Photofrin

Overdose

There is no information on overdosage situations involving PHOTOFRIN (porfimer sodium). Higher than recommended drug doses of two 2 mg/kg doses given two days apart (10 patients) and three 2 mg/kg doses given within two weeks (one patient), were tolerated without notable adverse reactions. Effects of overdosage on the duration of photosensitivity are unknown. Laser treatment should not be given if an overdose of PHOTOFRIN (porfimer sodium) is administered. In the event of an overdose, patients should protect their eyes and skin from direct sunlight or bright indoor lights for 30 days. At this time, patients should test for residual photosensitivity. PHOTOFRIN (porfimer sodium) is not dialyzable.

Light doses of two to three times the recommended dose have been administered to a few patients with superficial endobronchial tumors. One patient experienced life-threatening dyspnoea and the others had no notable complications. Increased symptoms and damage to normal tissue might be expected following an overdose of light. There is no information on overdose of laser light following PHOTOFRIN (porfimer sodium) injection in patients with esophageal cancer or in patients with high-grade dysplasia in Barrett's esophagus.

Contraindications

• PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) and laser light treatment.
• PDT is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers > 1 cm in diameter.

Undesirable effects

Systemically induced effects of photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN (porfimer sodium) will be photosensitive and must observe precautions to avoid sunlight and bright indoor light. Photosensitivity reactions occurred in approximately 20% of cancer patients and in 69% of high-grade dysplasia (HGD) in Barrett's esophagus (BE) patients treated with PHOTOFRIN (porfimer sodium). 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 (porfimer sodium) 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 (porfimer sodium) 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 (porfimer sodium) directly caused or accelerated a familial underlying condition is unknown.

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.

The following adverse reactions were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) is uncertain.

TABLE 6: Adverse Reactions Reported in 5% or More of Patientsa with Obstructing Esophageal Cancer

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.

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 (porfimer sodium) 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 dyspnoea. The incidences of bronchitis and dyspnoea 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 reactions usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnoea 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.

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 and WARNINGS AND PRECAUTIONS.

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

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.

TABLE 8: Adverse Reactions Reported in 5% or More of Patientsa with Superficial Endobronchial Tumors

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. Three patients experienced life-threatening dyspnoea: 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. 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 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 (porfimer sodium) PDT + 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 (porfimer sodium) injection 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 (porfimer sodium) PDT + OM group werewas 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 .

TABLE 9: Adverse Reactions Reported in ≥ 5% of Patients Treated with PHOTOFRIN (porfimer sodium) PDT in the Clinical Trials on High-Grade Dysplasia in Barrett's Esophagus

In patients with esophageal cancer, PDT with PHOTOFRIN (porfimer sodium) 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.

Therapeutic indications

PHOTOFRIN (porfimer sodium) ® 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 physician, cannot be satisfactorily treated with Nd:YAG laser therapy.

PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) is indicated for the reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC.

PHOTOFRIN (porfimer sodium) is indicated for the ablation of high-grade dysplasia in Barrett's esophagus patients who do not undergo esophagectomy.

Pharmacodynamic properties

The cytotoxic and antitumor actions of PHOTOFRIN (porfimer sodium) are light and oxygen dependent. PDT with PHOTOFRIN (porfimer sodium) is a two-stage process. The first stage is the intravenous injection of PHOTOFRIN (porfimer sodium). Clearance from a variety of tissues occurs over 40-72 hours, but tumors, skin, and organs of the reticuloendothelial system (including liver and spleen) retain PHOTOFRIN (porfimer sodium) for a longer period. Illumination with 630 nm wavelength laser light constitutes the second stage of therapy. Tumor selectivity in treatment occurs through a combination of selective retention of PHOTOFRIN (porfimer sodium) and selective delivery of light.

