Professional Drug Information > Dacarbazine

Dacarbazine (Systemic)

VA CLASSIFICATION
Primary: AN900

Commonly used brand name(s): DTIC; DTIC-Dome.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Melanoma, malignant (treatment)—Dacarbazine is indicated for treatment of metastatic malignant melanoma ^{{01} {09}}.

Lymphomas, Hodgkin's (treatment)¹—Dacarbazine is indicated for treatment of Hodgkin's disease as second-line therapy in combination with other effective agents ^{{01} {09}}.

[Sarcomas, soft tissue (treatment)]¹—Dacarbazine is used for treatment of some soft-tissue metastatic sarcomas ^{09}.

[Carcinoma, islet cell (treatment)]¹—Dacarbazine is used for treatment of islet cell carcinoma ^{{09} {10}}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    182.19 ^{11}

pKa—
    4.42

Mechanism of action/Effect:

Dacarbazine is thought to be an alkylating agent. Major action is believed to be alkylation; dacarbazine is cell cycle–phase-nonspecific. Dacarbazine may inhibit DNA and RNA synthesis via formation of carbonium ions. Some activity and toxicity may occur as the result of activation by hepatic enzymes.

Distribution:

Crosses the blood-brain barrier only to a limited extent.

Protein binding:

Very low ^{01}.

Biotransformation:

Hepatic, extensive ^{01}.

Half-life:


Normal:

Alpha phase: 19 minutes ^{01}.

Beta phase: 5 hours ^{01}.



Renal or hepatic function impairment:

Alpha phase: 55 minutes ^{01}.

Beta phase: 7.2 hours ^{01}.


Elimination:
    Renal; 40% of injected dose in 6 hours ^{01}, one half of that unchanged.


Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Dacarbazine is a potent carcinogen in animals. In rats, dacarbazine produced proliferative endocardial lesions, including fibrosarcomas and sarcomas; in mice, angiosarcomas of the spleen were induced ^{01}.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Studies in rats have shown that dacarbazine is teratogenic at doses 20 times the human daily dose given on day 12 of gestation. Administration of 10 times the human daily dose to male rats twice weekly for 9 weeks resulted in an increased incidence of fetal resorptions in female rats mated to them. Dacarbazine caused fetal skeletal anomalies in rabbits given seven times the human daily dose on days 6 to 15 of gestation.

FDA Pregnancy Category C.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while dacarbazine is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity). It is not known whether dacarbazine is distributed into breast milk.

Pediatrics

Appropriate studies on the relationship of age to the effects of dacarbazine have not been performed in the pediatric population.


Geriatrics


No information is available on the relationship of age to the effects of dacarbazine in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving dacarbazine.


Dental

The bone marrow depressant effects of dacarbazine may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Dacarbazine may also rarely cause stomatitis associated with considerable discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol    (dacarbazine-induced inhibition of xanthine oxidase may cause additive hypouricemic effects when used concurrently with allopurinol)


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of dacarbazine may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of dacarbazine, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


Hepatic enzyme inducers (see Appendix II )    (may enhance metabolism of dacarbazine by induction of hepatic microsomal enzymes; dosage adjustment may be necessary)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by dacarbazine therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by dacarbazine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the dacarbazine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (serum values may be transiently increased; may indicate hepatotoxicity ^{{01} {02} {03} {04}})


Blood urea nitrogen (BUN)    (concentrations may be transiently increased ^{{01} {02} {03} {04}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Hepatic function impairment
» Infection
» Renal function impairment    (reduced elimination; dosage reduction may be required)


Sensitivity to dacarbazine^{01}
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; (» = major clinical significance):
Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Bilirubin concentrations, serum and
Uric acid concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
According to some investigators, photodegradation products of dacarbazine solution may be responsible for some of its adverse effects, including local toxicity (burning and vein pain), nausea and vomiting, and hepatotoxicity.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia^{01}
    
extravasation and tissue damage^{01} or pain in injected vein^{01} (redness, swelling, or pain at site of injection)
    
leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—usually asymptomatic
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic

Note: The fall in leukocyte count usually begins within 16 to 20 days after administration, with the nadir at 21 to 25 days and recovery 3 to 5 days later. Leukopenia may be severe enough to be fatal ^{01}.
The nadir usually occurs 16 days after administration, with recovery 3 to 5 days later. Thrombocytopenia may be severe enough to be fatal ^{01}.


Incidence rare
    
Anaphylaxis^{01}{05} (shortness of breath; swelling of face)
    
hepatotoxicity, including hepatic vein thrombosis^{01}{03}{04}
and hepatocellular necrosis^{01}{02}{04} (fever; stomach pain; yellow eyes or skin)
    
stomatitis (sores in mouth and on lips)

Note: Hepatotoxicity is uniformly fatal ^{{01} {02} {03} {04}}. It has been reported with use of dacarbazine alone and in combination with other agents ^{{01} {02} {03} {04}}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
—greater than 90%^{01}    
Loss of appetite^{01}
    
nausea and vomiting^{01}

Note: Nausea and vomiting may last for 1 to 12 hours after administration but usually lessen considerably within 1 to 2 days after treatment is started ^{01}.


Incidence less frequent
    
Flushing of face^{01}
    
influenza-like syndrome ^{01}(fever; feelings of uneasiness; joint or muscle pain)
    
numbness of face^{01}

Note: The influenza-like syndrome begins after 7 days and may last 1 to 3 weeks; it may occur with repeated treatments.




