PATIENT DATA/BACKGROUND

Extravasation is a potential hazard of peripherally administered chemotherapy. Signs and symptoms of extravasation range from localized, self-limiting inflammation (irritants) to full-thickness destruction and sloughing of the skin (vesicants). Hyperpigmentation, induration and burning can also occur. Extravasation can occur without burning, stinging or even if blood returns well on aspiration. Severity of these reactions are not independent of the drug, but depend also on the site of the reaction, concentration of the drug in solution, diluent used to reconstitute the drug, admixed solution, condition of the surrounding skin, volume of extravasate, and the ability to detect and appropriately treat the complication ^[1].
Proper procedure for a cytotoxic drug extravasation include: stopping the administration of the cytotoxic agent, disconnecting the intravenous line at the point closest to the vascular access device, aspirating residual drug, estimating the amount of drug extravasated, applying warm or cold compresses as indicated, elevating the extremity, and administration of the correct antidote, if one exists. The prescriber and pharmacy specialist need to be notified and an occurrence report must be completed (National Institutes of Health Clinical Center Nursing Department, 1999).
A review of the current literature suggests that most drugs can be classified as either a vesicant or irritant. However, a clear distinction between these terms is not established. The following guidelines are recommendations from uncontrolled studies or case reports for the management of extravasation of cytotoxic agents since clear validation in controlled trials is unavailable ^[1].
Dimethyl sulfoxide (DMSO) is commercially available as a product from Edwards Lifesciences Research Medical Inc (800-453-8432) as a 99% sterile, non-pyogenic product. It is classified as a raw material and is not available from most pharmaceutical wholesalers. Bone marrow transplant units use Cryoserv (TM) as part of the processing process.

 RESPONSE

CARBOPLATIN

* ^[2].
** ^[3][4].
*** ^[5].
At concentrations between 0.3 milligrams per milliliter (mg/mL) to 5 mg/mL no problems have been reported following extravasation. However, extravasation at concentrations of 10 mg/mL or greater have resulted in erythema, tenderness, cellulitis, and/or induration (Tech Info, 2001a).
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CARMUSTINE - IRRITANT

* ^[2].
** ^[6].
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CISPLATIN - IRRITANT/VESICANT

* ^[5].
** ^[7][3][4].
Cisplatin is considered unlikely to cause tissue damage after extravasation, however, some cases have been associated with skin necrosis ^[8].
Cisplatin is considered a vesicant only when a large volume (greater than 20 milliliters (mL)) of concentrated cisplatin (greater than 0.4 milligrams/mL) is extravasated ^[8][9]. There are no clinical reports of the use of sodium thiosulfate following cisplatin extravasation. Its use for cisplatin extravasation is based on the ability of sodium thiosulfate to inactivate cisplatin ^[8].
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CYCLOPHOSPHAMIDE

* ^[2].
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DACARBAZINE - IRRITANT

* ^[3].
** ^[6][5].
Sodium thiosulfate is recommended only when concentrated dacarbazine is extravasated. There are no clinical reports of the use of sodium thiosulfate following dacarbazine extravasation. Its use for dacarbazine extravasation is based on evidence that it has worked as an antidote for dacarbazine-induced skin toxicity ^[8].
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DACTINOMYCIN - VESICANT

* ^[2][5].
** ^[6].
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DAUNORUBICIN - VESICANT

* ^{[10][11][2][6][3][4]}.
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DAUNORUBICIN CITRATE LIPOSOME
Additional studies are needed to classify DaunoXome(R) (daunorubicin citrate liposome) as either a vesicant or irritant ^[12].
Installation of local antidotes, local compression or other measures that may cause the release of daunorubicin from the liposome are inappropriate in the management of extravasation ^[12].
DaunoXome (R) (daunorubicin citrate liposome) extravasation has been reported. In 1 case report DaunoXome (R) extravasation occurred in 4 patients with AIDS-related Kaposi's sarcoma. Patients were treated with ice (n=4) and multiple subcutaneous steroid injections (n=3). Decreased sensation and a change in skin texture was noted in 3 patients. Symptoms resolved in all patients (n=4) after 6 months. Tissue necrosis was NOT observed in any of the cases ^[13].
Extravasation of approximately 3.7 milliliters (2 milligrams) of daunorubicin citrate liposome occurred in one patient and was treated immediately with HYDROCORTISONE infiltration and ICE PACKS. Another patient was presumed to have experienced extravasation because she manifested the same symptoms (paravenous pain and mild erythema at the injection site). Total resolution of pain and morbidity occurred in both patients ^[14].
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DOCETAXEL - IRRITANT/VESICANT

