Photofrin (Porfimer Sodium)

PHOTOFRIN®

Ligand

Porfimer Sodium

Antineoplastic Photosensitizing Agent

Action And Clinical Pharmacology: Pharmacodynamics: The cytotoxic and antitumor actions of porfimer sodium are light and oxygen dependent. Photodynamic therapy (PDT) with porfimer sodium is a 2 stage process. The first stage is the i.v. injection of porfimer sodium. Clearance from a variety of tissues occurs over 40 to 72 hours; but tumor, skin, and organs of the reticuloendothelial system (including liver and spleen) retain porfimer sodium for a longer period. Illumination with 630 nm wavelength laser light constitutes the second and final stage of therapy. Tumor selectivity in treatment occurs through a combination of selective retention of porfimer sodium and selective delivery of light. PDT-induced cytotoxicity may be due to free radical (superoxide or hydroxyl) generation and the production of singlet oxygen via energy transfer from light to triplet oxygen. Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. The laser treatment induces a photochemical, not a thermal effect.

Pharmacokinetics: A pharmacokinetic study was performed on 12 lung cancer patients given 2 mg/kg of porfimer sodium via the i.v. route. Samples of plasma were obtained up to 56 days post injection. Porfimer sodium was slowly cleared from the body with a mean apparent elimination half-life of 21.5 days (range 11 to 28 days).

No special precautions in renally impaired patients are necessary because excretion is primarily via the fecal route. The influence of impaired hepatic function on porfimer sodium disposition has not been evaluated.

Porfimer sodium was approximately 90% protein bound in human serum, studied in vitro. The binding was independent of concentration over the concentration range of 20 to 100 µg/mL.

Clinical Studies: Papillary Bladder Cancer: A Phase III, multicentre, randomized, open-label study was performed in patients with superficial papillary transitional cell carcinoma of the urinary bladder, stage TaG1 with frequently recurring disease or stages TaG2, T1G1-3. Following transurethral resection, patients were randomized to either single doses of porfimer sodium plus light or an observation control arm and the time to tumor recurrence was compared between groups. Efficacy analysis was performed on 30 patients. The median follow-up time for all randomized patients was 456 days. In the porfimer sodium group, 9 of 17 patients (53%) recurred compared with 10 of 13 patients (77%) in the observation group. The median time to tumor recurrence for patients who received porfimer sodium was 379 days versus 93 days for the observed group.

Esophageal Cancer: A Phase III, multicentre, randomized, open-label clinical trial was conducted comparing PDT with porfimer sodium and controlled uniform laser light versus thermal ablation therapy using the Nd: YAG laser for the removal of tumor mass and subsequent local palliation of dysphagia in 236 patients with partially obstructing esophageal carcinoma. Each course of PDT with porfimer sodium consisted of 1 injection of the drug followed by up to 2 laser light applications. A maximum of 3 courses of PDT with porfimer sodium was allowed. Repeat Nd:YAG laser sessions were given until maximal anticipated tumor debulking and palliation of dysphagia were achieved. Thus, a course of Nd: YAG laser therapy consisted of multiple laser application sessions. An unlimited number of Nd: YAG courses was permitted. Efficacy results after 1 course of therapy, based on all 236 randomized patients, are provided in Table I. Based on all courses, 9 PDT-treated patients and 2 Nd: YAG-treated patients had no visible evidence of tumor and were considered to be in complete response (CR). In 6 PDT-treated patients and 2 Nd: YAG-treated patients, CR was verified by pathology.

In addition, PDT with porfimer sodium was utilized in a Phase III, multicentre, single-arm study in 19 patients with completely obstructing esophageal carcinoma using the same schedule as above. Based on Month 1 assessments for Course 1 for all 19 patients enrolled, 42% of patients showed improvement in dysphagia grade, 32% of patients achieved partial objective tumor responses (PR), and median time to palliation failure was 30 days. Based on all courses, three patients achieved a complete tumor response; one of these was verified by pathology.

Indications And Clinical Uses: Papillary Bladder Cancer: Photodynamic therapy (PDT) with porfimer sodium is indicated following transurethral resection in patients with recurring superficial papillary bladder cancer as second-line treatment for thsoe who have failed a standard intravesical therapy.

