SYNONYM(S): Dihaematoporphyrin ether,¹ porphyrins²

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 A₂ release.²

PHARMACOKINETICS:

Adapted from standard reference² unless specified otherwise.

USES:

*Health Canada approved indication

SPECIAL PRECAUTIONS:

Contraindications²:

· 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)

Caution²:

· 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.

Adapted from standard reference² unless specified otherwise.

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 minutes² 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

INTERACTIONS:

Medications known to cause photosensitivity reactions may increase the photosensitivity reaction of porfimer.^2,17

Due to inhibition of thromboxane A₂ 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:

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:

Children:

References:

1. MARTINDALE- The Complete Drug Reference (database on the Internet). Porfimer sodium. Thomson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 24 August 2007.

2. Axcan Pharma Inc. PHOTOFRIN® Product Monograph. Mont-Saint-Hilaire, Quebec; 16 May 2005.

3. 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):201-7.

4. Rose BD, editor. Porfimer. Waltham, Massachusetts: UpToDate 15.2; 2007.

5. DRUGDEX® Evaluations (database on the Internet). Porfimer. Thompson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 16 August 2007.

6. 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):923-30.

7. Stephen Lam, MD. BC Cancer Agency Lung Tumour Group. Personal communication. Vancouver, British Columbia;18 September 2007.

8. Karasic DS, Pearson VE, Karasic DS, et al. Urticaria and respiratory distress due to porfimer sodium. Ann Pharmacother 2000;34(10):1208-9.

9. Koehler IK, Koehler IK. Acute immediate urticarialike reaction to i.v. injected photofrin. Lasers Surg Med 1997;20(1):97-8.

10. Axcan Scandipharm Inc. PHOTOFRIN® for Injection U.S. Package Insert. Birmingham, Alabama; 29 September 2005.

11. 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 2006.

12. Stephen Lam, MD. BC Cancer Agency Lung Tumour Group. Personal communication. Vancouver, British Columbia;24 August 2007.

13. 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 2005.

14. Shaw JW, Solimando DA, Jr. Updates of letrozole and porfimer sodium. Hosp Pharm 1998;33(3):264-9.

15. Axcan Scandipharm Inc. Patient Guide PHOTOFRIN®. Birmingham, Alabama; 2003.

16. 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):1125-31.

17. Drug Facts and Comparisons 4.0 (database on the Internet). Porfimer Sodium. Facts and Comparisons 4.0, 2007. Available from http://online.factsandcomparisons.com. Accessed 1 August 2007.

18. USPDI® Drug Information for the Health Care Professional (database on the Internet). Porfimer (Systemic). Thompson MICROMEDEX®, 2007. Available from http://www.micromedex.com/ Accessed 16 August 2007.

19. BC Cancer Agency Provincial Systemic Therapy Program. BCCA-Approved Parenteral Routes-Antineoplastic Drugs. Vancouver, British Columbia: BC Cancer Agency; 15 July 2004.