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  • CLASSES

    Other Alkylating Agents

    BOXED WARNING

    Bone marrow suppression, herpes infection, infection, neutropenia, radiation therapy, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Dacarbazine therapy is commonly associated with bone marrow suppression, especially neutropenia and thrombocytopenia, but anemia may also occur. Patients should be allowed to recover their blood cell counts to normal prior to dacarbazine administration. Dacarbazine should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Close monitoring of hematologic parameters is necessary during dacarbazine therapy. Administration of dacarbazine requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents. Patients with an active infection should be treated prior to receiving dacarbazine. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Hepatic disease, hepatotoxicity, renal impairment

    Dacarbazine is metabolized via hepatic pathways, so dosage adjustments may be necessary. Preexisting hepatic disease or renal impairment can cause accumulation of the drug worsening dacarbazine's toxicity. Dosing may need to be reduced in either clinical situation. Rarely, hepatotoxicity, including hepatic vein thrombosis and hepatocellular necrosis resulting in death, has been reported with dacarbazine therapy. Hepatic toxicity has been observed mostly when dacarbazine has been administered concomitantly with other chemotherapy agents; however, it has also been reported in some patients treated with dacarbazine alone.

    Pregnancy

    Dacarbazine was teratogenic in rats at doses 20-times the daily human dose on day 12 of gestation; fetal skeletal anomalies were observed in rabbits who received doses 7-times the daily human dose on days 6 to 15 of gestation. Dacarbazine may cause fetal harm when used during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during dacarbazine therapy.

    Secondary malignancy

    Dacarbazine has been shown to be carcinogenic in animal studies. The development of a secondary malignancy is a possibility following dacarbazine therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Alkylating antineoplastic agent; used in the treatment of melanoma, sarcoma, and Hodgkin's disease.

    COMMON BRAND NAMES

    DTIC-Dome

    HOW SUPPLIED

    Dacarbazine/DTIC-Dome Intravenous Inj Pwd F/Sol: 100mg, 200mg

    DOSAGE & INDICATIONS

    For the treatment of metastatic malignant melanoma.
    For the single-agent treatment of metastatic melanoma.
    Intravenous dosage
    Adults

    250 mg/m2 IV once daily for 5 days repeated every 3 weeks OR 2 to 4.5 mg/kg IV once daily for 10 day repeated every 4 weeks.

    For the first-line treatment of unresectable or metastatic melanoma, in combination with ipilimumab†.
    Intravenous dosage
    Adults

    850 mg/m2 IV plus ipilimumab 10 mg/kg IV repeated every 3 weeks (at weeks 1, 4, 7, and 10) for 4 doses followed by dacarbazine 850 mg/m2 IV every 3 weeks through week 22 (if no progressive disease) as induction therapy resulted in favorable overall survival in a randomized, double-blind, placebo-controlled, phase III trial. At week 24, patients with stable disease or an objective response received maintenance therapy with ipilimumab 10 mg/kg IV every 12 weeks until progressive disease.

    For the treatment of Hodgkin's disease.
    Intravenous dosage
    Adults

    375 mg/m2 IV days 1 and 15 every 28 days or 150 mg/m2/day IV for 5 days, repeated every 4 weeks. Either regimen may be given in combination with doxorubicin, bleomycin, and vinblastine (ABVD regimen).

    Children

    375 mg/m2 IV days 1 and 15 of therapy, repeated every 28 days.

    For the treatment of unresectable or metastatic osteogenic sarcoma†, in combination with mesna, ifosfamide, and doxorubicin.
    Intravenous dosage
    Adults

    250 mg/m2/day as a continuous IV infusion (CIV) for 4 days plus doxorubicin 15 mg/m2/day CIV for 4 days, ifosfamide 2,000 mg/m2/day CIV for 3 days, and mesna 2,000 mg/m2/day CIV for 4 days repeated every 21 days (MAID regimen) until disease progression (or a cumulative doxorubicin dose of 450 mg/m2) was evaluated in 69 patients with unresectable or metastatic Ewing sarcoma, osteosarcoma, or rhabdomyosarcoma in a nonrandomized, phase II trial. Due to life-threatening myelosuppression in the first 15 patients treated, the ifosfamide and mesna doses were reduced from 2,500 mg/m2/day to 2,000 mg/m2/day. Of the 31 patients with osteosarcoma, the ORR was 26% (complete response, 3%), the median time to progression was 6 months, and the median overall survival time was 10 months. Additionally, 1 patient with osteosarcoma who received multimodal therapy with surgery and/or radiotherapy had long-term disease free survival.

