Yes

Antineoplastic Agent, Alkylating Agent

Treatment of malignant melanoma, Hodgkin's disease, soft-tissue sarcomas, fibrosarcomas, rhabdomyosarcoma, islet cell carcinoma, medullary carcinoma of the thyroid, and neuroblastoma

C

Hypersensitivity to dacarbazine or any component

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. Use with caution in patients with bone marrow suppression; in patients with renal and/or hepatic impairment since dosage reduction may be necessary; avoid extravasation of the drug.

>10%:

Extravasation: Dacarbazine is an irritant; may cause tissue necrosis after extravasation; apply ice and consult extravasation policy if this occurs

Irritant chemotherapy: Pain and burning at infusion site

Gastrointestinal: Moderate to severe nausea and vomiting in 90% of patients and lasting up to 12 hours after administration; nausea and vomiting are dose-related and occur more frequently when given as a one-time dose, as opposed to a less intensive 5-day course; diarrhea may also occur

Emetic potential:

<500 mg: Moderately high (60% to 90%)

greater than or equal to 500 mg: High (>90%)

Time course of nausea/vomiting: Onset: 1-2 hours; Duration: 2-4 hours

1% to 10%:

Cardiovascular: Facial flushing

Dermatologic: Alopecia, rash

Flu-like effects: Fever, malaise, headache, myalgia, and sinus congestion may last up to several days after administration

Gastrointestinal: Anorexia, metallic taste

Hematologic: Myelosuppressive: Mild to moderate is common and dose-related; leukopenia and thrombocytopenia may be delayed 2-3 weeks and may be the dose-limiting toxicity

WBC: Mild (primarily leukocytes)

Platelets: Mild

Onset (days): 7

Nadir (days): 21-25

Recovery (days): 21-28

Neuromuscular & skeletal: Paresthesias

Respiratory: Sinus congestion

Miscellaneous: Anaphylactic reactions, hypocalcemia with high-dose Dtic®

<1%: Orthostatic hypotension, polyneuropathy, headache, and seizures have been reported, photosensitivity reactions, stomatitis, diarrhea, elevated LFTs, hepatic vein thrombosis and hepatocellular necrosis, weakness, blurred vision, anaphylaxis

Symptoms of overdose include myelosuppression, diarrhea

There are no known antidotes and treatment is primarily symptomatic and supportive

Metabolism may be increased by drugs that induce hepatic enzymes

Patients may experience impaired immune response to vaccines

Possible infection after administration of live vaccines in patients receiving immunosuppressants

Store intact vials under refrigeration (2°C to 8°C) and protect from light; vials are stable for 4 weeks at room temperature

Reconstitute with a minimum of 2 mL (100 mg vial) or 4 mL (200 mg vial) of SWI, D₅W, or NS; dilute to a concentration of 10 mg/mL as follows; reconstituted solution is stable for 24 hours at room temperature (20°C) and 96 hours under refrigeration (4°C)

100 mg vial = 9.9 mL

200 mg vial = 19.7 mL

500 mg vial = 49.5 mL

Further dilution in 200-500 mL of D₅W or NS is stable for 24 hours at room temperature and protected from light

Decomposed drug turns pink

Standard I.V. dilution:

Dose/250-500 mL D₅W or NS

Stable for 24 hours at room temperature and refrigeration (4°C) when protected from light

Alkylating agent which forms methylcarbonium ions that attack nucleophilic groups in DNA; cross-links strands of DNA resulting in the inhibition of DNA, RNA, and protein synthesis, but the exact mechanism of action is still unclear; originally developed as a purine antimetabolite, but it does not interfere with purine synthesis; metabolism by the host is necessary for activation of dacarbazine, then the methylated species acts by alkylation of nucleic acids; dacarbazine is active in all phases of the cell cycle

Onset of action: I.V.: 18-24 days

Absorption: Oral administration demonstrates slow and variable absorption; preferable to administer by I.V. route

Distribution: V_d: 0.6 L/kg, exceeding total body water and suggesting binding to some tissue (probably the liver)

Protein binding: Minimal (5%)

Metabolism: Extensive in the liver, and hepatobiliary excretion is probably of some importance; metabolites may also have an antineoplastic effect