*The available literature on the management of docetaxel extravasation is controversial. Several reports have demonstrated the use of either warm compresses/ soaks ^{[15][16][17][5]} or ice ^{[18][19][20][2]} in the management of docetaxel extravasation. Specific data (i.e. duration, frequency, etc) with the latter option is lacking. Outcomes varied for each treatment option.
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DOXORUBICIN - VESICANT

* ^{[10][11][2][6][3][4]}.
** ^[21]
Doxorubicin is one of the most problematic antineoplastic agents when extravasated as this agent produces severe and prolonged tissue necrosis due to the slow release of the tissue bound drug into surrounding viable tissue. The deep, penetrating lesions from doxorubicin extravasation heal very slowly, if at all, and surgical intervention is usually required ^[22].
SODIUM THIOSULFATE: Subcutaneous sodium thiosulfate 2% (sodium hyposulfite) added to therapy with subcutaneous hydrocortisone and topical betamethasone decreased the healing time by half for cytotoxic drug extravasation (including doxorubicin and epirubicin) when compared to therapy without sodium thiosulfate ^[23].
CORTICOSTEROIDS: Local therapy of anthracycline extravasation with corticosteroids is NOT recommended. Therapy of anthracycline extravasation with corticosteroids was once commonly used ^[24][25][26]. However, histological studies demonstrate that inflammation is not a major etiology of tissue necrosis. In fact, animal studies suggest that intradermal or subcutaneous injections of corticosteroids are ineffective and may possibly be harmful when used at high dosages ^[8].
HEAT: Do NOT apply heat to areas of extravasated doxorubicin. The cellular uptake of doxorubicin increases at temperatures above 37 degrees Celsius. In the mouse, heat has enhanced doxorubicin skin toxicity, while cold has significantly reduced it ^[8].
HYALURONIDASE: The use of hyaluronidase for doxorubicin extravasations may be detrimental and therefore NOT recommended ^[8].
SODIUM BICARBONATE: Local administration of sodium bicarbonate (8.4%) has also been recommended as an antidote for doxorubicin extravasation, however, because of conflicting data, its use is discouraged ^[8]. It is postulated that sodium bicarbonate may decrease the cellular uptake of doxorubicin and speed its removal from the affected area ^[25]. Other data show that sodium bicarbonate may itself cause tissue necrosis when extravasated and may actually increase the cellular uptake of anthracyclines in the tissue ^[8].
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DOXORUBICIN HYDROCHLORIDE LIPOSOME - IRRITANT

* ^[27]
Extravasation of doxorubicin hydrochloride liposome may occur even without stinging or burning and even if blood returns well on aspiration of the needle. If extravasation occurs, the infusion should be terminated and started in another vein. Apply ice for approximately 30 minutes ^[27].
Five clinical trials of doxorubicin hydrochloride liposome in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma resulted in 8 well-documented episodes of drug extravasation. Local edema was noted in all patients; none of the extravasations resulted in tissue necrosis. All patients were treated by removal of the catheter, elevation of the affected area, and direct application of ice to and around the affected area for 30-60 minutes ^[28].
Cutaneous necrosis was observed in one patient following extravasation of doxorubicin hydrochloride liposome. The author of the report suggests that extravasation of liposomal doxorubicin be managed similar to doxorubicin leakage into subcutaneous tissue (Lokich, 1999).
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EPIRUBICIN - VESICANT

* ^{[10][11][2][3][4]}.
SODIUM THIOSULFATE: Subcutaneous sodium thiosulfate 2% (sodium hyposulfite) added to therapy with subcutaneous hydrocortisone and topical betamethasone decreased the healing time by half for cytotoxic drug extravasation (including epirubicin) when compared to therapy without sodium thiosulfate ^[23].
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ETOPOSIDE - IRRITANT

* ^{[2][6][5][3][4][29]}.
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IDARUBICIN - VESICANT

* ^{[10][11][2][6]}.
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IFOSFAMIDE

