Porfimer Sodium

PHOTOFRIN (porfimer sodium) for Injection is a photosensitizing agent used in the photodynamic therapy (PDT) of tumors and of high-grade dysplasia (HGD) in Barrett's esophagus (BE). Following reconstitution of the freeze-dried product with 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intravenously. This is followed 40–50 hours later by illumination of the tumor or the esophageal segment with HGD in BE with laser light (630 nm wavelength). PHOTOFRIN (porfimer sodium) is not a single chemical entity; it is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units. It is a dark red to reddish brown cake or powder. Each vial of PHOTOFRIN contains 75 mg of porfimer sodium as a sterile freeze-dried cake or powder. Hydrochloric Acid and/or Sodium Hydroxide may be added during manufacture to adjust the pH to within 7.2-7.9. There are no preservatives or other additives. The structural formula below is representative of the components present in PHOTOFRIN (porfimer sodium) .

Figure 1 : Structure of Porfimer Sodium

Esophageal Cancer

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.

Endobronchial Cancer

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.

High-Grade Dysplasia in Barrett's Esophagus

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

Mechanism of Action

Cellular damage caused by photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) is a consequence of the propagation of radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium to molecular oxygen may then generate singlet oxygen. Subsequent radical reactions can form superoxide and hydroxyl radicals. Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. As opposed to a thermal effect, the laser treatment with porfimer sodium induces a photochemical effect. The necrotic reaction and associated inflammatory responses may evolve over several days.

Pharmacodynamics

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.

Pharmacokinetics

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.

Clinical Studies

Clinical studies of photodynamic therapy (PDT) with PHOTOFRIN (porfimer sodium) were conducted in patients with obstructing esophageal and endobronchial non-small-cell lung cancers, in patients with early-stage radiologically occult endobronchial cancer, and in patients with high-grade dysplasia (HGD) in Barrett's esophagus (BE). In all clinical studies, the method of PDT administration was essentially identical. A course of therapy consisted of one injection of PHOTOFRIN (porfimer sodium) (2 mg/kg administered as a slow intravenous injection over 3–5 minutes) followed by up to two non-thermal applications of 630 nm laser light. Light doses of 300 J/cm of diffuser length were used in esophageal cancer. Light doses of 200 J/cm of diffuser length were used in endobronchial cancer for both palliation of obstructing cancer and treatment of superficial lesions. For the ablation of HGD in BE, the light dose administered was 130 J/cm of diffuser length using a centering balloon for the first application and 50 J/cm of diffuser length without a centering balloon for the second application [see DOSAGE AND ADMINISTRATION]. In all cases, the first application of light occurred 40–50 hours after PHOTOFRIN (porfimer sodium) injection.

For treatment of esophageal cancer debridement of residua via endoscopy is optional 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN (porfimer sodium) were allowed after one month, up to a maximum of three courses.

For treatment of endobronchial cancer, debridement of residua was performed via bronchoscopy 96–120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN (porfimer sodium) were allowed after one month, up to a maximum of three courses.

For ablation of HGD in BE, a second laser light application of 50 J/cm of diffuser length without a centering balloon could be given 96-120 hours after the PHOTOFRIN (porfimer sodium) injection for untreated areas (“skip” areas). Additional courses of PDT with PHOTOFRIN (porfimer sodium) were allowed after three months, up to a maximum of three courses.

Esophageal Cancer

PDT with PHOTOFRIN (porfimer sodium) was utilized in a multicenter, single-arm study in 17 patients with completely obstructing esophageal carcinoma. Assessments were made at 1 week and 1 month after the last treatment procedure. As shown in Table 10, after a single course of therapy, 94% of patients obtained an objective tumor response and 76% of patients experienced some palliation of their dysphagia. On average, before treatment these patients had difficulty swallowing liquids, even saliva. After one course of therapy, there was a statistically significant improvement in mean dysphagia grade (1.5 units, p < 0.05) and 13 of 17 patients could swallow liquids without difficulty 1 week and/or 1 month after treatment. Based on all courses, three patients achieved a complete tumor response (CR). In two of these patients, the CR was documented only at Week 1 as they had no further assessments. The third patient achieved a CR after a second course of therapy, which was supported by negative histopathology and maintained for the entire follow-up of 6 months.