Pharmacokinetic properties

The pharmacokinetics of PHOTOFRIN (porfimer sodium) were studied in 18 cancer patients who received two doses of PHOTOFRIN (porfimer sodium) , 2 mg/kg each, administered 30 to 45 days apart as slow IV injection over 3 to 5 minutes. The mean Cmax values were comparable after the first and second administrations (43.1±10.5 mcg/mL and 41.3±8.7 mcg/mL, respectively). However, the mean AUC0-inf of porfimer was about 34% higher after the second administration than that after the first administration (3937±1034 mcg.h/mL and 2937±627 mcg.hour/mL, respectively), indicating some accumulation upon repeated administration. The elimination half-life of porfimer increased from 410 to 725 hours after the first and second administrations, respectively.

PHOTOFRIN (porfimer sodium) was approximately 90% protein bound in human serum, studied in vitro . The binding was independent of concentration over the concentration range of 20–100 mcg/mL.

The effect of gender was determined in 18 patients (8 males and 10 females) who received two administrations of PHOTOFRIN (porfimer sodium) 2 mg/kg within 30-45 days apart as slow IV injection over 3 to 5 minutes. The mean Cmax and AUC values were comparable between males and females following either the first or the second administrations.

The effect of hepatic and renal impairment has not been studied.

Date of revision of the text

Name of the medicinal product

Fertility, pregnancy and lactation

Pregnancy Category C. Porfimer sodium has been shown to have an embryocidal effect in rats and rabbits when given in doses 0.64 times the recommended human dose on a mg/m² basis. Porfimer sodium given to rat dams during fetal organogenesis intravenously at 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. Porfimer sodium caused no major malformations when given to rabbits intravenously during organogenesis at 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.

Porfimer sodium given to rats during late pregnancy through lactation intravenously at 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.

There are no adequate and well-controlled studies of PHOTOFRIN (porfimer sodium) in pregnant women. PHOTOFRIN (porfimer sodium) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Qualitative and quantitative composition

75 mg vial

PHOTOFRIN (porfimer sodium) for Injection is supplied as a freeze-dried cake or powder as follows:

NDC 76128-155-75, 75 mg vial.

PHOTOFRIN (porfimer sodium) freeze-dried cake or powder should be stored at Controlled Room Temperature 20–25°C (68–77°F).

Spills of PHOTOFRIN (porfimer sodium) should be wiped up with a damp cloth. Skin and eye contact should be avoided due to the potential for photosensitivity reactions upon exposure to light; use of rubber gloves and eye protection is recommended. All contaminated materials should be disposed of in a polyethylene bag in a manner consistent with local regulations.

PHOTOFRIN (porfimer sodium) is neither a primary ocular irritant nor a primary dermal irritant. However, because of its potential to induce photosensitivity, PHOTOFRIN (porfimer sodium) might be an eye and/or skin irritant in the presence of bright light. It is important to avoid contact with the eyes and skin during preparation and/or administration. As with therapeutic overdosage, any overexposed person must be protected from bright light.

Manufacturer details: n/a. Revised: 04/2011

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

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 photodynamic therapy (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.

Patients should be assessed for the possibility that a tumor may be eroding into a pulmonary blood vessel. 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.

PDT 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.

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 randomized study at the time of analysis was a minimum of two years (ranging from 2 to 5.6 years).

All patients who receive PHOTOFRIN (porfimer sodium) 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.

Ocular discomfort, commonly described as sensitivity to sun, bright lights, or car headlights, has been reported in patients who received PHOTOFRIN (porfimer sodium). For 30 days, when outdoors, patients should wear dark sunglasses which have an average white light 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 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 as a result of PDT of HGD in BE are common adverse reactions. 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 5. Special care should be taken during dilation to avoid perforation of the esophagus.

A high proportion of patients who developed an esophageal stricture received a nodule pretreatment prior to developing the event (49%) and/or had a mucosal segment treated twice (82%). Therefore, nodule pretreatment and re-treating the same mucosal segment more than once may influence the risk of developing an esophageal stricture.

Hepatic or Renal impairment will likely prolong the elimination of porfimer sodium leading to higher rates of toxicity. Patients with severe renal impairment or mild to severe hepatic impairment should be clearly informed that the period requiring the precautionary measures for photosensitivity may be longer than 90 days.

TABLE 5: Esophageal Dilations in Patients with Treatment-Related Strictures

No long-term studies have been conducted to evaluate the carcinogenic potential of porfimer sodium.

