Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4153
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PHOTOFRIN (Injection, Powder, For Solution)
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Photodynamic therapy 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, preceded by gentle debridement of residual tumor (see Administration of Laser Light). In clinical studies on esophageal and endobronchial cancers, 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 in Barrett's esophagus using photodynamic therapy with PHOTOFRIN and associated light delivery devices. For the treatment of esophageal and 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. Before each course of treatment, patients with esophageal cancer should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula . In patients with endobronchial lesions who have recentlyundergone radiotherapy, sufficient time (approximately 4 weeks) should be allowed between the therapies to ensure that the acute inflammation produced
by radiotherapy has subsided prior to PDT . All patients should be evaluated for the possibility that the tumor may be eroding into a major blood vessel . For the ablation of high-grade dysplasia in Barrett's esophagus, 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 high-grade dysplasia, 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.<br/>PHOTOFRIN Administration: PHOTOFRIN should be administered as a single slow intravenous injection over 3 to 5 minutes at 2 mg/kg 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 therange 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.<br/>Administration of Laser Light: Esophageal and 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 treatment effect. 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. Diffuser length should be sized to avoid exposure of nonmalignant tissue to light and to prevent overlapping of previously treated malignant tissue. Photoactivation of PHOTOFRIN is controlled by the total light dose delivered: Refer to the OPTIGUIDE���instructions for use for complete instructions concerning the fiber optic diffuser. High-Grade Dysplasia (HGD) in Barrett's Esophagus (BE) 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 11). Light Doses: 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 pivotal clinical study, acceptable light intensity for the balloon/diffuser combinations range from 200-270 mW/cm of diffuser. To calculate the light dose, the following specific light dosimetry equation applies for all fiber optic diffusers: Table 12 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. 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 pre-treatment and treatment of skipped areas, care should be taken to minimize exposure to normal tissue as it is also sensitized. Table 13 lists appropriate fiber opticpower outputs and treatment times using a light intensity of 400 mW/cm. A maximum of 7 cm of esophageal mucosa is treated at the first light session using an appropriate size of centering balloon and fiber optic diffuser (Table 11). Whenever possible, the segment selected for the first light application should contain all the areas of HGD. Also, whenever possible, the Barrett's esophagus (BE) segment selected for the first light application shouldinclude 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.<br/>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 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 14.
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Pharmacology: The cytotoxic and antitumor actions of PHOTOFRIN are light and oxygen dependent. Photodynamic therapy with PHOTOFRIN is a two-stage process. The first stage is the intravenous injection of PHOTOFRIN. 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 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 and selective delivery of light. Cellular damage caused by PHOTOFRIN PDT is a consequence of the propagation of radical reactions. Radical initiation may occur after PHOTOFRIN absorbs light to form a porphyrin excited state. Spin transfer from PHOTOFRIN 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 Arelease. The laser treatment induces a photochemical, not a thermal, effect. The necrotic reaction and associated inflammatory responses may evolve over several days.<br/>Pharmacokinetics: Following a 2 mg/kg dose of porfimer sodium to 4 male cancer patients, the average peak plasma concentration was 15��3 mcg/mL, the elimination half-life was 250��285 hours, the steady-state volume of distribution was 0.49��0.28 L/kg, and the total plasma clearance was 0.051��0.035 mL/min/kg. The mean plasma concentration at 48 hours was 2.6��0.4 mcg/mL. The influence of impaired hepatic function on PHOTOFRIN disposition has not been evaluated. PHOTOFRIN 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 pharmacokinetics of PHOTOFRIN was also studied in 24 healthy subjects (12 men and 12 women) who received a single dose of 2 mg/kg PHOTOFRIN given via the intravenous route. The serum decay was bi-exponential, with a slow distribution phase and a very long elimination phase. The elimination half-life was 415��104 hours (17��4.3 days). The Cwas determined to be 40��11.6 mcg/mL and AUCwas 2400��552 mcg���hour/mL. Women had a lower Cand a higher AUC. The clinical significance of these differences is unknown. The Twas approximately 1.5 hours in women and 0.17 hours in men. At the time of intended photoactivation 40-50 hours after injection, the pharmacokinetic profiles of PHOTOFRIN in men and women were similar.