Of the 17 treated patients, 11 (65%) received clinically important benefit from PDT. Clinically important benefit was defined hierarchically as a complete tumor response (3 patients), achievement of normal swallowing (2 patients went from Grade 5 dysphagia to Grade 1), or achievement of a marked improvement of two or more grades of dysphagia with minimal adverse reactions (6 patients). The median duration of benefit in these patients was 69 days. Duration of benefit was calculated only for the period with documented evidence of improvement. All of these patients were still in response at their last assessment and, therefore, the estimate of 69 days is conservative. The median survival for these 11 patients was 115 days.

Endobronchial Cancer

Two randomized multicenter Phase III studies were conducted to compare the safety and efficacy of PHOTOFRIN (porfimer sodium) PDT versus Nd:YAG laser therapy for reduction of obstruction and palliation of symptomatic patients with partially or completely obstructing endobronchial non-small-cell lung cancer. Assessments were made at 1 week and at monthly intervals after treatment. Table 11 shows the results from all randomized patients in the two studies combined. Objective tumor response rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60% for PDT and 41% for Nd:YAG.

Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity rating scale for dyspnoea, cough, and hemoptysis. Patients with moderate to severe symptoms are those most in need of palliation. Improvements of 2 or more grades are considered to be clinically significant. Table 12 shows the percentages of patients with moderate to severe symptoms at baseline who demonstrated a 2grade improvement at any time during the interval evaluated.

TABLE 10: Course 1 Efficacy Results in Patients with Completely Obstructing Esophageal Cancer

TABLE 11: Efficacy Results from Studies in Late-stage Obstructing Endobronchial Cancer – All Randomized Patientsa

TABLE 12: Efficacy Results from Studies in Late-stage Obstructing Endobronchial Cancer – Clinically Significant Improvements in Patients with Moderate to Severe Symptoms at Baselinea

In a separate retrospective analysis, patients were individually evaluated to identify those patients whose benefit to risk ratio was most favorable, i.e., those who obtained clinically important benefit with minimal adverse reactions. Clinically important benefit was defined as one of the following:

1. A substantial improvement in pulmonary symptoms at Month 1 or later (dyspnoea ≥ 2 grades, hemoptysis ≥ 3 grades, cough ≥ 3 grades or increase in FEV1 ≥ 40%);
2. A moderate improvement in symptoms at Month 2 or later (dyspnoea 1 grade, cough 2 grades, hemoptysis 2 grades or increase in FEV1 ≥ 20%); or
3. A durable objective tumor response (CR or PR maintained to Month 2 or longer).

Thirty-six (36) of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated patients (23%) received clinically important benefit with only minimal or moderate toxicities of short duration. Thirty-four (34) of 99 PDT-treated patients demonstrated improvements in 2 or more efficacy endpoints (dyspnoea, cough, hemoptysis, sputum, atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Performance Score or tumor response) and 29 patients had improvements in 3 or more.

The median duration of documented benefit in the 36 patients was 63 days. In these patients with late-stage obstructing lung cancer, median survival was 174 days in PDT-treated patients and 161 days in Nd:YAG-treated patients.

The efficacy of PHOTOFRIN (porfimer sodium) PDT was also evaluated in the treatment of microinvasive endobronchial tumors in 62 inoperable patients in three noncomparative studies. Microinvasive lung cancer is defined histologically as disease, which invades beyond the basement membrane but not through or into the cartilage. For 11 of the 62 patients, it was clearly documented that surgery and radiotherapy were not indicated. These 11 patients were all inoperable for medical or technical reasons. Radiotherapy was not indicated due to prior high-dose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in Table 13, the complete tumor response rate, biopsy-proven at least 3 months after treatment, was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years and disease-specific survival was 4.1 years.