Esophageal Cancer: Photodynamic therapy with porfimer sodium is indicated for the reduction of obstruction and palliation of dysphagia in patients with completely or partially obstructing esophageal cancer.

Contra-Indications: Patients with porphyria or in patients with known allergies to porphyrins.

Papillary Bladder Cancer: Patients with prior total bladder irradiation, or with a functional bladder capacity less than 200 mL, must not be treated with PDT to the bladder; there is the possibility of irreversible bladder contracture from increased fibrosis.

Patients with coexisting bladder tumors of stage greater than T1, who have invasive cancer, must not receive PDT.

Esophageal Cancer: PDT is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula.

Manufacturers’ Warnings In Clinical States: Caution: Porfimer sodium is an injectable photosensitizing drug for use in photodynamic therapy (PDT) for treatment of cancer. PDT is a photochemical process requiring specific lasers and fiber optics. PDT with porfimer sodium should only be used by physicians trained in the treatment of cancer using PDT with porfimer sodium and only in those facilities properly equipped for the procedure. Porfimer sodium will only be distributed to institutions with proper facilities and physicians with proper training. Porfimer sodium may cause residual photosensitivity for 30 days or more resulting in erythema and blistering of the skin where it is exposed to sunlight or brightly focused indoor light (e.g., from examination lamps, operating room lamps, floodlights, halogen lamps, etc.).

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 PDT is not recommended.

Tumors eroding into a major blood vessel should not be treated with PDT.

Precautions: All patients who receive porfimer sodium will be photosensitive for 30 days or more and must observe precautions to avoid exposure of eyes and skin to direct sunlight or brightly focused indoor light (from examination lamps, operating room lamps, floodlights, halogen lamps, etc.) UV sunscreens are of no value because photoactivation is caused by visible light. When outdoors, patients should wear dark sunglasses. The patient should not be kept in a completely darkened room during this period of time, since photobleaching due to exposure to low light levels such as ambient room light may be important in decreasing the period of photosensitivity. After 30 days, patients may expose a small area of skin (finger, dorsum of hand) to the sun for 5 minutes to test for residual photosensitivity. If significant erythema or blistering results, the patient should continue precautions against sun and bright light exposure for another 2 weeks before retesting the effects of limited sun exposure.

As a result of PDT treatment in esophageal cancer, 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.

Drug Interactions: There is no clinical information concerning drug-drug interactions involving porfimer sodium. However, it is possible that concomitant use of other agents known to produce photosensitivity reactions (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, and griseofulvin) would have the potential to increase the photosensitivity reaction.

Since the basic effects of PDT are thought to involve vasoconstriction and platelet activation and aggregation at the site of treatment, as well as the generation of active oxygen species, treatments which alter blood flow or availability of oxygen would be expected to affect the effectiveness of PDT. Data from animal models and in vitro tissue culture studies suggest the following: thromboxane A2 receptor antagonists, thromboxane synthetase inhibitors, drugs which quench active oxygen species, and compounds which react with hydroxyl radicals, including dimethyl sulfoxide (DMSO), ethanol, formate, and mannitol, have been shown to decrease the effectiveness of PDT. Steroids administered 24 to 48 hours following PDT enhanced antitumor effects, whereas steroids administered concomitantly inhibited the PDT effect. Animal or in vitro studies involving combination therapy with PDT and standard antineoplastic agents (including doxorubicin, mitomycin C, and BCG for bladder cancer, and mitomycin C in a colon cancer cell line) resulted in an increase in effectiveness compared with single therapies. Similarly, combinations of PDT with porfimer sodium and different photosensitizers with different biodistribution properties (including tetraphenylporphine sulfonate) resulted in enhanced tumor eradication in a murine mammary tumor model.

Pregnancy: There are no adequate and well controlled studies in pregnant humans. Porfimer sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing potential should practice an effective method of contraception during therapy, and have a pretreatment pregnancy test performed.

Lactation: Whether the drug is excreted in human milk is unknown, therefore, women receiving porfimer sodium must not breast-feed.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: The skin of all patients who receive porfimer sodium, will be photosensitive for 30 days or more (see Precautions). Photosensitivity reactions are avoidable through proper patient education. Reactions that do occur are most often limited to mild or moderate severity. The incidence of photosensitivity across all indications in clinical studies was 20%; this incidence was highest (40%) in patients with papillary bladder cancer whose activity was less impeded by their malignancy or concurrent illness. Ocular discomfort (sensitivity to sun, bright lights or car headlights) has also been reported.

