porfimer sodium
Dosage Form: injection, powder, for solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Photofrin
Esophageal Cancer
Photofrin® 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 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 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 is indicated for the ablation of high-grade dysplasia in Barrett's esophagus patients who do not undergo esophagectomy.
Photofrin Dosage and Administration
Photodynamic therapy (PDT) with Photofrin is a two- stage process requiring administration of both drug and light. The first stage of PDT is the intravenous injection of Photofrin at 2 mg/kg. Illumination with laser light 40–50 hours following injection with Photofrin constitutes the second stage of therapy. A second laser light application may be given 96-120 hours after injection [see Dosage and Administration (2.2)]. 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 and associated light delivery devices. PDT with Photofrin 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
Photofrin 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 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 with other drugs in the same solution. Photofrin, 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 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 is an opaque solution, in which detection of particulate matter by visual inspection is extremely difficult. Reconstituted Photofrin, 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.
Photoactivation
Esophageal Cancer
Initiate 630 nm wavelength laser light delivery to the patient 40–50 hours following injection with Photofrin. 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. No further injection of Photofrin 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 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 [see Contraindications (4)]. All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications (4)].
Endobronchial Cancer
Initiate 630 nm wavelength laser light delivery to the patient 40–50 hours following injection with Photofrin. 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. No further injection of Photofrin 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 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 [see Warnings and Precautions (5.8)].
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 [see Warnings and Precautions (5.6)]. All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel [see Contraindications (4)].
High-Grade Dysplasia (HGD) in Barrett's Esophagus (BE)
Prior to initiating treatment with Photofrin PDT, the diagnosis of HGD in BE should be confirmed by an expert GI pathologist.
Approximately 40-50 hours after Photofrin 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).
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| Treated Barrett's Mucosa Length (cm) | Fiber Optic Diffuser Length (cm) | Balloon Window Length (cm) |
| 6-7 | 9 | 7 |
| 4-5 | 7 | 5 |
| 1-3 | 5 | 3 |
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.
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| Balloon Window Length (cm) | Fiber Optic Diffuser Length (cm) | Light Intensity (mW/cm) | Required Power Output from Diffuser*(mW) | Treatment Time | |
| (sec) | (min:sec) | ||||
| 3 | 5 | 270 | 1 350 | 480 | 8:00 |
| 5 | 7 | 270 | 1 900 | 480 | 8:00 |
| 7 | 9 | 270 | 2 440 | 480 | 8:00 |
| 200 | 1 800 | 480 | 10:50 | ||
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.
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| Fiber Optic Diffuser Length (cm) | Required Power Output From Diffuser*(mW) | Treatment Time (sec) | Treatment Time (min:sec) |
| 1.0 | 400 | 125 | 2:05 |
| 1.5 | 600 | 125 | 2:05 |
| 2.0 | 800 | 125 | 2:05 |
| 2.5 | 1 000 | 125 | 2:05 |
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.
Repeat Light Application
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.
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| Procedure | Study Day | Light Delivery Devices | Treatment Intent |
| Photofrin Injection | Day 1 | NA | Uptake of photosensitizer |
| Laser Light Application | Day 3* | 3, 5 or 7 cm balloon (130 J/cm) | Photoactivation |
| Laser Light Application(Optional) | Day 5 | Short (≤2.5 cm) fiber optic diffuser (50 J/cm) | Treatment of "skip" areas only |
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.
Dosage Forms and Strengths
75 mg vial
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.
Warnings and Precautions
Esophageal Cancer
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.
Endobronchial Cancer
Patients should be assessed for the possibility that a tumor may be eroding into a pulmonary blood vessel [see Contraindications (4)]. 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.
High-Grade Dysplasia (HGD) in Barrett's Esophagus (BE)
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).
Photosensitivity
All patients who receive Photofrin will be photosensitive and must observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental lamps, operating room lamps, unshaded light bulbs at close proximity, etc.) for 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 photosensibility and will be of no value in protecting against induced photosensitivity reactions caused by visible light.
Ocular Sensitivity
Ocular discomfort, commonly described as sensitivity to sun, bright lights, or car headlights, has been reported in patients who received Photofrin. For 30 days, when outdoors, patients should wear dark sunglasses which have an average white light transmittance of <4%.
Use Before or After Radiotherapy
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.
Chest Pain
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.
Respiratory Distress
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
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 and Renal Impairment
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.
| Number of Dilations | Number of Patients with Strictures N=114 | Percentage of Patients with Strictures |
| 1 − 2 Dilations | 32 | 28% |
| 3 − 5 Dilations | 32 | 28% |
| 6 − 10 Dilations | 24 | 21% |
| >10 Dilations | 26 | 23% |
Adverse Reactions
Overall Adverse Reaction Profile
Systemically 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.
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 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.
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| 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) |
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 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 [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.
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| Number (%) of Patients | |||||||||
| SYSTEM ORGAN CLASS/ | Within 30 Days of Treatment | Entire Follow-up Period* | |||||||
| Adverse Reaction | 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) | |||||||
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