Extravasation Therapy

Cytotoxic Drugs

CARBOPLATIN

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite) 10%

Prepare a 0.17 moles/liter solution by mixing 4 milliliters sodium thiosulfate 10% weight/volume with 6 milliliters sterile water for injection Inject 5 milliliters into extravasation site.

Dimethylsulfoxide (DMSO) 99%

4 drops per 10 square centimeter of skin surface applied topically over area twice that affected every 8 hours for 7 days. Allow to air dry.

Local cooling

60 minutes every 8 hours for 3 days.

NOTES*

At concentrations between 0.3 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).

CARMUSTINE
Gliadel®

ANTIDOTE

COMMENTS

Hyaluronidase

150 International Units (IU)/milliliter, inject 1-2 milliliters subcutaneously

Heat

1-2 hours topical dry, warm heat.

Sodium thiosulfate 10%/distilled water 4:6 relation

FOR GREATER EXTRAVASATIONS: Local infiltration of 5 milliliters

Ice

Topical cooling for 24 hours

CISPLATIN

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite)

For extravasation of large amounts (greater than 20 milliliters) of highly concentrated (greater than 0.5 milligrams/milliliters) solutions: Prepare a 0.17 moles/liters solution by mixing 4 milliliters sodium thiosulfate 10% weight/volume with 6 milliliters sterile water for injection. Inject into extravasation site.

Dimethylsulfoxide (DMSO) 99%

4 drops per 10 square centimeter of skin surface applied topically over area twice that affected every 8 hours for 7 days. Allow to air dry.

Local cooling

60 minutes every 8 hours for 3 days.

NOTES*

Cisplatin is considered unlikely to cause tissue damage after extravasation, however, some cases have been associated with skin necrosis. 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. 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.

CYCLOPHOSPHAMIDE
Cytoxan®

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite) 10%

Prepare a 0.17 moles/liter solution by mixing 4 mL sodium thiosulfate 10% weight/volume with 6 mL sterile water for injection. Inject 5 mL into extravasation site.

DACARBAZINE

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite) 10%

Prepare a 0.17 moles/liter solution by mixing 4 milliliters sodium thiosulfate 10% weight/volume with 6 milliliters sterile water for injection. Inject into extravasation site.

NOTES*

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

DACTINOMYCIN
Cosmegen®

ANTIDOTE

COMMENTS

Local cooling

Can also cause phlebitis

DAUNORUBICIN
Cerubidine®

ANTIDOTE

COMMENTS

Dexrazoxane (Totect(TM), US; Savene(TM), Europe)

Intravenous infusion of 1000 milligrams per square meter (mg/m(2)) body surface area over 1-2 hours on day 1, no later than 6 hours of extravasation; repeat the same dose 24 hours later on day 2; followed by a 500-mg/m(2) dose after 48 hours on day 3. The recommended maximum dose is 2000 mg for the initial 2 doses, and 1000 mg for the third scheduled dose, corresponding to a body surface area of 2 m(2). Do not use dimethylsulfoxide (DMSO) in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.

Dimethylsulfoxide (DMSO)

Apply topically and allow to air dry. Repeat every 4-6 hours for 3-14 days.

Ice

Topical cooling may be more effective if protracted or repeated.

DAUNORUBICIN LIPOSOME
DaunoXome®

STUDIES

Additional studies are needed to classify DaunoXome(R) (daunorubicin citrate liposome) as either a vesicant or irritant.
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.
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.
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.

DOXORUBICIN
Adriamycin®

ANTIDOTE

COMMENTS

Dexrazoxane (Totect(TM), US; Savene(TM), Europe)

Intravenous infusion of 1000 milligrams per square meter (mg/m(2)) body surface area over 1-2 hours on day 1, no later than 6 hours of extravasation; repeat the same dose 24 hours later on day 2; followed by a 500-mg/m(2) dose after 48 hours on day 3. The recommended maximum dose is 2000 mg for the initial 2 doses, and 1000 mg for the third scheduled dose, corresponding to a body surface area of 2 m(2). Do not use dimethylsulfoxide (DMSO) in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.