* ^[3][4].
** ^[2].
CHONDROITINSULFATASE: A case of ifosfamide extravasation was successfully treated with chondroitinsulfatase. A 54-year-old woman experienced an inflamed, hot area in the antecubital fossa following ifosfamide extravasation. After the failure of topical corticosteroids to improve the condition, chondroitinsulfatase 150 turbidity-forming units in 3 milliliters (mL) of normal saline was injected subcutaneously around the area in 6 applications of 0.5 mL each. This was repeated again 12 hours later and marked improvement was observed. Chondroitinsulfatase is an enzyme similar to hyaluronidase. It depolymerizes hyaluronic acid as well as chondroitin sulfate and enhances the systemic uptake of drugs from tissues ^[30]. Chondroitinsulfatase may be a useful alternative to hyaluronidase in countries where hyaluronidase is not available ^[31].
HEAT: The application of heat may be harmful and is NOT recommended. Hyperthermia is known to enhance the cytotoxicity of ifosfamide in animals and in humans (Mateu, 1994).
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IRINOTECAN

^[32].
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MECHLORETHAMINE (CHLORMETHINE; MUSTINE) - VESICANT

* ^[6][5][3][4]
Topical cooling with an ice pack for 6 to 12 hours may minimize local reactions ^[33].
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MITOMYCIN - VESICANT

* ^{[2][3][4][34]}.
SODIUM THIOSULFATE: Subcutaneous sodium thiosulfate 2% (sodium hyposulfite) added to therapy with subcutaneous hydrocortisone and topical betamethasone decreased the healing time by half for cytotoxic drug extravasation (including mitomycin) when compared to therapy without sodium thiosulfate ^[23].
PYRIDOXINE: The use of subcutaneous pyridoxine (vitamin B6) may slow or prevent necrosis and decrease pain and tenderness associated with mitomycin extravasation. Effective doses have been 75 to 300 milligrams injected at the site of extravasation. The volume of injected pyridoxine ideally should be the same as the volume of extravasated mitomycin, if known. Local pain associated with pyridoxine injections has been a limiting factor, however. Pain might be minimized by diluting the pyridoxine injection by one- to three-fold, thus increasing the pH of the solution. It is postulated that the efficacy of pyridoxine is due to its conversion in tissue to pyridoxal and pyridoxal-5-phosphate, thus forming shift-base complexes with the extravasated mitomycin ^[35].
INEFFECTIVE antidotes for mitomycin extravasation include hyaluronidase, hydrocortisone, vitamin E, N-acetylcysteine, and diphenhydramine ^[9].
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MITOXANTRONE - IRRITANT

*^[6].
** ^[5]
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OXALIPLATIN - IRRITANT/VESICANT

* ^[2]
** ^{[36][37][38][39]}
**Oxaliplatin has been described as both an irritant and vesicant. Specific guidelines on the management of oxaliplatin extravasation are not available. Data exists for both the application of heat ^[36] or ice ^[37][38] to the area of extravasating. Symptoms of oxaliplatin-induced acute neuropathy may be precipitated or exacerbated by exposure to cold temperature or objects ^[39].
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PACLITAXEL - IRRITANT/VESICANT

* ^[7][6]
** ^{[40][2][5][41]}
*** ^[36][6][42]
*Impaired healing has been suggested with the use of hyaluronidase ^[7][6].
**Paclitaxel has been described as both an irritant and vesicant. Specific guidelines for the management of paclitaxel extravasation are not available. However, data exist for both the application of heat ^{[40][2][5][41]} or ice ^[36][6][42] to the area of extravasation. Based on animal data, topical heating or cooling is NOT effective and should be avoided. ^[43].
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TENIPOSIDE - IRRITANT

* ^{[6][3][4][29]}.
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TOPOTECAN

* ^[44]
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VINBLASTINE, VINCRISTINE, VINDESINE, VINORELBINE - VESICANTS

