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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 30 days. 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 endcouraged to expose their skin to ambient indor 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. UV (ultraviolet) sunscreens are of no value in protecting against photosensitivity reactions because photoactivation is caused by visible light.
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 transmittance of < 4%.
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.
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.
Patients with endobronchial lesions must be closely monitored between 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.
Women of childbearing potential should practice and effective method of contraception durnign therapy.
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, sulfonyurea hypoglycemic agents, thiazide diuretics, and grieseofulvin) could increase the 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 possibilites.
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.
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 dit 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. The mutagenicity of PHOTOFRIN without light has not been adequately determined. 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.
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 8mg/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 4mg/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.
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 reaction in nursing infants from PHOTOFRIN women receiving PHOTOFRIN must not breast feee.
Safety and effectiveness in children have not been established.
Approximately 70% of the patients treated with PDT using PHOTFRIN 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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