The toxicities associated with PDT across all indications are primarily local, in the immediate area that received laser light, and sometimes extending into adjacent tissues. The local/regional reactions are consistent with an inflammatory reaction induced by the photodynamic effect (see below for specific reactions by indication). The only other known systemic reaction (besides photosensitivity) is constipation.

Papillary Bladder Cancer: Patients with papillary bladder cancer may develop transient (up to several weeks) irritative bladder symptoms after photodynamic therapy with porfimer sodium. This post-PDT response, thought to be due to inflammation, includes increased micturition frequency (60% of patients), hematuria (56%), dysuria (36%), urgency (32%) and suprapubic pain (20%). Additional common urinary symptoms observed were strangury (32%), genital edema (24%), urinary incontinence (20%) and nocturia (12%) and urinary tract infection (12%). Transient reduction in bladder capacity may occur; irreversible bladder contracture occurred in 20% of patients, a median of 99 days post PDT.

Additional adverse reactions which occurred in ³10% of patients with papillary bladder cancer were anxiety (12%), insomnia (20%), peripheral edema (16%), nonspecific pain (12%), nausea (12%) and constipation (12%).

Esophageal Cancer: In a clinical trial involving patients with partially-obstructing esophageal cancer PDT with porfimer sodium was compared to surgical ablation with the Nd:YAG laser. Adverse events that occurred significantly more often in PDT-treated than in Nd: YAG-treated patients (besides photosensitivity) were fever (33% versus 10%, respectively), pleural effusion (28% versus 6%), respiratory insufficiency (10% versus 1%), anemia (26% versus 12%), and constipation (23% versus 9%). With the exception of anemia and respiratory insufficiency, these reactions were generally mild or moderate in severity and easily managed. Anemia was manageable by transfusion and was more common in patients with large tumors (>10 cm) and in tumors in the lower more vascular area of the esophagus. The etiology of respiratory insufficiency is unclear. Fever and pleural effusion, as well as pain (22% versus 20%), esophageal edema (6% versus 2%) and atrial fibrillation (8% versus 4%) are thought to be manifestations of a local/regional inflammatory reaction. Esophageal edema occurred more frequently when the tumor was located in the upper third of the esophagus; atrial fibrillation was more likely to occur when the tumor was in the middle of the esophagus.

Other adverse reactions which occurred commonly (>10% of either group of patients) in both the PDT group and the ND:YAG laser group were insomnia (14% versus 9%), abdominal pain (19% versus 11%), hematemesis (11% versus 7%), nausea (21% versus 15%), vomiting (16% versus 8%), dyspnea (18% versus 15%), pneumonia (16% versus 13%) and chest pain (23% versus 19%). Some of these adverse events reflect symptoms of esophageal cancer or concurrent conditions such as respiratory disease, although they may have been exacerbated by either treatment.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no information on overdosage situations involving porfimer sodium. Effects of overdosage on the duration of photosensitivity are unknown. Laser treatment should not be given if an overdose of porfimer sodium is administered. In the event of an overdose, patients should protect their eyes and skin from direct sunlight or bright indoor lights for 30 days. At this time, patients should test for residual photosensitivity (see Precautions). Porfimer sodium is not dialyzable.

Overdose of Laser Light Following Porfimer Sodium Injection: Papillary Bladder Cancer: Whole bladder photoradiation at light levels exceeding the recommended dose may significantly increase adverse urinary symptoms seen after PDT treatment, and may create irreversible bladder contracture in some patients.

Esophageal Cancer: There is no information on overdose of laser light following porfimer sodium injection in patients with esophageal carcinoma.

Dosage And Administration: Photodynamic therapy (PDT) with porfimer sodium is a 2 stage process requiring administration of both drug and light. Physicians should be trained in the safe and efficacious treatment of papillary bladder or esophageal cancer using photodynamic therapy with porfimer sodium and associated light delivery devices. The first stage of PDT is the i.v. injection of porfimer sodium at 2 mg/kg. The second stage of therapy is illumination with laser light 40 to 50 hours following injection with porfimer sodium. In patients with bladder cancer, no further doses of drug or light should be administered due to increased risk of bladder contracture; for esophageal cancer, patients may receive a second laser light application 96 to 120 hours after drug administration, and, if needed, up to 2 more courses of drug and light may be given, with each injection separated by a minimum of 30 days.