* ^{[2][5][6][3][4][34]}.
The application of heat increases local blood flow, which enhances absorption and removal of the drug from the site. Topical cooling is NOT recommended for the treatment of vinca alkaloid extravasation. In the animal model, however, the application of cold has increased ulceration after vinca alkaloid extravasation. In addition, the use of cooling in humans for vinca extravasation may have caused the need for skin excisions and grafting that might otherwise have been avoided by the use of hyaluronidase ^[8].
CHONDROITIN SULFATASE: Chondroitin sulfatase is an enzyme similar to hyaluronidase. It depolymerizes hyaluronic acid as well as chondroitin sulfate and enhances the systemic uptake of drugs from tissues ^[30]. Delayed treatment with chondroitin sulfatase prevented the development of necrosis in a patient following vindesine extravasation. Thirty-four hours after extravasation, 150 turbidity-reducing units of chondroitinsulfatase were administered subcutaneously around the area. Dry, hot compresses were also applied topically every 20 minutes. The entire treatment was repeated 12 and 24 hours after the first application. Chondroitinsulfatase may be a useful alternative to hyaluronidase in countries where hyaluronidase is not available ^[31].
CORTICOSTEROIDS: The use of hydrocortisone for vinca alkaloid extravasation is NOT recommended ^[8]. Although hydrocortisone has been used to treat vincristine extravasation, it has also been shown to increase the skin toxicity of vinca alkaloids in a murine model ^[8][9][45].
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 Reference

1. Finley RS & Balmer C: Locally reactive cytotoxic drugs and suggested interventions. Concepts in Oncology Therapeutics, 2nd. ASHP Publications Production Center, Bethesda, MD, 1998, pp 176.

2. Fenchel K & Karthaus M: Cytotoxic drug extravasation. Antibiot Chemother 2000; 50:144-148.

3. Bertelli G: Prevention and management of extravasation of cytotoxic drugs. Drug Safety 1995; 12:245-255.

4. Bertelli G, Gozza A, & Forno GB: Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. J Clin Oncol 1995; 13:2851-2855.

5. National Institutes of Health Clinical Center Nursing Department: SOP: care of the patient receiving intravenous cytotoxics or biological agents. NIH. Bethesda, MDAvailable from URL: http://www.cc.nih.gov/nursing/ivctxsop.html.

6. Balmer C & Irani M: Management of breast and prostate cancers In: Finley RS & Balmer C (Eds): Concepts in Oncology Therapeutics, 2nd. American Society of Health-System Pharmacists, Bethesda, MD, 1998, pp 211- 229.

7. Technical Information: Platinol(R)-AQ, cisplatin. Bristol-Myers Squibb Company, Princeton, NJ, USA, 2001b.

8. Bertelli G: Prevention and management of extravasation of cytotoxic drugs. Drug Safety 1995; 12:245-255.

9. Dorr RT: Pharmacologic management of vesicant chemotherapy extravasations. In: Dorr RT & Von Hoff DD (eds). Cancer Chemotherapy Handbook, 2nd ed. Appleton and Lange, Norwalk, CT::109-118, 1994.

10. Product Information: TOTECT(TM) IV injection, dexrazoxane IV injection. TopoTarget USA Inc, Rockaway, NJ, 2007.

11. Mouridsen HT, Langer SW, Buter J, et al: Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies. Ann Oncol 2007; 18(3):546-550.

12. Personal Communication: Gavin Choy, Pharm.D., Sr. Medical Information Associate, NeXstar Pharmaceuticals, July 2001a.

13. Cabriales S, Bresnahan J, Testa D, et al: Extravasation of liposomal daunorubicin in patients with AIDS-associated Kaposi's sarcoma: a report of four cases. Oncol Nurs Forum 1998; 25(1):67-70.

14. Guaglianone P, Chan K, DelaFlor-Weiss E, et al: Phase I and pharmacologic study of lipsomal daunorubicin (DaunoXome). Invest New Drugs 1994; 12:103-110.

15. El Saghir NS & Otrock ZK: Docetaxel extravasation into the normal breast during breast cancer treatment.. Anticancer Drugs 2004; 15:404-404.

16. Raley J, geisler JP, & Buekers TE: Docetaxel extravasation causing significant delayed tissue injury.. Gynecol Oncol 2000; 78:259-260.

17. Ascherman JA, Knowles SL, & Attkiss K: Docetaxel (Taxotere) extravasation: a report of five cases with treatment recommendations. Ann Plast Surg 2000; 45:438-441.

18. Ho C-H, Yang C-H, & Chu C-Y: Vesicant-type reaction due to docetaxel extravasation.. Acta Derm Venereol 2003; 83:467-468.

