Porfimer (Monograph)

Brand name: Photofrin
Drug class: Antineoplastic Agents

Introduction

Porfimer sodium is a photoactivated radical generator.

Uses for Porfimer

Porfimer sodium has the following uses:

Porfimer sodium is a photosensitizing agent used in the photodynamic therapy (PDT) of esophageal cancer, endobronchial cancer, and high-grade dysplasia in Barrett's esophagus. The drug has the following specific indications for use:

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. The drug has been designated an orphan drug by FDA for the photodynamic therapy of patients with primary or recurrent obstructing (either partially or completely) esophageal carcinoma.

Treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated.

Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC.

Ablation of high-grade dysplasia (HGD) in Barrett’s esophagus patients who do not undergo esophagectomy. The drug has been designated an orphan drug by FDA for the ablation of HGD in Barrett's esophagus in patients who are not considered to be candidates for esophagectomy.

Porfimer Dosage and Administration

General

Porfimer sodium is available in the following dosage form(s) and strength(s):

For injection: 75 mg porfimer sodium as a lyophilized powder in single-dose vial for reconstitution.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Photodynamic therapy (PDT) with porfimer sodium is a two-stage process requiring administration of both drug and light. The first stage of PDT is the IV injection of porfimer sodium at 2 mg/kg. Illumination with laser light 40–50 hours following injection with porfimer sodium constitutes the second stage of therapy. A second laser light application may be given 96-120 hours after injection. Healthcare providers 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 using PDT with porfimer sodium and associated light delivery devices. PDT with porfimer sodium should be applied only in those facilities properly equipped for the procedure.

Reconstitute each vial of porfimer sodium 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 porfimer sodium with other drugs in the same solution.

The recommended dosage of porfimer sodium is 2 mg/kg of body weight administered as a single slow IV injection over 3 to 5 minutes. See Full Prescribing Information for laser light doses for the specific indication (esophageal cancer, endobronchial cancer, or high-grade dysplasia in Barrett's esophagus).

See Full Prescribing Information for additional details on preparation and administration of PDT with porfimer sodium.

Cautions for Porfimer

Contraindications

• Porphyria.

• Existing tracheoesophageal or bronchoesophageal fistula.

• Tumors eroding into a major blood vessel.

• Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection of porfimer sodium and laser light treatment.

• Esophageal or gastric varices or esophageal ulcers >1 cm in diameter.

Warnings/Precautions

Gastroesophageal Fistula and Perforation

Serious and sometimes fatal gastrointestinal and esophageal necrosis and perforation can occur following treatment with porfimer sodium with PDT. Do not initiate porfimer sodium with PDT in patients with esophageal tumors eroding into the trachea or bronchial tree or bronchial wall because of the high likelihood of tracheoesophageal or bronchoesophageal fistula.

Pulmonary and Gastroesophageal Hemorrhage

Patients with large, centrally located tumors, cavitating tumors, or extensive tumors extrinsic to the bronchus are at high risk for fatal massive hemoptysis. Assess patients for tumors eroding into a pulmonary blood vessel and esophageal varices. Do not administer light directly to an area with esophageal varices because of the high risk of hemorrhage.

High-grade Dysplasia (HGD) in Barrett’s Esophagus

The long-term effect of PDT on HGD in Barrett's esophagus 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. Conduct endoscopic biopsy surveillance every 3 months, until 4 consecutive negative evaluations for HGD have been recorded; further follow-up may be scheduled every 6 to 12 months, as per judgment of healthcare providers. The follow-up period of the randomized study at the time of analysis was a minimum of 2 years (range 2 to 5.6 years).

Photosensitivity

All patients who receive porfimer sodium 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 photosensitivity and will be of no value in protecting against induced photosensitivity reactions caused by visible light.

Ocular Sensitivity

Sensitivity to sun, bright lights, or car headlights, causing ocular discomfort, can occur in patients who receive porfimer sodium. For at least 30 days and until ocular sensitivity resolves, instruct patients when outdoors to 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, allot sufficient time 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. Allow 2 to 4 weeks after PDT before commencing radiotherapy.

The acute inflammatory reaction from radiotherapy usually subsides within 4 weeks after completing radiotherapy. Allow 4 weeks after completing radiotherapy before commencing PDT.

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.

Airway Obstruction and Respiratory Distress

Porfimer sodium followed by PDT can cause treatment-induced inflammation and obstruct the main airway. Administer with caution to patients with endobronchial tumors in locations where treatment-induced inflammation can 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).

Monitor patients closely 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 occurred in 122 of 318 (38%) patients enrolled in three clinical studies of patients who received porfimer sodium with PDT to the esophagus. Nodule pretreatment and re-treating the same mucosal segment more than once may influence the risk of developing an esophageal stricture. A total of 49% of patients who developed a stricture received nodule pretreatment and 82% who developed a stricture had a mucosal segment treated twice. Overall, esophageal strictures occurred within six months following porfimer sodium with PDT. Multiple dilations of esophageal strictures may be required, as shown in the following table:

Risk of Prolonged Duration of Photosensitivity in Patients with Hepatic and Renal Impairment

Hepatic or renal impairment will likely prolong the elimination of porfimer sodium leading to higher rates of toxicity. Inform patients with severe renal impairment or mild to severe hepatic impairment that the period requiring the precautionary measures for photosensitivity may be longer than 90 days.

