Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

Transcription

1 DRUG NAME: Porfimer SYNONYM(S): Dihaematoporphyrin ether, 1 porphyrins 2 COMMON TRADE NAME(S): PHOTOFRIN CLASSIFICATION: Miscellaneous Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Porfimer, a mixture of porphyrins, is a photosensitizing agent with cytotoxic activity dependent on oxygen and light. 2 Tumour selectivity occurs as a result of selective retention of porfimer in tumour tissue and by selective delivery of light. 2 Photodynamic therapy (PDT) is a 2-stage process involving porfimer and laser light. PDT-induced cytotoxicity may be due to free radical generation and the production of singlet oxygen. 2 Tumour death also occurs through ischemic necrosis secondary to vascular occlusion, mediated by thromboxane A 2 release. 2 PHARMACOKINETICS: Oral Absorption Distribution slow distribution phase cross blood brain barrier? yes 3 volume of distribution L/kg plasma protein binding 90% Metabolism in tissues via slow photodestruction (photobleaching) 5 active metabolite(s) inactive metabolite(s) 5 yes Excretion primarily hepatic, elimination occurs over h from a variety of tissues; tumour, skin, and organs of the reticuloendothelial system (including liver and spleen) retain porfimer longer urine feces primarily terminal half life d (range: d) clearance ml/min/kg Sex no significant differences 6 Adapted from standard reference 2 unless specified otherwise. USES: Primary uses: Other uses: *Endobronchial non-small cell lung cancer Gastric cancer 4 *Esophageal cancer Rectal cancer 4 *High-grade dysplasia associated with Barrett s esophagus *Superficial papillary bladder cancer *Health Canada approved indication BC Cancer Agency Cancer Drug Manual Page 1 of 7 Porfimer

2 SPECIAL PRECAUTIONS: Contraindications 2 : porphyria or a history of hypersensitivity reaction to porphyrins tumours eroding into a major blood vessel (due to the risk of fatal massive hemoptysis) tracheoesophageal or bronchoesophageal fistula prior total bladder radiation or functional bladder capacity less than 200 ml (due to the risk of irreversible bladder contractures from increased fibrosis) coexisting bladder tumours of stage greater than T1 with invasive cancer emergency treatment of severe acute respiratory distress caused by obstruction (due to delay required between porfimer administration and laser light treatment) esophageal or gastric varices or esophageal ulcers >1 cm in diameter; esophageal tumour eroding into the trachea or bronchial tree (due to risk of fistula formation) Caution 2 : photosensitivity; avoid contact with the skin and eyes during preparation and administration due to the risk of irritation; if exposure occurs protect area from light; see paragraph following the Side Effects table endobronchial tumour treatment may result in an obstructed airway due to treatment induced inflammation; debridement of the treated area, approximately 24 hours after treatment, 7 is mandatory to remove exudates and necrotic tissue large centrally located tumours, cavitating tumours, or tumours extrinsic to the bronchus (due to risk of fatal hemoptysis) radiation; see Dosage Guidelines Carcinogenicity: No information found. Mutagenicity: Porfimer is not mutagenic in Ames test with and without light irradiation. 2 Porfimer with light irradiation is mutagenic in some mammalian in vitro mutation tests. 2 Only after light irradiation did porfimer induce a marginally positive response for clastogenicity in the mammalian in vitro chromosome test. 2 Porfimer without light irradiation is not clastogenic in the mammalian in vivo chromosome tests. 2 The overall mutagenicity risk of porfimer is considered minimal. 2 Fertility: No impairment of fertility in rats at doses equivalent to two times the maximum recommended human dose based on body weight and one-half the human dose based on body-surface area. 2 No evidence of teratogenicity in animals at doses equivalent to 2-4 times the maximum recommended human dose based on body weight. 2 Pregnancy: FDA Pregnancy Category C. 4 Animal studies have shown fetal risks and there are no controlled studies in women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus. Animal studies have shown maternal and fetal toxicity but no major malformations. 4 Breastfeeding is not recommended due to the potential secretion into breast milk. 4 SIDE EFFECTS: The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. 7 When placebo-controlled trials are available, adverse events are included if the incidence is >5% higher in the treatment group. BC Cancer Agency Cancer Drug Manual Page 2 of 7 Porfimer