19. Berghammer P, Pohnl R, & Baur M: Docetaxel extravasation. Support Care Cancer 2001; 9:131-134.

20. Harrison BR, Ketts JR, & Schultz MZ: Docetaxel-induced extravastion injury: a report of three cases.. J Oncol Pharm Pract 2000; 6:122-125.

21. Product Information: doxorubicin hcl iv injection, doxorubicin hcl iv injection. Pharmacia & Upjohn Company, Kalamazoo, MI, 2003.

22. Olver IN, Aisner J, Hament A, et al: A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. J Clin Oncol 1988; 6:1732-1735.

23. Tsavaris NB, Komitsopoulou P, Karagiaouris P, et al: Prevention of tissue necrosis due to accidental extravasation of cytostatic drugs by a conservative approach. Cancer Chemother Pharmacol 1992; 30:330-333.

24. Barlock AL, Howsen DM, & Hubbard SM: Nursing management of Adriamycin(R) extravasation. Am J Nurs 1979; 79:94-96.

25. Zweig JI & Kabakow B: An apparently effective countermeasure for doxorubicin extravasation. JAMA 1978; 239:2116.

26. Rudolph R, Stein MS, & Patillo RA: Skin ulcers due to Adriamycin(R). Cancer 1976; 38:1087-1094.

27. Product Information: DOXIL(R) IV injection, doxorubicin hcl liposome IV injection. Ortho Biotech Products,LP, Raritan, NJ, 2007.

28. Madhavan S & Northfelt DW: Lack of vesicant injury following extravasation of liposomal doxorubicin. J Natl Cancer Inst 1995; 87(20):1556-1557.

29. Lindley C, Finley RS, & LaCivita CL: Adverse Effects of Chemotherapy In: Young LY & Koda-Kimble MA (Eds): Applied Therapeutics: The Clinical Use of Drugs, 6th. Applied Therapeutics, Vancouver, WA, 1995, pp 91.1-91.33.

30. Mateu J, Alzamora M, Franco M, et al: Ifosfamide extravasation. Ann Pharmacother 1994; 28:1243-1244.

31. Mateu J & Llop C: Delayed treatment of vindesine extravasation. Ann Pharmacother 1994; 28:967-968.

32. Personal Communication: Brian R. Tevlin, RPh, Manager, Oncology Clinical Communications, Bayer Corporation, July 2001.

33. Product Information: Mustargen(R), mechlorethamine Hydrochloride for injection. Merk & Co., Inc., Whitehouse Station, NJ, 2002.

34. Dorr RT & Von Hoff DDDorr RT & Von Hoff DD: Cancer Chemotherapy Handbook, 2nd. Appleton & Lange, Norwalk, CT, 1994.

35. Rentschler R & Wilbur D: Pyridoxine: a potential local antidote for mitomycin-C extravasation. J Surg Oncol 1988; 37:269-271.

36. Anon: Extravasation of chemotherapy, prevention and management of. British Columbia cancer Agency. Available from URL: http://www.bccancer.bc.ca. As accessed 10/28/05.

37. Kennedy JG, Donahue JP, & Hoang B: Vesicant characteristics of oxaliplatin following antecubital extravasation.. Clin Oncol 2003; 15:237-239.

38. Foo KF, Michael M, & Toner G: A case report of oxaliplatin extravasation.. Ann Oncol 2003; 14:961-962.

39. Product Information: Eloxatin (TM), oxaliplatin. Sanofi-Synthelabo Inc., New York, NY, USA, 2005.

40. Rogers BB: Nursing implications in the administration of paclitaxel (TAXOL(R)).. Semin Oncol Nurs 1993; 9 (4;suppl 2):11-15.

41. Stanley A & Marsh S: The management of paclitaxel (TAXOL (R)) extravasation.. J Oncol Pharm Practice 1995; 1:24.

42. Dubois A, Fehr MK, & Bochtler H: Clinical course and management of paclitaxel extravasation.. Oncol rep 1996; 3:973-974.

43. Dorr RT & Alberts DS: Skin ulceration potential without therapeutic anticancer activity for epipodphyllotoxin commercial diluents.. Invest New Drugs 1983; 1:151-159.

44. Oostweegel LMM, Beijnen JH, & Mulder JW: Hepatitis during chlorguanide prophylaxis. . Ann Pharmacother 1998; 32:1023-1025.

45. Bellone JD: Treatment of vincristine extravasation (letter). JAMA 1981; 245:343.

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