Dimethylsulfoxide (DMSO)

Apply topically and allow to air dry. Repeat every 4-6 hours for 3-14 days.

Ice

Apply intermittently for 15 minutes, 4 times daily for 3 days.

NOTES***

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.
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.
CORTICOSTEROIDS: Local therapy of anthracycline extravasation with corticosteroids is NOT recommended. Therapy of anthracycline extravasation with corticosteroids was once commonly used.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.

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.
HYALURONIDASE: The use of hyaluronidase for doxorubicin extravasations may be detrimental and therefore NOT recommended.
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. It is postulated that sodium bicarbonate may decrease the cellular uptake of doxorubicin and speed its removal from the affected area. 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.

DOXORUBICIN HCl LIPOSOME
Doxil®

ANTIDOTE

COMMENTS

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. It is postulated that sodium bicarbonate may decrease the cellular uptake of doxorubicin and speed its removal from the affected area. 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.

Ice

Apply ice for 30 minutes

NOTES***

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

EPIRUBICIN
Ellence®

ANTIDOTE

COMMENTS

Dexrazoxane (Totect(TM), US; Savene(TM), Europe)

Intravenous infusion of 1000 milligrams per square meter (mg/m²) body surface area over 1-2 hours on day 1, no later than 6 hours of extravasation; repeat the same dose 24 hours later on day 2; followed by a 500-mg/m² dose after 48 hours on day 3. The recommended maximum dose is 2000 mg for the initial 2 doses, and 1000 mg for the third scheduled dose, corresponding to a body surface area of 2 m². Do not use dimethylsulfoxide (DMSO) in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.

Dimethylsulfoxide (DMSO)

Apply topically and allow to air dry. Repeat every 4-6 hours for a 14 days.

Ice packs

Topical cooling may be more effective if protracted or repeated.

NOTES*

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

ETOPOSIDE

ANTIDOTE

COMMENTS

Hyaluronidase

Reconstitute with normal saline. Inject 150 to 900 units subcutaneously or intradermally.

Heat

Apply warm compresses for 30 to 60 minutes, then alternate off/on every 15 minutes for 1 day.

IDARUBICIN
Idamycin®

ANTIDOTE

COMMENTS

Dexrazoxane (Totect(TM), US; Savene(TM), Europe)

Intravenous infusion of 1000 milligrams per square meter (mg/m(2)) body surface area over 1-2 hours on day 1, no later than 6 hours of extravasation; repeat the same dose 24 hours later on day 2; followed by a 500-mg/m(2) dose after 48 hours on day 3. The recommended maximum dose is 2000 mg for the initial 2 doses, and 1000 mg for the third scheduled dose, corresponding to a body surface area of 2 m(2). Do not use dimethylsulfoxide (DMSO) in patients who are receiving dexrazoxane to treat anthracycline-induced extravasation.

Dimethylsulfoxide (DMSO)

Apply topically and allow to air dry. Repeat every 4-6 hours for 3-14 days.

Ice packs

Topical cooling may be more effective if protracted or repeated.

IFOSFAMIDE
Ifex®

ANTIDOTE

COMMENTS

Dimethylsulfoxide (DMSO) 99%

4 drops per 10 square centimeters of skin surface. Apply topically over area twice the size of that affected, every 8 hours for 7 days. Allow to air dry.

Local cooling

60 minutes every 8 hours for 3 days.

NOTES**

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.
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

IRINOTECAN
Camptosar®

ANTIDOTE

COMMENTS

Flush site with water and apply ice.

Care should be taken to avoid extravasation of irinotecan. Monitor the infusion site for signs of inflammation.

MECHLORETHAMINE
Mustargen®

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite)

Prepare a 0.17 mole/liter solution by mixing 4 milliliters sodium thiosulfate 10% weight/volume with 6 milliliters sterile water for injection. Inject into extravasation site.

