Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 22 November 2019

Indication(s)

1INDICATIONS AND USAGE1.1PHOTOFRIN is a photodynamic therapy drug indicated for:Esophageal Cancer (1.1)• 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 (1.2)• Treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated• Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLCHigh-Grade Dysplasia in Barrett’s Esophagus (1.3)• Ablation of high-grade dysplasia (HGD) in Barrett’s esophagus (BE) patients who do not undergo esophagectomy

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Advisory information

contraindications
4 CONTRAINDICATIONS• PHOTOFRIN 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 and laser light treatment.• PDT is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter.
Adverse reactions
6 ADVERSE REACTIONS 6.1 Overall Adverse Reaction ProfileSystemically induced effects of photodynamic therapy (PDT) with PHOTOFRIN consist of photosensitivity and mild constipation. All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid sunlight and bright indoor light [see Warnings and Precautions (5.4)]. 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. 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 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 PDT for HGD in BE. The patient suffered from a PDT response with development of a deep esophageal ulcer. Within two months post PDT, the patient noted difficulty with his distant vision. A thorough eye examination revealed a change in the refractive error that later progressed to cataracts in both eyes. Both of his parents had a history of cataracts in their 70s. Whether PHOTOFRIN directly caused or accelerated a familial underlying condition is unknown.6.2 Adverse Reactions in Clinical TrialsBecause 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.Esophageal CarcinomaThe following adverse reactions were reported over the entire follow-up period in at least 5% of patients treated with PHOTOFRIN PDT, who had completely or partially obstructing esophageal cancer. Table 6 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse reactions to PDT with PHOTOFRIN is uncertain.TABLE 6. Adverse Reactions Reported in 5% or More of Patientsa with Obstructing Esophageal CancerSYSTEM ORGAN CLASS/Adverse ReactionN=88n (%)Patients with at Least One Adverse Reaction84 (95)BLOOD and LYMPHATIC SYSTEM DISORDERSAnemia28 (32)CARDIAC DISORDERSAtrial fibrillation9 (10)Cardiac failure6 (7)Tachycardia5 (6)GASTROINTESTINAL DISORDERSConstipation21 (24)Nausea21 (24)Abdominal pain18 (20)Vomiting15 (17)Dysphagia9 (10)Esophageal edema7 (8)Hematemesis7 (8)Dyspepsia5 (6)Esophageal stenosis5 (6)Diarrhea4 (5)Esophagitis4 (5)Eructation4 (5) Melena4 (5)GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONSPyrexia27 (31)Chest pain19 (22)Pain19 (22)Edema peripheral6 (7)Asthenia5 (6)Chest pain (substernal)4 (5)Edema generalized4 (5)INFECTIONS and INFESTATIONSCandidiasis8 (9)Urinary tract infection6 (7)INJURY, POISONING and PROCEDURAL COMPLICATIONSPost procedural complication4 (5)INVESTIGATIONSWeight decreased8 (9)METABOLISM AND NUTRITION DISORDERSAnorexia7 (8)Dehydration6 (7)MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERSBack pain10 (11)NEOPLASMS BENIGN, MALIGNANT and UNSPECIFIEDTumor hemorrhage7 (8)PSYCHIATRIC DISORDERSInsomnia12 (14)Confusional state7 (8)Anxiety6 (7)RESPIRATORY, THORACIC and MEDIASTINAL DISORDERSPleural effusion28 (32)Dyspnoea18 (20)Pneumonia16 (18)Pharyngitis10 (11)Respiratory insufficiency9 (10)Cough6 (7)Tracheoesophageal fistula5 (6)SKIN and SUBCUTANEOUS TISSUE DISORDERSPhotosensitivity reaction17 (19)VASCULAR DISORDERSHypotension6 (7)Hypertension5 (6)a Based on adverse reactions reported at any time during the entire period of follow-up.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.Obstructing Endobronchial CancerTable 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 PDT or Nd:YAG. These data are basedon 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 [see Warnings and Precautions (5.8)].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 (4) and Warnings and Precautions (5.2).