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.

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.