Porfimer Sodium

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.

For injection: 75 mg of porfimer sodium as a lyophilized powder in a single-dose vial for reconstitution. For injection: 75 mg porfimer sodium as a lyophilized powder in single-dose vial for reconstitution ( 3 )

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 )

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. […]

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. […]

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.

Lactation : Advice not to breastfeed. ( 8.2 )

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.

8.2 Lactation Risk Summary There are no data on the presence of porfimer sodium in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with PHOTOFRIN and for 5 months after the last dose.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to the initiation of PHOTOFRIN therapy [see Use in Specific Populations ( 8.1 )] . Contraception PHOTOFRIN may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Females Advise females of reproductive potential to use effective contraception during treatment with PHOTOFRIN and for 5 months after the final dose. Males Advise male patients with female partners of reproductive potential to use condoms during treatment with PHOTOFRIN and for 5 months following the final dose .

8.4 Pediatric Use Safety and effectiveness in pediatrics have not been established.

8.5 Geriatric Use Approximately 70% of the patients treated with PDT using PHOTOFRIN in clinical trials were over 60 years of age. No overall differences in safety or effectiveness were observed between these patients compared to younger patients.