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 CancerSYSTEM ORGANCLASS/ Adverse ReactionNumber (%) of PatientsWithin 30 Days of TreatmentEntire Follow-up PeriodaPDTNd:YAGPDTNd:YAGN=86n (%)N=86n (%)N=86n (%)N=86n (%)Patients with at Least One Adverse Reaction43 (50)33 (38)62 (72) 48 (56)GASTROINTESTINAL DISORDERSDyspepsia1 (1)4 (5)2 (2)5 (6)Constipation4 (5)1 (1)4 (5)2 (2)GENERAL DISORDERS and ADMINISTRATIONSITE CONDITIONSPyrexia7 (8)7 (8)14 (16)8 (9)Chest pain6 (7)6 (7)7 (8)8 (9)Pain1 (1)4 (5)4 (5)8 (9)Edema peripheral3 (3)3 (3)4 (5)3 (3)MUSCULOSKELETAL and CONNECTIVETISSUE DISORDERSBack pain3 (3)1(1)3 (3)5 (6)NERVOUS SYSTEMDISORDERSDysphonia3 (3)2 (2)4 (5)2 (2)PSYCHIATRICDISORDERSInsomnia4 (5)2 (2)4 (5)3 (4)Anxiety3 (3)0 (0)5 (6)0 (0)RESPIRATORY, THORACIC andMEDIASTINAL DISORDERSDyspnoea15 (17)7 (8)26 (30)13 (15)Cough5 (6)8 (9)13 (15)11 (13)Hemoptysis6 (7)5 (6)14 (16)7 (8)Pneumonia5 (6)4 (5)10 (12)5 (6)Bronchitis9 (10)2 (2)9 (10)2 (2)Productive cough4 (5)5 (6)7 (8)6 (7)Respiratory insufficiency0 (0)0 (0)5 (6)1 (1)Pleural effusion0 (0)0 (0)4 (5)1 (1)Pneumothorax0 (0)0 (0)0 (0)4 (5)SKIN and SUBCUTANEOUS TISSUE DISORDERSPhotosensitivity reaction16 (19)0 (0)18 (21)0 (0)a Follow-up was 33% longer for the PDT group than for the Nd:YAG group, introducing a bias against PDT when adverse reactions are compared for the entire follow-up period.Superficial Endobronchial TumorsThe 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 Adverse ReactionN=90n (%)Patients with at Least One Adverse Reaction44 (49)RESPIRATORY, THORACIC and MEDIASTINAL DISORDERSExudate20 (22)Bronchial mucus plug or bronchial obstruction19 (21)Edema16 (18)Bronchostenosis10 (11)Bronchial ulceration8 (9)Cough8 (9)Dyspnoea6 (7)SKIN and SUBCUTANEOUS TISSUE DISORDERSPhotosensitivity reaction20 (22)a Based on adverse reactions reported at any time during the entire period of follow-up.In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse 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 [see Warnings and Precautions (5.8)]. 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 [see Warnings and Precautions (5.2)]. 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%). High-Grade Dysplasia (HGD) in Barrett’s Esophagus (BE)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 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 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 PDT + OM group were 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 [see Warnings and Precautions (5.9)].TABLE 9. Adverse Reactions Reported in ≥5% of Patients Treated with PHOTOFRIN PDT in the Clinical Trials on High-Grade Dysplasia in Barrett・s EsophagusTreatment GroupsSYSTEM ORGANCLASS/Adverse ReactionHGDa PHOPDT+OM N=219n (%)HGDb OM OnlyN=69n (%)Otherc PHOPDT+OM N=99n (%)Total PHOPDT+OM N=318n (%)Patients with at Least OneAdverse Reaction206 (94)9 (13)97 (98)303 (95)GASTROINTESTINAL DISORDERS163 (74)6 (9)83 (84)246 (77)Nausea57 (26)1 (1)61 (62)118 (37)Vomiting63 (29)1 (1)34 (34)97 (31)Esophageal Strictured81 (37)033 (33)114 (36)Esophageal Narrowinge71 (32)4 (6)24 (24)95 (30)Dysphagia49 (22)026 (26)75 (24)Constipation25 (11)1 (1)7 (7)32 (10)Abdominal pain(Upper, lower, NOS)11 (5)1 (1)6 (6)17 (5)Esophageal pain13 (6)09 (9)22 (7)Dyspepsia10 (5)04 (4)14 (4)Hiccups16 (7)01 (1)17 (5) Odynophagia13 (6)04 (4)17 (5)GENERAL and ADMINISTRATION SITE CONDITIONS110 (50)062 (63)172 (54)Chest pain63 (29)037 (37)100 (31)Pyrexia41 (19)013 (13)54 (17)Chest discomfort13 (6)019 (19)32 (10)Pain11 (5)07 (7)18 (6)INJURY, POISONING and PROCEDURAL COMPLICATIONS24 (11)019 (19)43 (14)Post procedural pain14 (6)014 (14)28 (9)INVESTIGATIONS24 (11)011 (11)35 (11)Weight decreased15 (7)02 (2)17 (5)METABOLISM and NUTRITIONDISORDERS28 (13)016 (16)44 (14)Dehydration24 (11)08 (8)32 (10)RESPIRATORY, THORACIC andMEDIASTINAL DISORDERS35 (16)018 (18)53 (17)Pleural effusion22 (10)015 (15)37 (12)SKIN and SUBCUTANEOUSTISSUE DISORDERS115 (53)1 (1)28 (28)143 (45)Photosensitivity reaction102 (47)016 (16)118 (37)PHO: PHOTOFRINa Includes all HGD patients in the Safety population from PHO BAR 02 (N=133), TCSC 93-07 (N=44), and TCSC 96-01 (N=42).b Includes all HGD patients in the Safety population from PHO BAR 02 (N=69).c Includes patients with Barrett’s metaplasia, indefinite dysplasia, LGD, and adenocarcinoma at baseline in the Safety population from TCSC 93-07 (N=55) and TCSC 96-01 (N=44).d Esophageal stricture was defined as a dilated esophageal stenosis.e Esophageal narrowing was defined as an undilated esophageal stenosis.NOTE: Adverse reactions classified using MedDRA 5.0 dictionary with the exception of esophageal stricture and esophageal narrowing.Laboratory AbnormalitiesIn patients with esophageal cancer, PDT with PHOTOFRIN may result in anemia due to tumor bleeding. No significant effects were observed for other parameters in patients with endobronchial carcinoma or with HGD in BE.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of PHOTOFRIN with PDT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Infusion reactions: Infusion reactions including urticaria, bradycardia, hypotension, dizziness, and hypertension