In the presence of light, in vitro , porfimer sodium 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. Porfimer sodium PDT 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. Porfimer sodium PDT caused an increase in thymidine kinase mutants and DNA-protein cross-links in mouse L5178Y cells, but not mouse LYR83 cells Porfimer sodium PDT caused a light-dose dependant increase in DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. In the absence of light, porfimer sodium was negative in a Chinese hamster ovarian cells (CHO/HGPRT) mutation test. In vivo, porfimer sodium did not cause chromosomal aberrations in the mouse micronucleus test.

Porfimer sodium 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 porfimer sodium caused discoloration of testes and ovaries and hypertrophy of the testes. Porfimer sodium also caused decreased body weight in the parent rats.

Pregnancy Category C. Porfimer sodium has been shown to have an embryocidal effect in rats and rabbits when given in doses 0.64 times the recommended human dose on a mg/m² basis. Porfimer sodium given to rat dams during fetal organogenesis intravenously at 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. Porfimer sodium caused no major malformations when given to rabbits intravenously during organogenesis at 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.

Porfimer sodium given to rats during late pregnancy through lactation intravenously at 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.

There are no adequate and well-controlled studies of PHOTOFRIN (porfimer sodium) in pregnant women. PHOTOFRIN (porfimer sodium) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) , a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.

Safety and effectiveness in children have not been established.

Approximately 70% of the patients treated with PDT using PHOTOFRIN (porfimer sodium) 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.

Dosage (Posology) and method of administration

Photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) is a two-stage process requiring administration of both drug and light. The first stage of PDT is the intravenous injection of PHOTOFRIN (porfimer sodium) at 2 mg/kg. Illumination with laser light 40–50 hours following injection with PHOTOFRIN (porfimer sodium) constitutes the second stage of therapy. A second laser light application may be given 96-120 hours after injection. In clinical studies on endobronchial cancer, debridement via endoscopy was required 2-3 days after the initial light application. Standard endoscopic techniques are used for light administration and debridement. Practitioners should be fully familiar with the patient's condition and trained in the safe and efficacious treatment of esophageal or endobronchial cancer, or high-grade dysplasia (HGD) in Barrett's esophagus (BE) using PDT with PHOTOFRIN (porfimer sodium) and associated light delivery devices. PDT with PHOTOFRIN (porfimer sodium) should be applied only in those facilities properly equipped for the procedure.

The laser system must be approved for delivery of a stable power output at a wavelength of 630 ± 3 nm. Light is delivered to the tumor by cylindrical OPTIGUIDE™ fiber optic diffusers passed through the operating channel of an endoscope/bronchoscope. Instructions for use of the fiber optic and the selected laser system should be read carefully before use. OPTIGUIDE™ cylindrical diffusers are available in several lengths. The choice of diffuser tip length depends on the length of the tumor or Barrett's mucosa to be treated. Diffuser length should be sized to avoid exposure of nonmalignant tissue to light and to prevent overlapping of previously treated malignant tissue. Refer to the OPTIGUIDE™ instructions for use for complete instructions concerning the fiber optic diffuser.

PHOTOFRIN (porfimer sodium) should be administered as a single slow intravenous injection over 3 to 5 minutes at 2 mg/kg of body weight. Reconstitute each vial of PHOTOFRIN (porfimer sodium) with 31.8 mL of either 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), resulting in a final concentration of 2.5 mg/mL. Shake well until dissolved. Do not mix PHOTOFRIN (porfimer sodium) with other drugs in the same solution. PHOTOFRIN (porfimer sodium) , reconstituted with 5% Dextrose Injection (USP) or with 0.9% Sodium Chloride Injection (USP), has a pH in the range of 7 to 8. PHOTOFRIN (porfimer sodium) has been formulated with an overage to deliver the 75 mg labeled quantity. The reconstituted product should be protected from bright light and used immediately. Reconstituted PHOTOFRIN (porfimer sodium) is an opaque solution, in which detection of particulate matter by visual inspection is extremely difficult. Reconstituted PHOTOFRIN (porfimer sodium) , however, like all parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Precautions should be taken to prevent extravasation at the injection site. If extravasation occurs, care must be taken to protect the area from light. There is no known benefit from injecting the extravasation site with another substance.