3 ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics Many side effects are limited to the tumour site or organ system being treated. These are identified in italics. BE= High-grade dysplasia associated with Barrett s esophagus, ENSCLC= Endobronchial non-small cell lung cancer allergy/immunology hypersensitivity reaction 8,9 blood/bone marrow/ febrile neutropenia cardiovascular (arrhythmia) constitutional symptoms dermatology/skin gastrointestinal anemia (26%); secondary to tumour bleeding, 10 with treatment for esophageal cancer atrial fibrillation (3-8%); with treatment for BE and esophageal cancer; likely a manifestation of a local/regional inflammatory reaction insomnia (7-20%) fever (15-33%); with treatment for esophageal, endobronchial cancer, or BE; likely a manifestation of a local/regional inflammatory reaction or the endoscopic procedure 7 extravasation hazard: irritant 11 ; if extravasation occurs, protect the area from light for a minimum of 30 days photosensitivity; (<100%) typically mild to moderate, see paragraph following the Side Effects table emetogenic potential: rare 12,13 constipation (5-27%); typically mild to moderate diarrhea (16%); with treatment for BE dysphagia (19%); with treatment for BE esophageal edema (6%); with treatment for esophageal cancer; likely a manifestation of a local/regional inflammatory reaction esophageal stenosis/stricture (40%); with treatment for BE; typically mild to moderate and occurs during the second course of treatment; esophageal dilation may be required nausea (12-21%) vomiting (16-38%); with treatment for BE and esophageal cancer hemorrhage infection lymphatics hematemesis (11%); with treatment for esophageal cancer non-fatal hemoptysis (12%), fatal massive hemoptysis (10%); however, 3% treatmentassociated events within 30 days of treatment; with treatment for ENSCLC; see Caution section bronchitis (11%); with treatment for ENSCLC; typically mild to moderate and occurs within 1 week of treatment; typically resolves within 10 days with antibiotic treatment pneumonia (13-16%); with treatment for BE, esophageal cancer, and ENSCLC peripheral edema (16%); with treatment for bladder cancer fluid imbalance (<1%); with disseminated intraperitoneal malignancies metabolic/laboratory elevated serum transaminases and alkaline phosphatase levels 14 (~10%) 14 ; typically mild to moderate 14 neurology anxiety (5-12%) ocular/visual cataracts (<1%); accelerated development ocular sensitivity; see paragraph following the Side Effects table pain abdominal pain (19-20%); with treatment for BE and esophageal cancer chest pain (9-25%); with treatment for BE, esophageal cancer, and ENSCLC non-specific pain (12-22%) pulmonary cough (17%); with treatment for ENSCLC BC Cancer Agency Cancer Drug Manual Page 3 of 7 Porfimer