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION PHOTOFRIN (2.1)• PHOTOFRIN administration: 2 mg/kg intravenousPhotoactivation (2.2)Esophageal Cancer• Laser light dose of 300 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, 96-120 hours after initial injectionEndobronchial Cancer• Laser light dose of 200 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, after gentle debridement of residual tumor 96-120 hours after initial injectionHigh-Grade Dysplasia in Barrett’s Esophagus• Laser light dose of 130 J/cm of fiber optic diffuser length 40–50 hours following injection with PHOTOFRIN; repeated, if needed, with a light dose of 50 J/cm of fiber optic diffuser length 96-120 hours after initial injection
Use in special populations
8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy 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 in pregnant women. PHOTOFRIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether PHOTOFRIN 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, a decision should be made whether not to treat or to discontinue breastfeeding, taking into account the importance of the drug to the mother.8.4 Pediatric UseSafety and effectiveness in children have not been established.8.5 Geriatric UseApproximately 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.

Interactions

7 DRUG INTERACTIONS7.1 Other Photosensitizing AgentsThere 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.7.2 Concomitant TherapyPhotodynamic therapy (PDT) with PHOTOFRIN 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, ß-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.

More information

Category Value
Authorisation number NDA020451
Agency product number Y3834SIK5F
Orphan designation No
Product NDC 76128-155
Date Last Revised 05-09-2019
Type HUMAN PRESCRIPTION DRUG
RXCUI 242166
Marketing authorisation holder Pinnacle Biologics, Inc.