PHOTOFRIN SIDE EFFECTS
SIDE EFFECTS
Overall Adverse Reaction Profile
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.
Adverse Reactions in Clinical Trials
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.
Esophageal Carcinoma
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 1 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 1: Adverse Reactions Reported in 5% or More of Patientsa with Obstructing Esophageal Cancer
| SYSTEM ORGAN CLASS/ Adverse Reaction | N=88 n (%) |
| Patients with at Least One Adverse Reaction | 84 (95) |
| BLOOD and LYMPHATIC SYSTEM DISORDERS | |
| Anemia | 28 (32) |
| CARDIAC DISORDERS | |
| Atrial fibrillation | 9 (10) |
| Cardiac failure | 6 (7) |
| Tachycardia | 5 (6) |
| GASTROINTESTINAL DISORDERS | |
| Constipation | 21 (24) |
| Nausea | 21 (24) |
| Abdominal pain | 18 (20) |
| Vomiting | 15 (17) |
| Dysphagia | 9 (10) |
| Esophageal edema | 7 (8) |
| Hematemesis | 7 (8) |
| Dyspepsia | 5 (6) |
| Esophageal stenosis | 5 (6) |
| Diarrhea | 4 (5) |
| Esophagitis | 4 (5) |
| Eructation | 4 (5) |
| Melena | 4 (5) |
| GENERAL DISORDERS & ADMINISTRATION SITE CONDITIONS | |
| Pyrexia | 27 (31) |
| Chest pain | 19 (22) |
| Pain | 19 (22) |
| Edema peripheral | 6 (7) |
| Asthenia | 5 (6) |
| Chest pain (substernal) | 4 (5) |
| Edema generalized | 4 (5) |
| INFECTIONS and INFESTATIONS | |
| Candidiasis | 8 (9) |
| Urinary tract infection | 6 (7) |
| INJURY, POISONING and PROCEDURAL COMPLICATIONS | |
| Post procedural complication | 4 (5) |
| INVESTIGATIONS | |
| Weight decreased | 8 (9) |
| METABOLISM AND NUTRITION DISORDERS | |
| Anorexia | 7 (8) |
| Dehydration | 6 (7) |
| MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS | |
| Back pain | 10 (11) |
| NEOPLASMS BENIGN, MALIGNANT and UNSPECIFIED | |
| Tumor hemorrhage | 7 (8) |
| PSYCHIATRIC DISORDERS | |
| Insomnia | 12 (14) |
| Confusional state | 7 (8) |
| Anxiety | 6 (7) |
| RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS | |
| Pleural effusion | 28 (32) |
| Dyspnoea | 18 (20) |
| Pneumonia | 16 (18) |
| Pharyngitis | 10 (11) |
| Respiratory insufficiency | 9 (10) |
| Cough | 6 (7) |
| Tracheoesophageal fistula | 5 (6) |
| SKIN and SUBCUTANEOUS TISSUE DISORDERS | |
| Photosensitivity reaction | 17 (19) |
| VASCULAR DISORDERS | |
| Hypotension | 6 (7) |
| Hypertension | 5 (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 Cancer
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.
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 2: Adverse Reactions Reported in 5% or More of Patients with Obstructing Endobronchial Cancer
| SYSTEM ORGAN CLASS/Adverse Reaction | Number (%) of Patients | |||
| Within 30 Days of Treatment | Entire Follow-up Perioda | |||
| PDT N=86 n (%) |
Nd:YAG N=86 n (%) |
PDT N=86 n (%) |
Nd:YAG N=86 n (%) |
|
| Patients with at Least One Adverse Reaction | 43(50) | 33 (38) | 62 (72) | 48 (56) |
| GASTROINTESTINAL DISORDERS | ||||
| Dyspepsia | 1(1) | 4 (5) | 2 (2) | 5 (6) |
| Constipation | 4(5) | 1 (1) | 4 (5) | 2 (2) |
| GENERAL DISORDERS and ADMINISTRATION SITE CONDITIONS | ||||
| Pyrexia | 7(8) | 7 (8) | 14 (16) | 8 (9) |
| Chest pain | 6(7) | 6 (7) | 7 (8) | 8 (9) |
| Pain | 1(1) | 4 (5) | 4 (5) | 8 (9) |
| Edema peripheral | 3(3) | 3 (3) | 4 (5) | 3 (3) |
| MUSCULOSKELETAL and CONNECTIVE TISSUE DISORDERS | ||||
| Back pain | 3(3) | 1 (1) | 3 (3) | 5 (6) |
| NERVOUS SYSTEM DISORDERS | ||||
| Dysphonia | 3(3) | 2 (2) | 4 (5) | 2 (2) |
| PSYCHIATRIC DISORDERS | ||||
| Insomnia | 4(5) | 2 (2) | 4 (5) | 3 (4) |
| Anxiety | 3(3) | 0 (0) | 5 (6) | 0 (0) |
| RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS | ||||
| Dyspnoea | 15(17) | 7 (8) | 26 (30) | 13 (15) |
| Cough | 5(6) | 8 (9) | 13 (15) | 11 (13) |
| Hemoptysis | 6(7) | 5 (6) | 14 (16) | 7 (8) |
| Pneumonia | 5(6) | 4 (5) | 10 (12) | 5 (6) |
| Bronchitis | 9(10) | 2 (2) | 9 (10) | 2 (2) |
| Productive cough | 4(5) | 5 (6) | 7 (8) | 6 (7) |
| Respiratory insufficiency | 0(0) | 0 (0) | 5 (6) | 1 (1) |
| Pleural effusion | 0(0) | 0 (0) | 4 (5) | 1 (1) |
| Pneumothorax | 0(0) | 0 (0) | 0 (0) | 4 (5) |
| SKIN and SUBCUTANEOUS TISSUE DISORDERS | ||||
| Photosensitivity reaction | 16(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 Tumors
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 3: Adverse Reactions Reported in 5% or More of Patientsa with Superficial Endobronchial Tumors
| Adverse Reaction | N=90 n (%) |
| Patients with at Least One Adverse Reaction | 44 (49) |
| RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS | |
| Exudate | 20 (22) |
| Bronchial mucus plug or bronchial obstruction | 19 (21) |
| Edema | 16 (18) |
| Bronchostenosis | 10 (11) |
| Bronchial ulceration | 8 (9) |
| Cough | 8 (9) |
| Dyspnoea | 6 (7) |
| SKIN and SUBCUTANEOUS TISSUE DISORDERS | |
| Photosensitivity reaction | 20 (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. 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%).
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 (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 4: 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
| SYSTEM ORGAN CLASS/Adverse Reaction | Treatment Groups | |||
| HGDa PHOPDT +OM N=219 n (%) |
HGDb OM Only N=69 n (%) |
Otherc PHOPDT+ OM N=99 n (%) |
Total PHOPDT +OM N=318 n (%) |
|
| Patients with at Least One Adverse Reaction | 206 (94) | 9 (13) | 97 (98) | 303 (95) |
| GASTROINTESTINAL DISORDERS | 163 (74) | 6 (9) | 83 (84) | 246 (77) |
| Nausea | 57 (26) | 1 (1) | 61 (62) | 118 (37) |
| Vomiting | 63 (29) | 1 (1) | 34 (34) | 97 (31) |
| Esophageal Strictured | 81 (37) | 0 | 33 (33) | 114 (36) |
| Esophageal Narrowinge | 71 (32) | 4 (6) | 24 (24) | 95 (30) |
| Dysphagia | 49 (22) | 0 | 26 (26) | 75 (24) |
| Constipation | 25 (11) | 1 (1) | 7 (7) | 32 (10) |
| Abdominal pain (Upper, lower, NOS) | 11 (5) | 1 (1) | 6 (6) | 17 (5) |
| Esophageal pain | 13 (6) | 0 | 9 (9) | 22 (7) |
| Dyspepsia | 10 (5) | 0 | 4 (4) | 14 (4) |
| Hiccups | 16 (7) | 0 | 1 (1) | 17 (5) |
| Odynophagia | 13 (6) | 0 | 4 (4) | 17 (5) |
| GENERAL and ADMINISTRATION SITE CONDITIONS | 110 (50) | 0 | 62 (63) | 172 (54) |
| Chest pain | 63 (29) | 0 | 37 (37) | 100 (31) |
| Pyrexia | 41 (19) | 0 | 13 (13) | 54 (17) |
| Chest discomfort | 13 (6) | 0 | 19 (19) | 32 (10) |
| Pain | 11 (5) | 0 | 7 (7) | 18 (6) |
| INJURY, POISONING and PROCEDURAL COMPLICATIONS | 24 (11) | 0 | 19 (19) | 43 (14) |
| Post procedural pain | 14 (6) | 0 | 14 (14) | 28 (9) |
| INVESTIGATIONS | 24 (11) | 0 | 11 (11) | 35 (11) |
| Weight decreased | 15 (7) | 0 | 2 (2) | 17 (5) |
| METABOLISM and NUTRITION DISORDERS | 28 (13) | 0 | 16 (16) | 44 (14) |
| Dehydration | 24 (11) | 0 | 8 (8) | 32 (10) |
| RESPIRATORY, THORACIC and MEDIASTINAL DISORDERS | 35 (16) | 0 | 18 (18) | 53 (17) |
| Pleural effusion | 22 (10) | 0 | 15 (15) | 37 (12) |
| SKIN and SUBCUTANEOUS TISSUE DISORDERS | 115 (53) | 1 (1) | 28 (28) | 143 (45) |
| Photosensitivity reaction | 102 (47) | 0 | 16 (16) | 118 (37) |
| PHO: PHOTOFRIN (porfimer sodium) a 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 Abnormalities
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.
SRC: NLM .