TABLE 13: Overall Efficacy Results in Patients with Superficial Endobronchial Tumors

High-Grade Dysplasia in Barrett's Esophagus

The safety and efficacy of PDT with PHOTOFRIN (porfimer sodium) in ablation of HGD in patients with BE was assessed in one controlled randomized clinical study and two supportive studies.

A multicenter, pathology blinded, randomized, controlled study was conducted in North America and Europe to assess the efficacy of PDT with PHOTOFRIN (porfimer sodium) for Injection plus omeprazole (PHOTOFRIN (porfimer sodium) PDT + OM) in producing complete ablation of HGD in patients with BE compared to control patients receiving omeprazole alone (OM Only). A total of 485 patients with the diagnosis of HGD were screened for the study; 208 (43%) were randomized to treatment, 237 (49%) were excluded because the diagnosis of HGD was not confirmed and 40 (8%) did not meet other screening criteria or declined to participate in the study. The high patient exclusion rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of HGD in BE should be confirmed by an expert GI pathologist. Patients were centrally randomized in a 2:1 proportion to receive PHOTOFRIN (porfimer sodium) PDT + OM (138 patients) or OM Only (70 patients). All patients underwent rigorous systematic quarterly endoscopic biopsy surveillance. Four-quadrant jumbo biopsies at every 2 cm of the entire Barrett's mucosa were obtained at each follow-up visit (every three months or six months if four consecutive quarterly follow-up endoscopic biopsy results were negative for HGD). All histological assessments were carried out at a central pathology laboratory and read by pathologists blinded to the treatment administered.

A total of 208 patients who had biopsy-proven HGD in BE were enrolled in the initial 2-year phase of the study. Of those, 199 patients were considered evaluable: 130 of 138 (94%) patients randomized to the PHOTOFRIN (porfimer sodium) PDT + OM group and 69 of 70 (99%) randomized to the OM Only group had no esophageal invasive cancer, suspicion of esophageal invasive cancer, lymph node involvement, or metastases, and had received at least one PHOTOFRIN (porfimer sodium) PDT course or one week of OM treatment, respectively. A disproportionate percentage of patients were discontinued from the OM Only group during the initial 2-year phase leaving 81 (59%) patients in the PHOTOFRIN (porfimer sodium) PDT + OM group and 21 (30%) patients in the OM Only group at the end of the 2-year phase. Consequently, a total of 102 patients who completed the initial 2-year phase were eligible for continuation into the long-term phase until completion of 5 years; of those, 48 (59%) patients from the PHOTOFRIN (porfimer sodium) PDT + OM group and 13 (62%) patients from the OM Only group consented to pursue the long-term phase until completion of 5 years. The mean age was 66 years (38 to 89 years) in the PHOTOFRIN (porfimer sodium) PDT + OM group, and 67 (36 to 88 years) in the OM Only group. The patients in both treatment groups were predominantly male (85%), Caucasian (99%), and former smokers (64%). These characteristics are typical of patients with HGD in BE. Patients randomized to the PHOTOFRIN (porfimer sodium) PDT + OM treatment received up to three courses of treatment separated by at least 90 days. Each course consisted of intravenous administration of 2.0 mg/kg of PHOTOFRIN (porfimer sodium) followed 40-50 hours later by a 630 nm laser light dose of 130 J/cm of diffuser length delivered using a centering balloon. A second laser light dose of 50 J/cm of diffuser length could be administered without a centering balloon 96-120 hours after the injection of PHOTOFRIN (porfimer sodium) for treatment of “skip” areas. Since centering balloons are up to 7 cm in length, patients with more extensive HGD were treated with two or three courses. Both the PHOTOFRIN (porfimer sodium) PDT treatment group and the control group received 20 mg of omeprazole BID to decrease reflux esophagitis. The mean duration of the follow-up period was 34 months (0-67 months) for the PHOTOFRIN (porfimer sodium) PDT + OM group and 25 months (0-65 months) for the OM Only group.