Those not indicating need for medical attention
Incidence less frequent
    
Loss of hair^{01}



Those indicating the need for medical attention if they occur after medication is discontinued
    
Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin; unusual bleeding or bruising)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dacarbazine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to dacarbazine

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects
Other medications, especially other bone marrow depressants or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, herpes zoster, hepatic function impairment, infection, or renal function impairment

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Frequency of nausea, vomiting, and loss of appetite; importance of continuing medication despite stomach upset; should lessen after 1 or 2 days

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands are washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling doctor or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
May cause adverse effects such as blood problems, loss of hair, and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially anemia, extravasation, pain in injected vein, leukopenia, thrombocytopenia, anaphylaxis, hepatotoxicity, and stomatitis

Physician or nurse can help in dealing with side effects

Possibility of hair loss; normal hair growth should return after treatment has ended


General Dosing Information
Patients receiving dacarbazine should be under supervision of a physician experienced in cancer chemotherapy.

A variety of dosage schedules and regimens of dacarbazine, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, on the basis of clinical response and degree of bone marrow depression.

Dacarbazine may be administered into the tubing of a freely running intravenous solution ^{06} over a 1- to 2-minute period, or by intravenous infusion over a 15- to 30-minute period. Administration by intravenous infusion may prevent pain along the injected vein.

Care should be taken to avoid extravasation of dacarbazine because of the risk of severe pain and tissue necrosis.

If extravasation of dacarbazine occurs during intravenous administration, as indicated by local burning or stinging, the injection and infusion should be stopped immediately and resumed, completing the dose, in another vein.

If marked leukopenia (particularly granulocytopenia) or thrombocytopenia occurs, dacarbazine should be discontinued until leukocyte and platelet counts return to satisfactory levels, usually within a week after the nadir.

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of dacarbazine. These may include extra care in performing invasive procedures, regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusion may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Safety considerations for handling this medication
There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Dacarbazine may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, dacarbazine is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses):    —doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
   —cyclophosphamide, vincristine, doxorubicin, and dacarbazine (CYVADIC).
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.


Parenteral Dosage Forms

DACARBAZINE FOR INJECTION USP

Usual adult dose
Melanoma, malignant
Intravenous, 2 to 4.5 mg per kg of body weight a day for ten days; may be repeated every twenty-eight days ^{01}, or

Intravenous, up to 250 mg per square meter of body surface area a day for five days; may be repeated every twenty-one days ^{01}.

Lymphomas, Hodgkin's¹
Intravenous, 150 mg per square meter of body surface area a day for five days, in combination with other agents; may be repeated every twenty-eight days ^{01}, or

Intravenous, 375 mg per square meter of body surface area on day 1, in combination with other agents, repeated every fifteen days ^{01}.


Note: Dacarbazine may be as effective at the lower dosage as at the higher dosage.
Dacarbazine has also been administered as a single daily dose of 850 mg per square meter of body surface area every twenty-one to forty-two days, with no apparent increase in hematologic toxicity, although extreme nausea and vomiting may occur.


Usual pediatric dose
Dosage has not been established.

Strength(s) usually available
U.S.—


100 mg (Rx) [DTIC-Dome (mannitol 37.5 mg)][Generic](mannitol)


200 mg (Rx) [DTIC-Dome (mannitol 75 mg)][Generic](mannitol)

Canada—


200 mg [DTIC]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by the manufacturer. Protect from light.

Preparation of dosage form:
Dacarbazine for Injection USP may be prepared for parenteral use by adding 9.9 mL (100-mg vial), 19.7 mL (200-mg vial), or 49.5 mL (500-mg vial) of sterile water for injection to the vial, producing a colorless or clear yellow solution containing 10 mg of dacarbazine per mL.

Reconstituted solutions may be further diluted with up to 250 mL of 5% dextrose injection or 0.9% sodium chloride injection for administration by intravenous infusion.

Stability:
Reconstituted solutions of dacarbazine are stable for up to 72 hours at 4 °C (39 °F) or for up to 8 hours at normal room conditions (temperature and light). Solutions further diluted for administration by intravenous infusion are stable for up to 24 hours at 4 °C (39 °F) or for up to 8 hours at normal room conditions (temperature and light) ^{01}. A change in color of the solution to pink indicates decomposition.

Revised: 09/30/1997

References

1. DTIC-Dome package insert (Miles—US), Rev 6/88; Rev 2/95, Rec 7/97.
   

2. Joensuu H, Soderstrom KO, Nikkanen V. Fatal necrosis of the liver during ABVD chemotherapy for Hodgkin's disease. A case report. Cancer 1986 Oct 1; 58: 1437-40.
   

3. McClay E, Lusch CJ, Mastrangelo MJ. Allergy-induced hepatic toxicity associated with dacarbazine. Cancer Treat Rep 1987 Feb; 71: 219-20.
   

4. Ceci G, Bella M, Melissar M, et al. Fatal hepatic vascular toxicity of DTIC. Is it really a rare event? Cancer 1988 May; 61: 1988-91.
   

5. Abhyankar S, Rao SP, Pollio L, et al. Anaphylactic shock due to dacarbazine. Am J Dis Child 1988 Sep; 142: 918.
   

6. Per reviewer comment 3/14/90.
   

7. no reference
   

8. no reference
   

9. Reviewers' responses to Hematologic-Oncologic Disease Advisory Panel Memo #9 of 1/30/97.
   

10. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Company; 1997. p. 1697.
    

11. Fleeger CA, editor. USAN 1994. USAN and the USP dictionary of drug names. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1993.
    

Link to Page

Print Page

Email Page