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PHOTOFRIN (porfimer sodium) for Injection is supplied as a freeze-dried cake or powder as follows: NDC 58914-155-75���75 mg vial PHOTOFRIN freeze-dried cake or powder should be stored at Controlled Room Temperature 20���25��C (68���77��F) [see USP]. Spills and Disposal Spills of PHOTOFRIN should be wiped up with a damp cloth. Skin and eye contact should be avoided due to the potential for photosensitivity reactions upon exposure to light; use of rubber gloves and eye protection is recommended. All contaminated materials should be disposed of in a polyethylene bag in a manner consistent with local regulations. Accidental Exposure PHOTOFRIN is neither a primary ocular irritant nor a primary dermal irritant. However, because of its potential to induce photosensitivity, PHOTOFRIN might be an eye and/or skin irritant in the presence of bright light. It is important to avoid contact with the eyes and skin during preparation and/or administration. As with therapeutic overdosage, any overexposed person must be protected from bright light. Manufactured by WYETH-AYERST LEDERLE PARENTERALS, INC. Carolina, Puerto Rico 00987 for Axcan Scandipharm Inc. Birmingham, AL 35242 For inquiries call Axcan Scandipharm Inc. at: 1-800-742-6706 September 29, 2005
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porfimer sodium
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PHOTOFRIN (Injection, Powder, For Solution)
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Systemically induced effects associated with 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 . Photosensitivity reactions occurred in approximately 20% of cancer patients and in 68% 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, itching, 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 nodules, increased wrinkles and increased skin fragility. These manifestations may be attributable to a pseudoporphyria state (temporary drug-induced cutaneous porphyria). Most toxicities associated with 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 following the use of PDT with PHOTOFRIN in patients with overtly disseminated intraperitoneal malignancies. Fluid imbalance is an expected PDT treatment-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.<br/>Esophageal Carcinoma: The following adverse events 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 7 presents data from 88 patients who received the currently marketed formulation. The relationship of many of these adverse events to PDT with PHOTOFRIN is uncertain. Location of the tumor was a prognostic factor for three adverse events: 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 events 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 events have included angina pectoris, bradycardia, myocardial infarction, sick sinus syndrome, and supraventricular tachycardia. Respiratory events 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 events to the administration of light wassuggestive of mediastinal inflammation in some patients. Vision-related events of abnormal vision, diplopia, eye pain and photophobia have been reported.<br/>Obstructing Endobronchial Cancer: Table 8 presents adverse events 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 events caused by these acute acting therapies would occur within 30 days of treatment, Table 8 presents those events occurring within 30 days of a treatment procedure, as well asthose 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 event 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 fever, bronchitis, chest pain, and dyspnea. The incidences of bronchitis and dyspnea 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 events usually resolved within 10 days with antibiotic therapy. Treatment-related worsening of dyspnea is generally transient and self-limiting. Debridement of the treated area is mandatory to remove exudate and necrotic tissue. Life-threatening respiratory insufficiency likely due to therapy occurred in 3% of PDT-treated patients and 2% of Nd:YAG-treated patients . There was a trend toward a higher rate of fatal massive hemoptysis (FMH) occurring on the PDT arm (10%) versus the Nd:YAG arm (5%), however, the rate of FMH occurring within 30 days of treatment was the same for PDT and Nd:YAG (4% total events, 3% treatment-associated events). Patients who have received radiation therapy have a higher incidence of FMH after treatment with PDT and after other forms of local therapy than patients who have not received radiation therapy, but analyses suggest that this increased risk may be due to associated prognostic factors such as having a centrally located tumor. The incidence of FMH in patients previously treated with radiotherapy was 21% (6/29) in the PDT group and 10% (3/29) in the Nd:YAG group. In patients with no prior radiotherapy,
the overall incidence of FMH was less than 1%. Characteristics of patients at high risk for FMH are described in WARNINGS and CONTRAINDICATIONS. Other serious or notable adverse events 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.<br/>Superficial Endobronchial Tumors: The following adverse events 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. In patients with superficial endobronchial tumors, 44 of 90 patients (49%) experienced an adverse event, 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 dyspnea: 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%).<br/>High-Grade Dysplasia (HGD) in Barrett's Esophagus (BE): Table 10 presents adverse events that were reported, regardless of the relationship to treatment, 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 treatment-associated adverse events 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 (69%) or moderate (24%) intensity. Almost all (98%) of the photosensitivity reactions were considered to be associated with treatment. 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, itching, burning sensation, and feeling of heat. The majority of esophageal stenosis and strictures reported in the PHOTOFRIN PDT + OM group were of mild (55%) or moderate (37%) 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 associated with treatment. Most esophageal strictures were manageable through dilations . Laboratory Abnormalities In 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.
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Photodynamic therapy with PHOTOFRIN is indicated for:
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PHOTOFRIN
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