    For the treatment of of unresectable or metastatic Ewing's sarcoma†, in combination with mesna, ifosfamide, and doxorubicin.
    Intravenous dosage
    Adults

    250 mg/m2/day as a continuous IV infusion (CIV) for 4 days plus doxorubicin 15 mg/m2/day CIV for 4 days, ifosfamide 2,000 mg/m2/day CIV for 3 days, and mesna 2,000 mg/m2/day CIV for 4 days repeated every 21 days (MAID regimen) until disease progression (or a cumulative doxorubicin dose of 450 mg/m2) has been studied. The MAID regimen was evaluated in 69 patients with unresectable or metastatic Ewing sarcoma, osteosarcoma, or rhabdomyosarcoma in a nonrandomized, phase II trial. Due to life-threatening myelosuppression in the first 15 patients treated, the ifosfamide and mesna doses were reduced from 2,500 mg/m2/day to 2,000 mg/m2/day. Of the 13 patients with Ewing sarcoma, the overall response rate was 77% (complete response, 15%), the median time to progression was 14 months, and the median overall survival time was 28 months. Additionally, 3 patients with Ewing sarcoma who received multimodal therapy with surgery, radiotherapy, or both had long-term disease free survival.

    For the treatment of unresectable or metastatic rhabdomyosarcoma†, in combination with mesna, ifosfamide, and doxorubicin.
    Intravenous dosage
    Adults

    250 mg/m2/day as a continuous IV infusion (CIV) for 4 days plus doxorubicin 15 mg/m2/day CIV for 4 days, ifosfamide 2,000 mg/m2/day CIV for 3 days, and mesna 2,000 mg/m2/day CIV for 4 days repeated every 21 days (MAID regimen) until disease progression (or a cumulative doxorubicin dose of 450 mg/m2) was evaluated in 69 patients with unresectable or metastatic Ewing sarcoma, osteosarcoma, or rhabdomyosarcoma (RMS) in a nonrandomized, phase II trial. Due to life-threatening myelosuppression in the first 15 patients treated, the ifosfamide and mesna doses were reduced from 2,500 mg/m2/day to 2,000 mg/m2/day. Of the 25 patients with RMS, the ORR was 64% (complete response, 28%), the median time to progression was 10 months, and the median overall survival time was 15 months. Additionally, 3 patients with RMS who received multimodal therapy with surgery and/or radiotherapy had long-term disease-free survival.

    For the the first-line treatment of unresectable or metastatic soft-tissue sarcoma†, in combination with mesna, ifosfamide, and doxorubicin.
    Intravenous dosage
    Adults

    250 mg/m2 per day as a continuous IV infusion over 24 hours (CIV) for 4 days in combination with doxorubicin 15 mg/m2 per day CIV for 4 days, ifosfamide 2,000 mg/m2 per day CIV for 3 days, and mesna 2,500 mg/m2 per day CIV for 4 days repeated every 21 days (median of 3 cycles) (MAID regimen) was evaluated in patients with soft-tissue and bone sarcomas in a randomized, phase III trial. Five cycles of an intensified MAID regimen was compared with 6 cycles of a more standard MAID regimen (dacarbazine 300 mg/m2 per day IV over 1 hour on days 1, 2, and 3 plus doxorubicin 20 mg/m2 per day as an IV bolus or CIV on days 1, 2, and 3; ifosfamide 2.5 grams/m2 per day IV over 3 hours on days 1, 2 and 3; and mesna 2.5 grams/m2 per day CIV on days 1, 2, and 3) in patients with inoperable locally advanced or metastatic soft-tissue sarcoma in another randomized, phase III study.