MITOMYCIN

ANTIDOTE

COMMENTS

Dimethylsulfoxide (DMSO)

Apply topically and allow to air dry. Repeat every 4-6 hours for a 14 days.

Ice

Topical cooling may be more effective if protracted or repeated.

NOTES**

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.
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.

INEFFECTIVE antidotes for mitomycin extravasation include hyaluronidase, hydrocortisone, vitamin E, N-acetylcysteine, and diphenhydramine

MITOXANTRONE
Novantrone®

ANTIDOTE

COMMENTS

Unknown

May cause ulcerations (rare)

Ice

Apply cold packs for 15-20 minutes 4 times per day for 1-2 days.

OXALIPLATIN

ANTIDOTE

COMMENTS

Sodium thiosulfate (sodium hyposulfite) 10%

Prepare a 0.17 mole/liter solution by mixing 4 milliliters sodium thiosulfate 10% weight/volume with 6 milliliters sterile water for injection. Inject 5 milliliters into extravasation site.

Warm compresses or

Apply warm compresses to extravasation site for 1 hour. Caution- excessive heat can cause tissue damage.

NOTES**

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 or ice to the area of extravasating. Symptoms of oxaliplatin-induced acute neuropathy may be precipitated or exacerbated by exposure to cold temperature or objects.

PACLITAXEL
Taxol®

ANTIDOTE

COMMENTS

Hyaluronidase

Reconstitute with normal saline. Inject 150 to 300 units subcutaneously or intradermally.

Warm Soaks or

Apply warm packs for 15-20 minutes 4 times per day for 1-2 days.

Cold compresses

Apply ice to the area for 15-20 minutes each hour for 4 hours. Caution- excessive cold can cause tissue damage

NOTES**

Impaired healing has been suggested with the use of hyaluronidase. 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 or ice to the area of extravasation.Based on animal data, topical heating or cooling is NOT effective and should be avoided.

TENIPOSIDE
Vumon®

ANTIDOTE

COMMENTS

Hyaluronidase

Reconstitute with normal saline. Inject 150 to 900 units subcutaneously or intradermally.

Heat

Apply warm compresses for 30 to 60 minutes, then alternate off/on every 15 minutes for 1 day.

TOPOTECAN
Hycamtin®

ANTIDOTE

COMMENTS

Local cooling

VINBLASTINE
VINCRISTINE
VINDESINE
VINORELBINE

ANTIDOTE

COMMENTS

Hyaluronidase

Reconstitute with normal saline. Inject 150 to 900 units subcutaneously or intradermally.

Heat

Apply warm packs for 15-20 minutes 4 times per day for 1-2 days

NOTES***

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.
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. 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.

CORTICOSTEROIDS: The use of hydrocortisone for vinca alkaloid extravasation is NOT recommended. 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

Neoplastic and non-neoplastic drugs that act as vesicants or irritants

Vesicants

Irritants

Antineoplastic drugs

Non-antineoplastic drugs

Amsacrine

Aminophylline

Bleomycin

Dactinomycin

Chlordiazepoxide

Bortezomib

Daunorubicin

Diazepam

Carboplatin

Docetaxel (rare)

Digoxin

Carmustine

Doxorubicin

Nafcillin

Cisplatin*

Epirubicin

Nitroglycerine

Cyclophosphamide

Idarubicin

Phenytoin

Dacarbazine*

Mechlorethamine

Promethazine

Docetaxel

Mitomycin

Propylene glycol

Etoposide

Oxaliplatin (rare)

Sodium thiopental

Fluorouracil/Floxuridine

Paclitaxel (rare)

Tetracycline

Ifosfamide

Streptozocin

Mitoxantrone

Vinblastine

Oxaliplatin

Vincristine

Paclitaxel

Vindesine

Teniposide

Vinorelbine

Thiotepa