4 ORGAN SITE SIDE EFFECT Clinically important side effects are in bold, italics Many side effects are limited to the tumour site or organ system being treated. These are identified in italics. BE= High-grade dysplasia associated with Barrett s esophagus, ENSCLC= Endobronchial non-small cell lung cancer dyspnea (10-32%); with treatment for BE, esophageal cancer, and ENSCLC; typically transient and self-limiting hiccups (11%); with treatment for BE renal/genitourinary increased sputum (9%); with treatment for ENSCLC Adapted from standard reference 2 unless specified otherwise. pleural effusion (6-28%); with treatment for BE and esophageal cancer; typically mild to moderate; likely a manifestation of a local/regional inflammatory reaction respiratory insufficiency (7-10%, severe 3%); with treatment for ENSCLC and esophageal cancer irritative bladder symptoms; with treatment for bladder cancer; may occur for several weeks and includes: increased micturition (60%), hematuria (56%), dysuria (36%), urgency (32%), strangury (32%), genital edema (24%), suprapubic pain (20%), urinary incontinence (20%), nocturia (12%), urinary tract infection (12%), and transient reduction in bladder capacity; irreversible bladder contracture (20%), typically occurs several months post-pdt 2 Toxicities associated with PDT, except for photosensitivity and constipation, occur primarily within the same physiological system as the tumour or in the immediate area that received laser light. 2 Toxicities occasionally extend into adjacent tissues. 2 Local reactions are consistent with an inflammatory reaction induced by the photodynamic effect. 2 The necrotic reaction and associated inflammatory responses may evolve over several days. 2 Photosensitivity, caused by residual drug in the skin, typically occurs for >30 days after treatment. 2 Symptoms include mild to moderate erythema, swelling, itching, burning sensations, blisters, or feeling hot. 2 Ocular discomfort, commonly described as sensitivity to sun, bright lights, or car headlights has also been reported. 2 Other less common skin manifestations, in areas where photosensitivity reactions occurred, include increased hair growth, skin discolouration, skin nodules, increased wrinkles, and increased skin fragility which may be attributed to a temporary drug induced cutaneous porphyria. 2 Protection: Avoid exposure of skin and eyes to direct sunlight or brightly focused indoor light (from examination lamps, dental lamps, operating room lamps, floodlights, halogen lamps, etc.). 2 Conventional UV sunscreens are not effective at protecting against photosensitivity reactions as photoactivation is caused by visible light. 2 For >30 days, when outdoors, wear protective clothing and dark sunglasses. 2 Patients should not stay in a darkened room, but should be encouraged to expose their skin to ambient indoor light as porfimer will be inactivated gradually and safely through a photobleaching reaction. 2 The level of photosensitivity will vary for different areas of the body depending on the extent of previous exposure to light. 2 Testing: Before exposing any area of skin to direct sunlight or bright indoor light, test for residual photosensitivity beginning 30 days after porfimer treatment. 2 A small area of skin should be exposed to sunlight for 10 minutes 2 by cutting a 2 inch hole in a brown paper bag and placing a hand in the bag. 15 Expose only the unprotected patch to sunlight. 15 The tissue around the eyes may be more sensitive; therefore, it is not recommended that the face be used for testing. 2 If no photosensitivity reaction occurs within 24 hours, gradually resume exposure to sunlight, continuing to exercise caution and gradually increasing exposure. 2 If any photosensitivity reaction occurs, such as redness, burning sensation, itch, blisters, or swelling, 7,15 continue precautions for another two weeks before retesting. 2 Photosensitivity may persist for >90 days. 2 Patients travelling to a different geographical area with more sunshine should retest their level of photosensitivity. 2 Short courses of oral corticosteroids have been used to manage symptoms of photosensitivity. 16 BC Cancer Agency Cancer Drug Manual Page 4 of 7 Porfimer

5 INTERACTIONS: Medications known to cause photosensitivity reactions may increase the photosensitivity reaction of porfimer. 2,17 Due to inhibition of thromboxane A 2 corticosteroids given prior and concurrently may inhibit the effect of PDT 2,10,18 Animal and in vitro data suggest that the efficacy of porfimer may be altered by drugs which alter blood flow; cause vasoconstriction; decrease clotting, platelet aggregation, or availability of oxygen or free radicals. 2,17 SUPPLY AND STORAGE: Injection: Axcan Pharma Inc. supplies porfimer as preservative-free 15 and 75 mg vials of freeze-dried cake or powder. Store at room temperature. 2 For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. SOLUTION PREPARATION AND COMPATIBILITY: For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix. Compatibility of selected drugs: Do not mix with other drugs in the same solution. 2 PARENTERAL ADMINISTRATION: Subcutaneous Intramuscular Direct intravenous Intermittent infusion Continuous infusion Intraperitoneal Intrapleural Intrathecal Intra-arterial Intravesical BCCA administration guideline noted in bold, italics by physician only 19 ; over 3-5 minutes 2 into tubing of running IV; see Prevention and Management of Extravasation of Chemotherapy BC Cancer Agency Cancer Drug Manual Page 5 of 7 Porfimer

