WARNINGS
Following injection with PHOTOFRIN® precautions must be taken to avoid exposure of skin and eyes to direct sunlight or bright indoor light (see PRECAUTIONS, General Precautions and Information for Patients).
Esophageal Cancer
If the esophageal tumor is eroding into the trachea or bronchial tree, the likelihood of tracheoesophageal or bronchoesophageal fistula resulting from treatment is sufficiently high that PDT is not recommended.
Patients with esophageal varices should be treated with extreme caution. Light should not be given directly to the variceal area because of the high risk of bleeding.
Endobronchial Cancer
Patients should be assessed for the possibility that a tumor may be eroding into a pulmonary blood vessel (see CONTRAINDICATIONS). Patients at high risk for fatal massive hemoptysis (FMH) include those with large, centrally located tumors, those with cavitating tumors or those with extensive tumor extrinsic to the bronchus.
If the endobronchial tumor invades deeply into the bronchial wall, the possibility exists for fistula formation upon resolution of tumor.
Photodynamic therapy should be used with extreme caution for endobronchial tumors in locations where treatment-induced inflammation could 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.
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. It is recommended that endoscopic biopsy surveillance be conducted every three months, until four consecutive negative evaluations for HGD have been recorded; further follow-up may be scheduled every 6 to 12 months, as per judgment of physicians. The follow-up period of the pivotal study at the time of analysis was a minimum of two years (ranging from 2 to 3.6 years).
PRECAUTIONS
General Precautions and Information for Patients
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 UV (ultraviolet) sunscreens are of no value in protecting against photosensitivity reactions because photoactivation is caused by visible light.
Ocular Sensitivity
Ocular discomfort, commonly described as sensitivity to sun, bright lights, or car headlights, has been reported in patients who received PHOTOFRIN®. For 30 days, when outdoors, patients should wear dark sunglasses which have an average white light transmittance of <4%.
Use Before or After Radiotherapy
If PDT is to be used before or after radiotherapy, sufficient time should be allotted 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. It is recommended that 2 to 4 weeks be allowed after PDT before commencing radiotherapy. Similarly, if PDT is to be given after radiotherapy, the acute inflammatory reaction from radiotherapy usually subsides within 4 weeks after completing radiotherapy, after which PDT may be given.
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.
Respiratory Distress
Patients with endobronchial lesions must be closely monitored 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.
Esophageal Strictures
Esophageal strictures as a result of PDT of HGD in BE are common adverse events. An esophageal stricture was defined as a fixed lumen narrowing with solid food dysphagia and requiring dilation.
Regardless of the indication, esophageal strictures were reported in 122 of the 318 (38%) patients enrolled in the three clinical studies. Overall, esophageal strictures occurred within six months following PDT and were manageable through dilations. Multiple dilations of esophageal strictures may be required, as shown in Table 6. Special care should be taken during dilation to avoid perforation of the esophagus.
TABLE 6. Esophageal Dilations in Patients with Treatment-related Strictures | Number of Dilations | Number of Patients with Strictures, N=122 | Percentage of Patients with Strictures |
| 1 − 2 Dilations | 38 | 31% |
| 3 − 5 Dilations | 33 | 27% |
| 6 − 10 Dilations | 26 | 21% |
| > 10 Dilations | 25 | 20% |
A high proportion of patients who developed an esophageal stricture received a nodule pre-treatment prior to developing the event (49%) and/or had a mucosal segment treated twice (82%). Therefore, nodule pre-treatment and re-treating the same mucosal segment more than once may influence the risk of developing an esophageal stricture.
Prior to initiating treatment with PHOTOFRIN® PDT, the diagnosis of HGD in BE should be confirmed by an expert GI pathologist. Photodynamic therapy with PHOTOFRIN® should be applied by physicians trained in the endoscopic use of PDT with PHOTOFRIN®, and only in those facilities properly equipped for the procedure.
Avoidance of Pregnancy
Women of childbearing potential should practice an effective method of contraception during therapy (see Pregnancy).
Drug Interactions
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, β-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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies have been conducted to evaluate the carcinogenic potential of PHOTOFRIN®. In vitro , PHOTOFRIN® PDT did not cause mutations in the Ames test, nor did it cause chromosome aberrations or mutations (HGPRT locus) in Chinese hamster ovary (CHO) cells. PHOTOFRIN® caused <2-fold, but significant, increases in sister chromatid exchange in CHO cells irradiated with visible light and a 3-fold increase in Chinese hamster lung fibroblasts irradiated with near UV light. PHOTOFRIN® PDT caused an increase in thymidine kinase mutants and DNA-protein cross-links in mouse L5178Y cells, but not mouse LYR83 cells. PHOTOFRIN® PDT caused a light-dose dependant increase in DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. PHOTOFRIN® was negative in a Chinese hamster ovarian cells (CHO/HGPRT) mutation test. In vivo, PHOTOFRIN® did not cause chromosomal aberrations in the mouse micronucleus test.
PHOTOFRIN® given to male and female rats intravenously, at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) before conception and through Day 7 of pregnancy caused no impairment of fertility. In this study, long-term dosing with PHOTOFRIN® caused discoloration of testes and ovaries and hypertrophy of the testes. PHOTOFRIN® also caused decreased body weight in the parent rats.
Pregnancy: Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. PHOTOFRIN® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PHOTOFRIN® given to rat dams during fetal organogenesis intravenously at 8 mg/kg/d (0.64 times the clinical dose on a mg/m2 basis) for 10 days caused no major malformations or developmental changes. This dose caused maternal and fetal toxicity resulting in increased resorptions, decreased litter size, delayed ossification, and reduced fetal weight. PHOTOFRIN® caused no major malformations when given to rabbits intravenously during organogenesis at 4 mg/kg/d (0.65 times the clinical dose on a mg/m2 basis) for 13 days. This dose caused maternal toxicity resulting in increased resorptions, decreased litter size, and reduced fetal body weight.
PHOTOFRIN® given to rats during late pregnancy through lactation intravenously at 4 mg/kg/d (0.32 times the clinical dose on a mg/m2 basis) for at least 42 days caused a reversible decrease in growth of offspring. Parturition was unaffected.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PHOTOFRIN®, women receiving PHOTOFRIN® must not breast feed.
Pediatric Use
Safety and effectiveness in children have not been established.
Use in Elderly Patients
Approximately 70% of the patients treated with PDT using PHOTOFRIN® in clinical trials were over 60 years of age. There was no apparent difference in effectiveness or safety in these patients compared to younger people. Dose modification based upon age is not required.
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