    For the treatment of carcinomatous meningitis† due to melanoma.
    Intrathecal dosage
    Adults

    The use of IT dacarbazine for the treatment of carcinomatous meningitis due to melanoma has not been established. Dacarbazine doses of 5 mg, 10 mg, or 20 mg administered by lumbar puncture or intraventricularly via an Ommaya reservoir in 2 patients with melanoma and CNS involvement in a small case series. Both patients had received radiotherapy (2,000 cGy in 4 fractions) prior to receiving dacarbazine. In a 25-year-old woman, 6 doses of IT dacarbazine (5 mg, 10 mg, 10 mg, 10 mg, 20 mg, and 20 mg) were given over a period of 25 days. Cerebrospinal fluid (CSF) cytology decreased from Papanicolaou class IV to II and the patient experienced symptom improvement. However, she presented with a 1.9 cm left occipital metastasis 21 weeks after treatment and received an additional 30 mg of dacarbazine intraventricularly through an Ommaya reservoir over a period of 15 days. The CSF cytology class again decreased (from class V to II) but the patient died 4 months later. In a 52-year-old man, IT dacarbazine was given twice weekly for 6 doses (5 mg, 10 mg, 10 mg, 10 mg, 20 mg, and 20 mg); the first 3 doses were administered via lumbar puncture and the last 3 doses were administered intraventricularly via an Ommaya reservoir. The patient experienced severe hypertension (blood pressure increase from 140/90 to 300/170 mmHg), hyperventilation, flushing, and fecal incontinence during the sixth IT dacarbazine dose; the episode abated 45 minutes after antihypertension medicine was given. Therapy was discontinued and the patient died 4 months later.

    For the treatment of advanced neuroblastoma†, in combination with other chemotherapy agents.
    Intravenous dosage
    Children

    Dacarbazine as a component of MADDOC and ACVD has been studied. 750 mg/m2 IV every 6 to 8 weeks plus mechlorethamine 4 mg/m2 IV, doxorubicin 40 mg/m2 IV, cisplatin 45 mg/m2 IV, vincristine 2 mg/m2 IV (Max dose: 2 mg), and cyclophosphamide 750 mg/m2 IV repeated every 3 to 4 weeks (MADDOC regimen) was given to 25 patients aged 13 to 38 months in a nonrandomized study; 7 patients received MADDOC for up to 2 years (n = 7) and 18 patients received 2 cycles of induction therapy with cisplatin 100 mg/m2 IV on day 1 and cyclophosphamide 1,000 mg/m2/day IV on days 1 through 3 repeated every 3 to 4 weeks followed by 10 cycles of MADDOC. Treatment with MADDO led to an event-free survival (EFS) rate of 72% and a failure-free local control rate of 84% at a median follow-up time of 85 months (range, 23 to 137 months). All patients had surgery and/or a biopsy, and 19 patients received radiotherapy (dose range, 14.4 to 36 Gy). Additionally, 13 of 18 surviving patients had no evidence of disease at a median follow-up of 94 months. Dacarbazine 250 mg/m2/day IV over 30 minutes on days 1 through 4 plus doxorubicin 35 mg/m2 IV push on day 1, cyclophosphamide 150 mg/m2/day IV push or PO on days 1 through 7, and vincristine 1.5 mg/m2 IV push on day 8 (ACVD regimen) every 3 to 4 weeks followed by or alternating with other chemotherapy regimens was evaluated in 299 children (median age, 33 months) with stage IV neuroblastome in 3 clinical trials (Trial NB 79, NB 82, and NB 85). Favorable initial overall remission rates (ORR) of 86% to 100% (complete remission [CR] rates, 11% to 37%) were seen. Additionally, the median EFS and overall survival (OS) times for all patients were 11.6 and 17 months, respectively, and the 5- to 8-year EFS and OS rates were 13% and 10%, respectively.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1000 mg/m2 IV as a single dose.

    Elderly

    1000 mg/m2 IV as a single dose.

    Adolescents

    375 mg/m2 IV as a single dose; single doses of 900 mg/m2 IV have been given off-label for neuroblastoma.

    Children

    375 mg/m2 IV as a single dose; single doses of 900 mg/m2 IV have been given off-label for neuroblastoma.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage should be modified depending on clinical response and degree of hepatic dysfunction, but no quantitative recommendations are available.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available.

    ADMINISTRATION

     
     
    NOTE: The correct dose of dacarbazine will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering solutions of cytotoxic drugs.
    Dacarbazine is administered intravenously.
    Care should be taken to avoid extravasation; dacarbazine may also be irritating to the vein.
     
    Reconstitution:
    Reconstitute 100 or 200 mg vials with 9.9 or 19.7 mL, respectively, of sterile water for injection to give IV solutions containing 10 mg/ml of dacarbazine.
     