Thromboembolism

Thromboembolic events can occur following photodynamic therapy with porfimer sodium. Most reported events occurred in patients with other risk factors for thromboembolism including advanced cancer, following major surgery, prolonged immobilization, or cardiovascular disease.

Embryo-fetal Toxicity

Based on animal studies, porfimer sodium may cause embryo-fetal toxicity when administered to a pregnant woman. IV administration of porfimer sodium to pregnant rats and rabbits during the period of organogenesis at dose levels approximately 0.64 times the recommended human dose of porfimer sodium based on body surface area (BSA) resulted in increased fetal resorptions, decreased litter size, and reduced fetal weight but did not cause fetal malformations. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with porfimer sodium and for 5 months after the final dose.

Specific Populations

Pregnancy

Based on animal studies, porfimer sodium may cause embryo-fetal toxicity when administered to a pregnant woman. There are no available data on porfimer sodium use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. IV administration of porfimer sodium to pregnant rats and rabbits during the period of organogenesis at dose levels approximately 0.64 times the recommended human dose of porfimer sodium based on BSA resulted in increased fetal resorptions, decreased litter size, and reduced fetal weight, but did not cause fetal malformations.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.

Lactation

There are no data on the presence of porfimer sodium in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with porfimer sodium and for 5 months after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to the initiation of porfimer sodium therapy.

Porfimer sodium may cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with porfimer sodium and for 5 months after the final dose.

Advise male patients with female partners of reproductive potential to use condoms during treatment with porfimer sodium and for 5 months following the final dose.

Pediatric Use

Safety and effectiveness in pediatrics have not been established.

Geriatric Use

Approximately 70% of the patients treated with PDT using porfimer sodium in clinical trials were over 60 years of age. No overall differences in safety or effectiveness were observed between these patients compared to younger patients.

Common Adverse Effects

• Most common adverse reactions (>10%) in patients with esophageal cancer: Anemia, pleural effusion, pyrexia, constipation, nausea, chest pain, pain, abdominal pain, dyspnea, photosensitivity reaction, pneumonia, vomiting, insomnia, back pain, pharyngitis.

• Most common adverse reactions (>10%) in patients with obstructing endobronchial cancer: Dyspnea, photosensitivity reaction, hemoptysis, pyrexia, cough, pneumonia.

• Most common adverse reactions (>10%) in patients with superficial endobronchial tumors: Exudate, photosensitivity reaction, bronchial obstruction, edema, bronchostenosis.

• Most common adverse reactions (>10%) in patients with high-grade dysplasia in Barrett’s esophagus: Photosensitivity reaction, esophageal stenosis, vomiting, chest pain, nausea, pyrexia, constipation, dysphagia, abdominal pain, pleural effusion, dehydration.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Other Photosensitizing Agents: May increase the risk of photosensitivity reaction.

Actions

Mechanism of Action

Porfimer sodium is a mixture of oligomers formed by ether and ester linkages of up to 8 porphyrin units. The cytotoxic and antitumor actions of porfimer sodium are light and oxygen dependent. Photodynamic therapy (PDT) with porfimer sodium is a two-stage process. The first stage is the IV administration of porfimer sodium. 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 porfimer sodium for a longer period. The second stage is the illumination with 630 nm wavelength laser light. Tumor selectivity in treatment occurs through a combination of selective retention of porfimer sodium and selective delivery of light.

Cellular damage caused by PDT with porfimer sodium is a consequence of the propagation of radical reactions. Radical initiation may occur after porfimer sodium absorbs light to form a porphyrin excited state. Spin transfer from porfimer sodium 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 A2 release. As opposed to a thermal effect, the laser treatment with porfimer sodium induces a photochemical effect. The necrotic reaction and associated inflammatory responses may evolve over several days.

Advice to Patients

• Advise patients to avoid exposure of skin and eyes to direct sunlight or bright indoor light for at least 30 days following treatment with porfimer sodium. Inform patients that photosensitivity might last for more than 90 days if patients suffer from renal or hepatic impairment. Instruct patients to wear protective clothing and dark sunglasses when outdoors, which have an average white light transmittance of <4%. Encourage patients to expose their skin to ambient indoor light to facilitate elimination of porfimer sodium from their skin.

• Inform patients that treatment with porfimer sodium and photodynamic therapy might lead to adverse reactions which include chest pain, respiratory distress or esophageal strictures. Advise patients to contact their healthcare providers for new or worsening adverse reactions.

• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with porfimer sodium and for 5 months after the final dose.

• Advise male patients with female partners of reproductive potential to use condoms during treatment with porfimer sodium and for 5 months following the final dose.

• Advise women not to breastfeed during treatment with porfimer sodium and for 5 months after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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