The primary efficacy endpoint was the Complete Response rate (CR3 or better) at any one of the endoscopic assessment time points. The CR3 or better response was defined as the complete ablation of HGD and referred to as a composite of the following three response levels.

1. CR1 – Complete replacement of all Barrett's metaplasia and dysplasia with normal squamous cell epithelium;
2. CR2 – Ablation of all histological grades of dysplasia, including patients with indefinite grade of dysplasia, but some areas of Barrett's epithelium still remain; and
3. CR3 – Ablation of all areas of HGD but with some areas of low-grade dysplasia with or without areas which are indefinite for dysplasia, or areas of Barrett's metaplastic epithelium.

Additional efficacy endpoints included:

1. Quality of Complete Response, which consisted of CR1 and CR2 or better.
2. Duration of CR;
3. Time to Progression to Cancer.

Table 14 presents the overall clinical response for both treatment groups in the intent-to-treat (ITT) population whose response was CR3 or better at any one of the evaluation time points. Overall, PHOTOFRIN (porfimer sodium) PDT + OM was effective in eliminating HGD in patients with BE. The proportion of responders was significantly higher in the PHOTOFRIN (porfimer sodium) PDT + OM group than in the OM Only group (77% vs. 39%, respectively; p < 0.0001).

The quality of response in the PHOTOFRIN (porfimer sodium) PDT + OM group was significantly better than that measured in the OM Only group at all response levels (p < 0.0001). Seventy-two (52%) patients in the PHOTOFRIN (porfimer sodium) PDT + OM group achieved a CR1 response as compared to only five (7%) patients in the OM Only group. Eighty-one (59%) patients in the PHOTOFRIN (porfimer sodium) PDT + OM group achieved a CR2 or better response as compared to ten (14%) patients in the OM Only group.

TABLE 14: Complete Response Rates After a Minimum Follow-Up of 24 Months in the ITT Population

At the end of the long-term phase, the median response duration was 44.6 months (95% CI: 15.0-not reached, months) in the PHOTOFRIN (porfimer sodium) PDT + OM group compared to 3.2 months (95% CI: 3.03.4, months) in the OM Only group.

At the end of the initial 2 year phase, the time to progression to cancer was significantly longer in the PHOTOFRIN (porfimer sodium) PDT + OM group compared to the OM Only group (HR=0.36 (95% CI: 0.19-0.69), a hazard ratio less than 1 favors the PHOTOFRIN (porfimer sodium) PDT + OM group). The proportion of patients' progression to cancer was lower in the PHOTOFRIN (porfimer sodium) PDT + OM group than in the OM Only group: 13% (18 of 138 patients) vs. 28% (20 of 70 patients).

Complete response was influenced by the following factors: treatment with PHOTOFRIN (porfimer sodium) PDT + OM (vs. OM Only), single focus of HGD (vs. multiple foci), and prior omeprazole intake of at least 3 months (yes vs. no). Complete response was not influenced by the duration of HGD, length of BE, nodular conditions, gender, age, smoking history, and study center's size.

Two uncontrolled, supportive studies were conducted that were physician-sponsored, single center Phase II trials. Both studies included patients that had low-grade dysplasia (LGD), HGD and early adenocarcinoma. All HGD in BE patients were treated with PHOTOFRIN (porfimer sodium) PDT and omeprazole.

The first study enrolled 99 patients (44 with HGD); the purpose of this study was to determine the required light dose to produce effective results. The second study enrolled 86 patients (42 with HGD), who were randomized to receive either PHOTOFRIN (porfimer sodium) PDT with prednisone or PHOTOFRIN (porfimer sodium) PDT without prednisone to determine whether steroid treatment would reduce the incidence and severity of esophageal strictures.