    Intravenous bolus:
    Withdraw the appropriate dose from the reconstituted IV solution and administer by slow IV push over 2—3 minutes.
     
    Intravenous infusion:
    Withdraw the appropriate dose from the reconstituted IV solution and dilute in 250 mL of 5% Dextrose injection or 0.9% Sodium Chloride injection. Infuse over 15—30 minutes.

    Intrathecal Administration

    Reconstitution:
    Reconstitute dacarbazine to a concentration of 5 mg/0.5 mL. Add 0.2 mL of 8.4% sodium bicarbonate solution (1 mEq/mL) per 5 mg of dacarbazine to neutralize citric acid present in the commercial formulation (DTIC-Dome(R)).

    STORAGE

    Generic:
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    DTIC-Dome:
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Dacarbazine (DTIC) hypersensitivity

    Dacarbazine therapy is contraindicated in patients with a history of dacarbazine (DTIC) hypersensitivity.

    Bone marrow suppression, herpes infection, infection, neutropenia, radiation therapy, requires an experienced clinician, thrombocytopenia, varicella, viral infection

    Dacarbazine therapy is commonly associated with bone marrow suppression, especially neutropenia and thrombocytopenia, but anemia may also occur. Patients should be allowed to recover their blood cell counts to normal prior to dacarbazine administration. Dacarbazine should be used cautiously in patients who have had previous myelosuppressive therapy such as chemotherapy or radiation therapy. Close monitoring of hematologic parameters is necessary during dacarbazine therapy. Administration of dacarbazine requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents. Patients with an active infection should be treated prior to receiving dacarbazine. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy.

    Intramuscular injections

    Intramuscular injections should not be given to patients with platelet counts < 50,000/mm3 who are receiving dacarbazine. IM injections may cause bleeding, bruising, or hematomas due to dacarbazine-induced thrombocytopenia.

    Extravasation, intramuscular administration, subcutaneous administration

    Patients should be closely monitored for extravasation during dacarbazine IV infusions. Dacarbazine is considered an irritant, phlebitis, cellulitis and local irritation and pain are associated with extravasation of dacarbazine. Intramuscular administration and subcutaneous administration of dacarbazine should be avoided due severe local irritation associated with extravasation.

    Dental disease, dental work

    Myelosuppressive effects of dacarbazine can increase the risk of infection or bleeding; therefore, dental work should be delayed until blood counts have returned to normal. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Hepatic disease, hepatotoxicity, renal impairment

    Dacarbazine is metabolized via hepatic pathways, so dosage adjustments may be necessary. Preexisting hepatic disease or renal impairment can cause accumulation of the drug worsening dacarbazine's toxicity. Dosing may need to be reduced in either clinical situation. Rarely, hepatotoxicity, including hepatic vein thrombosis and hepatocellular necrosis resulting in death, has been reported with dacarbazine therapy. Hepatic toxicity has been observed mostly when dacarbazine has been administered concomitantly with other chemotherapy agents; however, it has also been reported in some patients treated with dacarbazine alone.

    Accidental exposure, ocular exposure

    Use care to avoid accidental exposure to dacarbazine during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. Following skin or ocular exposure, skin and eyes should be thoroughly rinsed.

    Vaccination

    Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.

    Pregnancy

    Dacarbazine was teratogenic in rats at doses 20-times the daily human dose on day 12 of gestation; fetal skeletal anomalies were observed in rabbits who received doses 7-times the daily human dose on days 6 to 15 of gestation. Dacarbazine may cause fetal harm when used during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during dacarbazine therapy.

    Secondary malignancy

    Dacarbazine has been shown to be carcinogenic in animal studies. The development of a secondary malignancy is a possibility following dacarbazine therapy.