Half-life (biphasic): Initial: 20-40 minutes; Terminal: 5 hours

Elimination: Hepatobiliary; ~30% to 50% of dose excreted unchanged in the urine by tubular secretion

I.V. (refer to individual protocols):

Pediatric solid tumors: 200-470 mg/m²/day over 5 days every 21-28 days

Pediatric neuroblastoma: 800-900 mg/m² as a single dose on day 1 of therapy every 3-4 weeks in combination therapy

Hodgkin's disease: 375 mg/m² on days 1 and 15 of treatment course, repeat every 28 days

Adults:

Malignant melanoma: 2-4.5 mg/kg/day for 10 days, repeat in 4 weeks OR may use 250 mg/m²/day for 5 days, repeat in 3 weeks

Hodgkin's disease: 150 mg/m²/day for 5 days, repeat every 4 weeks OR 375 mg/m² on day 1, repeat in 15 days of each 28-day cycle in combination with other agents OR 375 mg/m² repeated in 15 days of each 28-day cycle

Dosing adjustment in renal impairment: Adjustment is warranted

Dosing adjustment/comments in hepatic impairment: Monitor closely for signs of toxicity

CBC (with differential, erythrocyte, and platelet count), liver function tests

May cause headache

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Limit oral intake for 4-6 hours before therapy. Do not use alcohol, aspirin-containing products, and OTC medications without consulting prescriber. It is important to maintain adequate nutrition and hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during therapy; frequent small meals may help. You may experience nausea or vomiting (frequent small meals, frequent mouth care, sucking lozenges, or chewing gum may help). If this is ineffective, consult prescriber for antiemetic medication. You may experience loss of hair (reversible); you will be more susceptible to infection (avoid crowds and exposure to infection as much as possible); you will be more sensitive to sunlight; use sunblock, wear protective clothing and dark glasses, or avoid direct exposure to sunlight. Flu-like symptoms (eg, malaise, fever, myalgia) may occur 1 week after infusion and persist for 1-3 weeks; consult prescriber for severe symptoms. Report fever, chills, unusual bruising or bleeding, signs of infection, excessive fatigue, yellowing of eyes or skin, or change in color of urine or stool. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.

Extravasation management: Local pain, burning sensation, and irritation at the injection site may be relieved by local application of hot packs; if extravasation occurs, apply cold packs; protect exposed tissue from light following extravasation

Injection: 100 mg (10 mL, 20 mL); 200 mg (20 mL, 30 mL); 500 mg (50 mL)

Berg SL, Grisell DL, DeLaney TF, et al, "Principles of Treatment of Pediatric Solid Tumors," Pediatr Clin North Am, 1991, 38(2):249-67.

Bonfante V, Santoro A, Viviani S, et al, "ABVD in the Treatment of Hodgkin's Disease," Semin Oncol, 1992, 19(2 Suppl 5):38-44.

Buesa JM and Urrechaga E, "Clinical Pharmacokinetics of High-Dose DTIC," Cancer Chemother Pharmacol, 1991, 28(6):475-9.

Finklestein JZ, Albo V, Ertel I, et al, "5-(3,3-Dimethyl-l-triazeno) imidazole-4-carboxamide (NSC-45388) in the Treatment of Solid Tumors in Children," Cancer Chemother Rep, 1975, 59(2 Pt 1):351-7.

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Keohan ML and Taub RN, "Chemotherapy for Advanced Sarcoma: Therapeutic Decisions and Modalities," Semin Oncol, 1997, 24(5):572-9.

Mutz ID and Urban CE, "Dimethyl-triazeno-imidazole-carboxamide (DTIC) in Combination Chemotherapy for Childhood Neuroblastoma," Wien Klin Wochenschr, 1978, 90(24):867-70.

Rusthoven JJ, Quirt IC, Iscoe NA, et al, "Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Response Rates of Carmustine, Dacarbazine, and Cisplatin With and Without Tamoxifen in Patients With Metastatic Melanoma. National Cancer Institute of Canada Clinical Trials Group" J Clin Oncol, 1996, 14(7):2083-90.

Yuen AR and Horning SJ, "Hodgkin's Disease: Management of First Relapse," Oncology, 1996, 10(2):233-40, 245.