. 37 0 33 36 Esophageal Narrowing Esophageal narrowing was defined as an undilated esophageal stenosis. 32 6 24 30 Vomiting 29 1 34 31 Nausea 26 1 62 37 Dysphagia 22 0 26 24 Constipation 11 1 7 10 Hiccups 7 0 1 5 Esophageal pain 6 0 9 7 Odynophagia 6 0 4 5 Abdominal Pain (Upper, lower, NOS) 5 1 6 5 Dyspepsia 5 0 4 4 SKIN and SUBCUTANEOUS TISSUE DISORDERS Skin and Subcutaneous Tissue 53 1 28 45 Photosensitivity reaction 47 0 16 37 GENERAL and ADMINISTRATION SITE CONDITIONS General 50 0 63 54 Chest pain 29 0 37 31 Pyrexia 19 0 13 17 Chest discomfort 6 0 19 10 Pain 5 0 7 6 RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS Respiratory 16 0 18 17 Pleural effusion 10 0 15 12 METABOLISM and NUTRITION DISORDERS Metabolism and Nutrition 13 0 16 14 Dehydration 11 0 8 10 INVESTIGATIONS Investigations 11 0 11 11 Weight decreased 7 0 2 5 INJURY, POISONING and PROCEDURAL COMPLICATIONS Injury and Procedural 11 0 19 14 Post procedural pain 6 0 14 9 NOTE: Adverse reactions classified using MedDRA 5.0 dictionary with the exception of esophageal stricture and esophageal narrowing. Laboratory Abnormalities In patients with esophageal cancer, PDT with PHOTOFRIN may result in anemia due to tumor bleeding. No significant effects were observed for other parameters in patients with endobronchial carcinoma or with HGD in BE. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PHOTOFRIN with PDT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, and hypertension.

8.1 Pregnancy Risk Summary Based on animal studies, PHOTOFRIN may cause embryo-fetal toxicity when administered to a pregnant woman. There are no available data on PHOTOFRIN use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Intraveneous administration of porfimer sodium to pregnant rats and rabbits during the period of organogenesis at dose levels approximately 0.64 times the recommended human dose of PHOTOFRIN based on body surface area (BSA) resulted in increased fetal resorptions, decreased litter size, and reduced fetal weight, but did not cause fetal malformations. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. Data Animal Data Intravenous administration of porfimer sodium to pregnant rats for 10 days during the period of organogenesis at dose levels 0.64 times the recommended human dose of PHOTOFRIN based on BSA resulted in maternal and embryo-fetal toxicity resulting in increased resorptions, decreased litter size, delayed ossification, and reduced fetal weight but did not cause major fetal malformations. Intravenous administration of porfimer sodium to pregnant rabbits for 13 days during the period of organogenesis at dose levels 0.65 times the recommended human dose of PHOTOFRIN based on BSA caused maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body weight but did not cause major fetal malformations. Intravenous administration of porfimer sodium to rats for at least 42 days during late pregnancy (post- organogenesis, GD17-PND21) through lactation at dose levels 0.32 times the recommended human dose of PHOTOFRIN based on BSA caused a reversible decrease in growth of offspring. Parturition was unaffected.