A CR3 or better response was demonstrated in 93% of 44 patients with HGD in the first study and in 95% of 42 patients with HGD in the second study after a minimum follow-up of 12 months. A CR2 or better response was achieved in 82% of patients in the first study and in 91% of patients in the second study. A CR1 response occurred in 57% of patients in the first study and in 60% of the second study. Progression to cancer during the above follow-up period occurred in 18% of patients in the first study and in 7% of patients in the second study. No reduction in the incidence or severity of esophageal strictures was found in the prednisone group in the second study.

Porfimer makes your body's tissues more sensitive to the effects of light.

Porfimer is used together with "photodynamic" laser light therapy to reduce the size of tumors in the lungs or esophagus (the tube that connects your mouth and stomach).

Porfimer may also be used for purposes not listed in this medication guide.

Porfimer sodium is a prescription medication used in combination with light therapy to treat or relieve the symptoms of certain types of cancers or pre-cancerous conditions. 

Porfimer sodium belongs to a class of medications called photosensitizing agents. These help to increase the senstivity of tumors to certain types of light, leading to the death of cancer cells.  Porfimer sodium is used specifically in combination with laser light therapy in the treatment of certain types of cancer.

This medication comes in injectable form and is injected into a vein usually during a doctor's office visit by a healthcare professional. You will visit the doctor's office again typically 1-3 days after your injection to reveive light therapy. This gives time for the medication to be absorbed into the tumor cells.

Common side effects include photosensitivity and mild constipation.

Porfimer sodium is a prescription medication used to treat or relieve the symptoms of certain types of cancers or pre-cancerous conditions, including the following:

• Treats the symptoms of esophageal cancer (cancer of the esophagus) that is completely, or almost completely, blocking the esophagus
• Treats a certain type of lung cancer called non-small cell lung cancer when you and your doctor decide that radiation and surgery should not be used
• Relieves the symptoms of non-small cell lung cancer in patients whom the airways are blocked
• High-grade dysplasia in Barrett's Esophagus. This refers to a pre-cancerous condition of the esophagus.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with porfimer sodium. See the "Porfimer sodium Precautions" section.

The side effects you experience may differ depending on which section of your body the laser light is directed at.

Common side effects of porfimer sodium (used together with laser light therapy) include the following:

• photosensitivity. Photosensitivity means your skin may be more sensitive to sunlight or bright indoor lights. Photosensitivity will most likely start occuring when the skin is exposed to laser light treatment. It can continue for several weeks after your treatment session. You should limit your time outdoors for at least 30 days after light treatment. When you are outside, wear suncreen and protective clothing such as long sleeves and a wide-brimmed hat. Symptoms of photosensitivity may include:
  • redness
  • swelling
  • blistering
• anemia. Anemia is a condition in which your body does not make enough healthy red blood cells to carry oxygen throughout your body. Symptoms of anemia may include the following:
  • tiredness
  • lack of energy or feeling sluggish   
  • headaches
  • difficulty breathing 
• constipation
• nausea
• vomiting
• pleural effusion. Pleural effusion refers to a buildup of fluid within the lungs, making it difficult to breathe.
• difficulty breathing
• difficulty swallowing
• chest pain
• fever
• coughing up blood
• narrowing of the esophagus (may lead to difficulty swallowing)
• abdominal pain
• narrowing of the airways (may lead to difficulty breathing)

This is not a complete list of porfimer sodium side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if porfimer sodium crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using porfimer sodium.

Use this medication exactly as prescribed by your doctor. It will be injected into a vein by a healthcare professional.

The dose your doctor recommends may be based on the following:

• the condition being treated
• your weight
• other medical conditions you may have
• how you respond to this medication

The recommended dose of porfimer sodium for the treatment of cancer is based on your weight. It is usually injected one time, 1-3 days before treatment with laser light therapy. You may receive additional doses of laser light for a certain amount of time after the initial injection of porfimer sodium.