Systemically induced effects associated with 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 PRECAUTIONS). Photosensitivity reactions occurred in approximately 20% of cancer patients and in 68% of high-grade dysplasia (HGD) in Barrett's esophagus (BE) patients treated with PHOTOFRIN^® . Typically these reactions were mostly mild to moderate erythema but they also included swelling, itching, 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 nodules, increased wrinkles and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria).

Most toxicities associated with 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 following the use of PDT with PHOTOFRIN^® in patients with overtly disseminated intraperitoneal malignancies. Fluid imbalance is an expected PDT treatment-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.

The following adverse events 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 7 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse events to PDT with PHOTOFRIN^® is uncertain.

^a Based on adverse events reported at any time during the entire period of follow-up.

Location of the tumor was a prognostic factor for three adverse events: 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 events 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 events have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia. Respiratory events 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 events to the administration of light was suggestive of mediastinal inflammation in some patients. Vision-related events of abnormal vision, diplopia, eye pain and photophobia have been reported.

Table 8 presents adverse events 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 events caused by these acute acting therapies would occur within 30 days of treatment, Table 8 presents those events 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 event 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).

^a Follow-up was 33% longer for the PDT group than for the Nd:YAG group, introducing a bias against PDT when adverse events are compared for the entire follow-up period.

Transient inflammatory reactions in PDT-treated patients occur in about 10% of patients and manifest as fever, 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 were mild or moderate in intensity. The events 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).

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 WARNINGS and CONTRAINDICATIONS.

Other serious or notable adverse events 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.

The following adverse events 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.

^a Based on adverse events reported at any time during the entire period of follow-up.

In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse event, 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 PRECAUTIONS). 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). 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%).

Table 10 presents adverse events that were reported, regardless of the relationship to treatment, over the follow-up period in at least 5% of patients with HGD in BE in either controlled or uncontrolled clinical trials.

Table 10. Treatment Emergent Adverse Events Reported in ≥5% of Patients Treated with PHOTOFRIN^® PDT in the Clinical Trials on High-Grade Dysplasia in Barrett's Esophagus^a

^A Includes all HGD patients in the Safety population from PHO BAR 01 (N=133), TCSC 93-07 (N=44), and TCSC 96-01 (N=42)
^B Includes all HGD patients in the Safety population from PHO BAR 01 (N=69)
^C Includes patients with Barrett's metaplasia, indefinite dysplasia, LGD, and adenocarcinoma at baseline in the Safety population from TCSC 93-07 (N=55) and TCSC 96-01 (N=44)
^d In the controlled clinical trial, an esophageal stricture was defined as a fixed lumen narrowing with solid food dysphagia which required dilations; In the uncontrolled clinical trials, an esophageal stricture was defined as any dilated esophageal narrowing.
^e An esophageal narrowing was defined as an undilated esophageal stenosis.
NOTE: Adverse events classified using MedDRA 5.0 dictionary, except esophageal strictures/narrowing.

In the PHOTOFRIN^® PDT + OM group, severe treatment-associated adverse events 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<^® injection and was of mild (69%) or moderate (24%) intensity. Almost all (98%) of the photosensitivity reactions were considered to be associated with treatment. 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, itching, burning sensation, and feeling of heat.

The majority of esophageal stenosis and strictures reported in the PHOTOFRIN^® PDT + OM group were of mild (55%) or moderate (37%) 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 associated with treatment. Most esophageal strictures were manageable through dilations (see PRECAUTIONS).

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.

There have been no formal interaction studies of PHOTOFRIN^® and any other drugs. However, it is possible that concomitant use of other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, and fluoroquinolones) could increase the risk of photosensitivity reaction.

PHOTOFRIN^® PDT causes direct intracellular damage by initiating radical chain reactions that damage intracellular membranes and mitochondria. Tissue damage also results from ischemia secondary to vasoconstriction, platelet activation and aggregation and clotting. Research in animals and in cell culture has suggested that many drugs could influence the effects of PDT, possible examples of which are described below. There are no human data that support or rebut these possibilities.

Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, b-carotene, ethanol, formate and mannitol would be expected to decrease PDT activity. Preclinical data also suggest that tissue ischemia, allopurinol, calcium channel blockers and some prostaglandin synthesis inhibitors could interfere with PHOTOFRIN^® PDT. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A₂ inhibitors, could decrease the efficacy of PDT. Glucocorticoid hormones given before or concomitant with PDT may decrease the efficacy of the treatment.

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