    Breast-feeding

    It is not known whether dacarbazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity from dacarbazine demonstrated in animal studies, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

    ADVERSE REACTIONS

    Severe

    thrombosis / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    erythema / Early / 1.0-10.0
    elevated hepatic enzymes / Delayed / 0-1.0
    anemia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    urticaria / Rapid / 1.0-10.0
    malaise / Early / 1.0-10.0
    myalgia / Early / 1.0-10.0
    fever / Early / 1.0-10.0
    diarrhea / Early / 0-1.0
    photosensitivity / Delayed / 0-1.0
    vomiting / Early / 90.0
    nausea / Early / 90.0
    anorexia / Delayed / 90.0
    flushing / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    paresthesias / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Aldesleukin, IL-2: (Moderate) The safety and efficacy of aldesleukin, IL 2 in combination with any antineoplastic agents have not been established. Hypersensitivity reactions have been reported in patients receiving combination regimens containing sequential high dose aldesleukin, IL 2 and dacarbazine. Aldesleukin, IL 2 can decrease dacarbazine serum concentrations by increasing the volume of distribution of dacarbazine by 36 percent via an unknown mechanism.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely. Carbamazepine may potentially accelerate the hepatic metabolism of dacarbazine, DTIC.
    Carbidopa; Levodopa: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
    Carbidopa; Levodopa; Entacapone: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
    Celecoxib: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Diclofenac: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
    Diphenhydramine; Ibuprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Esomeprazole; Naproxen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flucytosine: (Minor) Flucytosine can cause significant hematologic toxicity. It should be used cautiously with all antineoplastic agents, especially those that cause bone marrow depression.
    Flurbiprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fosphenytoin: (Moderate) Subtherapeutic phenytoin concentrations may occur during the use of selected concurrent chemotherapy treatments; patients receiving phenytoin or fosphenytoin may require close clinical monitoring to ensure appropriate clinical outcomes are achieved during and following the completion of chemotherapy cycles.
    Hydrocodone; Ibuprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketoprofen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Levodopa: (Moderate) Levodopa response may be decreased during chemotherapy with dacarbazine, DTIC. If dacarbazine is used in a patient stabilized on levodopa therapy, practitioners may wish to be alert for needed adjustments in the levodopa regimen to maintain patient status.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nabumetone: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenytoin: (Moderate) Subtherapeutic phenytoin concentrations may occur during the use of selected concurrent chemotherapy treatments. Because case reports of this interaction often include chemotherapy regimens of several different agents, it is not always clearly known which agent may be involved in the interaction, or the precise mechanism of interaction.
    Piroxicam: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Quinine: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with quinine, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. In addition, the therapeutic effects of quinine, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Rofecoxib: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sargramostim, GM-CSF: (Major) Sargramostim, GM-CSF, induces the proliferation of hematopoietic progenitor cells, and, because antineoplastic agents exert their toxic effects against rapidly growing cells, sargramostim is contraindicated for use in patients during the 24 hours before or after cytotoxic chemotherapy.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sulindac: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tolmetin: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Valdecoxib: (Major) Leukopenia and thrombocytopenia are common toxicities of dacarbazine, DTIC. Due to the thrombocytopenic effects of dacarbazine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.

    PREGNANCY AND LACTATION

    Pregnancy

    Dacarbazine was teratogenic in rats at doses 20-times the daily human dose on day 12 of gestation; fetal skeletal anomalies were observed in rabbits who received doses 7-times the daily human dose on days 6 to 15 of gestation. Dacarbazine may cause fetal harm when used during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during dacarbazine therapy.

    It is not known whether dacarbazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity from dacarbazine demonstrated in animal studies, a decision should be made whether to discontinue breast-feeding or to discontinue the drug, taking into account the importance of the drug to the mother.

    MECHANISM OF ACTION

    Dacarbazine is classified as an alkylating agent and exerts its chemotherapeutic effects by substituting an alkyl group for a hydrogen ion in various organic compounds, forming covalent linkages with sulfhydryl groups and thereby inhibiting DNA replication, RNA transcription, and nucleic acid function. It requires activation by the cytochrome P-450 system to its alkylating form. Dacarbazine exhibits minimal immunosuppressive activity, and it does not appear to be schedule-dependent.

    PHARMACOKINETICS

    Dacarbazine, DTIC is administered intravenously.  At therapeutic concentrations DTIC is not appreciably bound to human plasma protein. Dacarbazine, DTIC is extensively degraded. Besides unchanged DTIC, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of DTIC that is excreted in the urine. Some of the drug's metabolites may be active and may contribute to antineoplastic activity. The drug's disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 

    Intravenous Route

    After intravenous (IV) administration, the volume of distribution exceeds total body water content, which suggests localization in tissues such as the liver. Roughly 40% of an IV dose is excreted by the kidneys unchanged within 6 hours, mostly by renal tubular secretion versus glomerular filtration.