Porfimer Sodium Administration: Porfimer sodium should be reconstituted according to the directions given under Reconstitution, and administered as a single slow i.v. injection over 3 to 5 minutes at 2 mg/kg body weight. As with all i.v. injections, care should be taken to prevent extravasation at the injection site. If extravasation occurs, the area should be protected from light for a minimum of 30 days. There is no known benefit from injecting the extravasation site with another substance.

Photoactivation of Porfimer Sodium: Uniform and complete light delivery to the tumor mass is essential for activation of porfimer sodium. Light from a laser is delivered to the tumor via Optiguide Fiber Optic Diffusers, designed specifically for use in photodynamic therapy. While there are numerous lasers available for medical applications, the use of the Optiguide Fiber Optics for photoactivation of porfimer sodium requires an accepted laser operating at a wavelength of 630±3 nm, and producing a stable power output. The choice of the type and size of the fiber optic diffuser tip will depend on the tumor location and size.

Photoactivation of porfimer sodium is controlled by the total energy delivered to the tumor site. This is determined by the power delivered from the Optiguide Fiber Optic to the tumor site and the total treatment time.

The Optiguide Package insert provides details relating to the assembly, function and operation of the fiber optic light delivery system, including accepted laser light sources, and should be used in conjunction with the information presented for each indication below.

Superficial Papillary Bladder Cancer: Whole bladder treatment will require a total light delivery of 15 joules/cm using the spherical diffuser. Approximately 40 to 50 hours after injection with porfimer sodium, the patient should be anesthetized and the bladder distended with a volume of saline or water sufficient to smooth mucosal folds, without compromising circulation. This “treatment volume” should be within 50 to 75% of the bladder’s functional capacity, as measured by cystometrography.

Referring to the Optiguide Package Insert, attach the Optiguide Model DSPH spherical diffuser to an aceptable laser light source. To minimize the treatment time and thus the period of bladder distention, the total power output at the fiber optic tip should be at least 1.25 watts but less than the maximum power specification for the fiber optic.

The cystocope should be positioned securely at the bladder neck using clamps and metal rods, a gooseneck or similar stationary apparatus, and should not be moved once it is secured. The patient is placed in Trendelenberg position which relaxes the abdominal wall to facilitate centering the treatment tip. By adjusting the position of the patient, the cystoscope is aimed at the point where the posterior wall meets the dome, which is the maximum distance from the bladder neck. The trigone should not be visible. Correct placement of the fiber tip in the center of the bladder is essential to ensure uniform irradiation of the bladder, as areas which receive excessive amounts of light may result in pain or sensitivity post-treatment. Correct placement can be achieved by one of two methods:

a. Ultrasound Imaging: Ultrasound imaging is recommended to verify the mid-bladder placement of the fiber tip, as well as to monitor the bladder volume during treatment: (1) after the bladder is filled, an initial examination of the bladder is made in cross-sectional and longitudinal planes using an ultrasound apparatus. (2) The probe is then placed in the longitudinal position in the midline of the abdomen just above the symphysis pubis. Once the bladder filling has begun, the fluid can be easily detected as a black or clear space in the ultrasound image. The probe may have to be moved side to side (right to left or left to right) to locate the optimum long axis of the bladder once the bladder is filled. (3) Once the bladder has been filled, the cystocope can easily be imaged by ultrasound. (4) Centering of the cystoscope and laser fiber should be done using the linear distance calipers on the ultrasound equipment.

b. Sounding: To determine the midpoint of the bladder by sounding, a urethral catheter with one end plugged to prevent leakage is directed to the dome. The maximum distance is measured from the bladder neck to the point where the posterior bladder wall meets the dome. The spherical diffuser tip is passed through the port of the cystocope to the midpoint of the neck-dome measurement. Once the spherical diffuser tip is situated at the midpoint of the bladder, the catheter should be withdrawn.