6 DOSAGE GUIDELINES: Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities. Adults: BCCA usual dose noted in bold, italics Cycle Length: Intravenous: n/a 2 : 2 mg/kg IV for one dose on day 1 followed by illumination with appropriate laser light approximately hours after injection of porfimer Depending on the indication: a second laser light application hours after drug administration may be given 2 treatment may be repeated a minimum of 30 days after initial therapy (90 days for BE) 2 Concurrent radiation: Dosage in myelosuppression: Sufficient time between radiation and PDT is required to ensure that the inflammatory response produced by one treatment has subsided before commencing the other treatment. It is recommended that two to four weeks be allowed after PDT before radiation is initiated; the inflammatory response from PDT will depend on tumour size and the extent of surrounding tissue that receives light. 2 The acute inflammatory reaction from radiation usually subsides within four weeks after completing radiation. 2 modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression" Dosage in renal failure: no adjustment required 2 Dosage in hepatic failure: Dosage in dialysis: not dialyzable 2 Children: safety and efficacy have not been established 2 REFERENCES: 1. MARTINDALE- The Complete Drug Reference (database on the Internet). Porfimer sodium. Thomson MICROMEDEX, Available from Accessed 24 August Axcan Pharma Inc. PHOTOFRIN Product Monograph. Mont-Saint-Hilaire, Quebec; 16 May Schmidt MH, Meyer GA, Reichert KW, et al. Evaluation of photodynamic therapy near functional brain tissue in patients with recurrent brain tumors. Journal of Neuro-Oncology 2004;67(1-2): Rose BD, editor. Porfimer. Waltham, Massachusetts: UpToDate 15.2; BC Cancer Agency Cancer Drug Manual Page 6 of 7 Porfimer

7 5. DRUGDEX Evaluations (database on the Internet). Porfimer. Thompson MICROMEDEX, Available from Accessed 16 August Houle JM, Clervoix N, Bain S, et al. Lack of effect of sex and disease state on the pharmacokinetics of porfimer sodium. Clin Pharmacokinet 2006;45(9): Stephen Lam, MD. BC Cancer Agency Lung Tumour Group. Personal communication. Vancouver, British Columbia;18 September Karasic DS, Pearson VE, Karasic DS, et al. Urticaria and respiratory distress due to porfimer sodium. Ann Pharmacother 2000;34(10): Koehler IK, Koehler IK. Acute immediate urticarialike reaction to i.v. injected photofrin. Lasers Surg Med 1997;20(1): Axcan Scandipharm Inc. PHOTOFRIN for Injection U.S. Package Insert. Birmingham, Alabama; 29 September BC Cancer Agency Provincial Systemic Therapy Program. Provincial Systemic Therapy Program Policy III-20: Prevention and management of extravasation of chemotherapy. Vancouver, British Columbia: BC Cancer Agency; 1 September Stephen Lam, MD. BC Cancer Agency Lung Tumour Group. Personal communication. Vancouver, British Columbia;24 August BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November Shaw JW, Solimando DA, Jr. Updates of letrozole and porfimer sodium. Hosp Pharm 1998;33(3): Axcan Scandipharm Inc. Patient Guide PHOTOFRIN. Birmingham, Alabama; Wolfsen HC, Hemminger LL, Wallace MB, et al. Clinical experience of patients undergoing photodynamic therapy for Barrett's dysplasia or cancer. Alim Pharmacol Ther 2004;20(10): Drug Facts and Comparisons 4.0 (database on the Internet). Porfimer Sodium. Facts and Comparisons 4.0, Available from Accessed 1 August USPDI Drug Information for the Health Care Professional (database on the Internet). Porfimer (Systemic). Thompson MICROMEDEX, Available from Accessed 16 August BC Cancer Agency Provincial Systemic Therapy Program. BCCA-Approved Parenteral Routes-Antineoplastic Drugs. Vancouver, British Columbia: BC Cancer Agency; 15 July BC Cancer Agency Cancer Drug Manual Page 7 of 7 Porfimer