Initiate 630 nm wavelength laser light delivery to the patient 40– 50 hours following injection with PHOTOFRIN (porfimer sodium) A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN (porfimer sodium). No further injection of PHOTOFRIN (porfimer sodium) should be given for such retreatment with laser light. Before providing a second laser light treatment, the residual tumor may be debrided. The debridement is optional since the residua will be removed naturally by peristaltic action of the esophagus. Vigorous debridement may cause tumor bleeding.

Photoactivation of PHOTOFRIN (porfimer sodium) is controlled by the total light dose delivered. In the treatment of esophageal cancer, a light dose of 300 Joules/cm (J/cm) of diffuser length should be delivered. The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 12 minutes and 30 seconds.

For the treatment of esophageal cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of PDT (each separated by a minimum of 30 days) can be given. Before each course of treatment, patients with esophageal cancer should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula. All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel.

Initiate 630 nm wavelength laser light delivery to the patient 40– 50 hours following injection with PHOTOFRIN (porfimer sodium). A second laser light treatment may be given as early as 96 hours or as late as 120 hours after the initial injection with PHOTOFRIN (porfimer sodium). No further injection of PHOTOFRIN (porfimer sodium) should be given for such retreatment with laser light. Before providing a second laser light treatment, the residual tumor should be debrided. Vigorous debridement may cause tumor bleeding. For endobronchial tumors, debridement of necrotic tissue should be discontinued when the volume of bleeding increases, as this may indicate that debridement has gone beyond the zone of the PDT effect.

Photoactivation of PHOTOFRIN (porfimer sodium) is controlled by the total light dose delivered. In the treatment of endobronchial cancer, a light dose of 200 J/cm of diffuser length should be delivered. The total power output at the fiber tip is set to deliver the appropriate light dose using exposure times of 8 minutes and 20 seconds. For noncircumferential endobronchial tumors that are soft enough to penetrate, interstitial fiber placement is preferred to intraluminal activation, since this method produces better efficacy and results in less exposure of the normal bronchial mucosa to light. It is important to perform a debridement 2 to 3 days after each light administration to minimize the potential for obstruction caused by necrotic debris.

For the treatment of endobronchial cancer, patients may receive a second course of PDT a minimum of 30 days after the initial therapy; up to three courses of PDT (each separated by a minimum of 30 days) can be given. In patients with endobronchial lesions who have recently undergone radiotherapy, sufficient time (approximately 4 weeks) should be allowed between the therapies to ensure that the acute inflammation produced by radiotherapy has subsided prior to PDT. All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel.

Prior to initiating treatment with PHOTOFRIN (porfimer sodium) PDT, the diagnosis of HGD in BE should be confirmed by an expert GI pathologist.

Approximately 40-50 hours after PHOTOFRIN (porfimer sodium) administration light should be delivered by a X-Cell Photodynamic Therapy (PDT) Balloon with Fiber Optic Diffuser. The choice of fiber optic/balloon diffuser combination will depend on the length of Barrett's mucosa to be treated (Table 1).

TABLE 1: Fiber Optic Diffuser/Balloon Combinationa

Photoactivation is controlled by the total light dose delivered. The objective is to expose and treat all areas of HGD and the entire length of BE. The light dose administered will be 130 J/cm of diffuser length using a centering balloon. Based on the randomized clinical study, acceptable light intensity for the balloon/diffuser combinations range from 200-270 mW/cm of diffuser length.

To calculate the light dose, the following specific light dosimetry equation applies for all fiber optic diffusers:

Light Dose (J/cm) = Power Output From Diffuser (W) x Treatment Time (s) /Diffuser Length (cm)

Table 2 provides the settings that will be used to deliver the dose within the shortest time (light intensity of 270 mW/cm). A second option (light intensity of 200 mW/cm) has also been included where necessary to accommodate lasers with a total capacity that does not exceed 2.5 W.

TABLE 2: Fiber Optic Power Outputs and Treatment Times Required to Deliver 130 J/cm of Diffuser Length Using the Centering Balloon

Note: No more than 1.5 times the required diffuser power output should be needed from the laser. If more than this is required, the system should be checked.