Calculation of Treatment Time: The surface area of the bladder wall and the subsequent treatment time required to deliver a total light dose of 15 joules/cmshould be calculated knowing the bladder treatment volume (i.e., the volume instilled to distend the bladder) and the laser power output from the fiber optic tip, as follows:

Treatment time = Dose (joules/cm2) / Power Density (seconds)

Light Dose = 15 joules/ cm2

Heavy Dose = Power Output (watts)/ Bladder surface area

Bladder Surface Area = 4.83 X (bladder treatment volume) 2/3

Urine production or irrigant leakage during treatment can change the bladder surface area and therefore the power density and the delivered light dose. The bladder volume, power output at the fiber tip and positioning of the fiber tip should be checked at the beginning, middle (particularly if the total treatment time is to exceed 45 minutes) and end, and at any time that bleeding is observed or significant changes in bladder volume, fiber power output or fiber tip position are suspected. Whenever treatment is interrupted, “pause” the laser output, ensuring that the original laser settings and elapsed treatment time are retained. If the bladder appears to be filling during the procedure, sufficient urine should be evacuated to restore the original volume. By the end of the preocedure, the cumulative laser light dose should total 15±1 joules/cm

The patient should remain under observation for 24 hours postcystoscopy or until the physician determines that he or she may be safely discharged.

No further courses of treatment with porfimer sodium or light should be used to treat superficial papillary bladder cancer, due to increased risk of bladder contracture.

Esophageal Cancer: Approximately 40 to 50 hours after porfimer sodium administration, light is delivered to the tumor by cylindrical Optiguide Fiber Optic Diffusers passed through the operating channel of an endoscope. The diffusers may be used either interstitially or intraluminally. Complete photoactivation of porfimer sodium for reduction of obstruction and palliation of dysphagia in patients with complete or partially obstructing esophageal cancer requires 300 joules of energy for each cm of tumor length. This is achieved by using appropriate power levels for a treatment time of 12 minutes, 30 seconds. Optiguide cylindrical diffusers are available in several lengths (refer to Optiguide Package Insert) and 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. The power (mW) should be set to 400´length (cm) of diffuser to deliver 300 joules of energy per cm of tumor length in 12 minutes, 30 seconds.

Tumors with lengths that differ from available diffuser lengths may require multiple use of a single Optiguide Fiber Optic Diffuser or the use of 2 or more Optiguide Fiber Optic Diffusers of differing lengths. An exposure time of 12.5 minutes is used for each segment treated. Diffusers or combinations of diffusers should be selected to minimize patient treatment time. Examples of diffuser lengths/tumor sizes follow.

Debridement of residua should be performed via endoscopy 2 days after light treatment. Patients with residual tumor may be retreated with laser light at the time of debridement at the same dose as used in the initial treatment, provided the second light dose is administered 96 to 120 hours after porfimer sodium injection.

Patients may receive a second course of PDT a minimum of 30 days after initial therapy; up to 3 courses of PDT (each injection separated by a minimum of 30 days) can be given. Before each course of treatment, patients should be evaluated for the presence of a tracheoesophageal or bronchoesophageal fistula (see Contraindications).

Reconstitution: Photofrin in the 75 or 15 mg vial should be reconstituted as follows with 5% Dextrose for injection, USP resulting in a final concentration of 2.5 mg porfimer sodium/mL.

Store reconstituted solutions at 2 to 8°C protected from light. Discard unused portion after 24 hours.

Incompatibilites: Photofrin should only be reconstituted with Dextrose 5% in water. Photofrin should not be mixed with other drugs in the same solution.

Special Instructions: Spills and Disposal: Spills of porfimer sodium should be wiped up with a damp cloth, at which time the wearing of rubber gloves and eye protection are recommended. Skin and eye contact should be avoided. All contaminated materials should be disposed of in a polyethylene bag in a manner consistent with local regulations.

Accidental Exposure: Porfimer sodium is neither a primary ocular irritant nor a primary dermal irritant. Because of its potential to induce photosensitivity, porfimer sodium 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 accidentally exposed persons must be protected from bright light.

Availability And Storage: Each vial contains: porfimer sodium 15 or 75 mg as a sterile freeze-dried cake or powder. Sodium hydroxide and/or hydrochloric acid are used in the manufacturing process to adjust pH. There are no antimicrobial preservatives or formulation excipients. Vials of 15 and 75 mg. Store unreconstituted porfimer sodium for injection at 15 to 25°C.

PHOTOFRIN® Ligand Porfimer Sodium Antineoplastic Photosensitizing Agent

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