Short fiber diffusers ( ≤ 2.5 cm) are to be used to pretreat nodules with 50 J/cm of diffuser length prior to regular balloon treatment in the first laser light session or for the treatment of “skip” areas (i.e., an area that does not show sufficient mucosal response) after the first light session. For this treatment, the fiber optic diffuser is used without a centering balloon, and a light intensity of 400 mW/cm should be used. For nodule pretreatment and treatment of skipped areas, care should be taken to minimize exposure to normal tissue as it is also sensitized. Table 3 lists appropriate fiber optic power outputs and treatment times using a light intensity of 400 mW/cm.

TABLE 3: Short Fiber Optic Diffusers to be Used Without a Centering Balloon to Deliver 50 J/cm of Diffuser Length at a Light Intensity of 400 mW/cm

A maximum of 7 cm of esophageal mucosa is treated at the first light session using an appropriate size of centering balloon and fiber optic diffuser (Table 1). Whenever possible, the segment selected for the first light application should contain all the areas of HGD. Also, whenever possible, the BE segment selected for the first light application should include normal tissue margin of a few millimeters at the proximal and distal ends.

Nodules are to be pretreated at a light dose of 50 J/cm of diffuser length with a short ( ≤ 2.5 cm) fiber optic diffuser placed directly against the nodule followed by standard balloon application as described above.

A second laser light application may be given to a previously treated segment that shows a “skip” area, using a short, ≤ 2.5 cm, fiber optic diffuser without centering balloon at the light dose of 50 J/cm of the diffuser length. Patients with BE > 7 cm, should have the remaining untreated length of Barrett's epithelium treated with a second PDT course at least 90 days later.

The treatment regimen is summarized in Table 4.

TABLE 4: High-Grade Dysplasia in Barrett's Esophagus

For the ablation of HGD in BE, patients may receive an additional course of PDT at a minimum of 90 days after the initial therapy; up to three courses of PDT (each injection separated by a minimum of 90 days) can be given to a previously treated segment which still shows HGD, low-grade dysplasia, or Barrett's metaplasia, or to a new segment if the initial Barrett's segment was > 7 cm in length. Both residual and additional segments may be treated in the same light session(s) provided that the total length of the segments treated with the balloon/diffuser combination is not greater than 7 cm. In the case of a previously treated esophageal segment, if it has not sufficiently healed and/or histological assessment of biopsies is not clear, the subsequent course of PDT may be delayed for an additional 1-2 months.

Interaction with other medicinal products and other forms of interaction

Systemically induced effects of photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN (porfimer sodium) will be photosensitive and must observe precautions to avoid sunlight and bright indoor light. Photosensitivity reactions occurred in approximately 20% of cancer patients and in 69% of high-grade dysplasia (HGD) in Barrett's esophagus (BE) patients treated with PHOTOFRIN (porfimer sodium). 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 (porfimer sodium) 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 (porfimer sodium) 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 (porfimer sodium) directly caused or accelerated a familial underlying condition is unknown.

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.

The following adverse reactions were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) is uncertain.

TABLE 6: Adverse Reactions Reported in 5% or More of Patientsa with Obstructing Esophageal Cancer

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.

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 (porfimer sodium) 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 dyspnoea. The incidences of bronchitis and dyspnoea 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 reactions usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnoea 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.

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 and WARNINGS AND PRECAUTIONS.

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

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.

TABLE 8: Adverse Reactions Reported in 5% or More of Patientsa with Superficial Endobronchial Tumors

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. Three patients experienced life-threatening dyspnoea: 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. 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 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 (porfimer sodium) PDT + 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 (porfimer sodium) injection 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 (porfimer sodium) PDT + OM group werewas 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 .

TABLE 9: Adverse Reactions Reported in ≥ 5% of Patients Treated with PHOTOFRIN (porfimer sodium) PDT in the Clinical Trials on High-Grade Dysplasia in Barrett's Esophagus

In patients with esophageal cancer, PDT with PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) 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.

Photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) 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 (porfimer sodium) 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.