Dacarbazine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Generic: 100 mg (1 ea); 200 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 200 mg (1 ea)

Pharmacology

Mechanism of Action

Dacarbazine is an alkylating agent which is converted to the active alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide] via the cytochrome P450 system. The cytotoxic effects of MTIC are manifested through alkylation (methylation) of DNA at the O⁶, N⁷ guanine positions which lead to DNA double strand breaks and apoptosis. Dacarbazine is non-cell cycle specific (Marchesi 2007).

Pharmacokinetics/Pharmacodynamics

Distribution

Exceeds total body water; suggesting binding to some tissue (probably liver) (Perry 2012)

Metabolism

Extensively hepatic to the active metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]

Excretion

Urine (~40%; as unchanged drug)

Half-Life Elimination

Biphasic: Initial: 19 minutes, 55 minutes (renal and hepatic dysfunction); Terminal: 5 hours, 7.2 hours (renal and hepatic dysfunction)

Use: Labeled Indications

Hodgkin lymphoma: Treatment of Hodgkin lymphoma (in combination with other chemotherapy agents)

Melanoma, metastatic malignant: Treatment of metastatic malignant melanoma

Use: Off Label

Medullary thyroid cancer (advanced)cyes

Data from a small number of patients studied in a limited number of clinical trials suggest that dacarbazine (in combination with fluorouracil with or without streptozocin or with cyclophosphamide and vincristine) may be beneficial for the treatment of advanced refractory medullary thyroid cancer Orlandi 1994, Schlumberger 1995, Wu 1994.

According to guidelines from the American Thyroid Association for management of medullary thyroid carcinoma, combination chemotherapy with dacarbazine should not be administered as first-line therapy in patients with persistent or recurrent disease; tyrosine kinase inhibitors should be first-line systemic therapy in the setting of symptomatic or progressive metastatic disease Wells 2015.

Pancreatic neuroendocrine tumors (advanced)b

Data from a phase II study suggest that dacarbazine may be beneficial for the treatment of advanced pancreatic neuroendocrine tumors Ramanathan 2001.

Pheochromocytoma (malignant)c

Data from a limited number of patients in a small non-randomized study suggest that dacarbazine (in combination with cyclophosphamide and vincristine) may be beneficial for the treatment of malignant pheochromocytoma Huang 2008.

Soft-tissue sarcomas (advanced)a

Data from a phase III randomized study in patients with advanced soft-tissue and bone sarcomas and data from a phase II study in patients with inoperable or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma support the use of dacarbazine (in combination with doxorubicin, ifosfamide, and mesna) for the treatment of this condition Antman 1993, Antman 1998. The phase III study supports the use of dacarbazine (in combination with doxorubicin) if patients cannot tolerate ifosfamide therapy Antman 1993. Data from another phase III study also support the use of continuous infusion dacarbazine (in combination with doxorubicin) for the treatment of advanced soft tissue sarcomas Zalupski 1991.

Contraindications

Hypersensitivity to dacarbazine or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Prior severe myelosuppression

Dosage and Administration

Dosing: Adult

Note: Dacarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

Hodgkin lymphoma:

ABVD regimen: IV: 375 mg/m² on days 1 and 15 every 4 weeks (in combination with doxorubicin, bleomycin, and vinblastine) for 2 to 4 cycles (Bonadonna 2004; Engert 2010)

A-AVD regimen: IV: 375 mg/m² on days 1 and 15 every 4 weeks (in combination with brentuximab vedotin, doxorubicin, and vinblastine) for up to 6 cycles (Connors 2018). Administer primary prophylaxis with G-CSF (filgrastim) beginning with cycle 1.

Melanoma, metastatic malignant: IV: 250 mg/m² over 30 minutes once daily on days 1 to 5 every 3 weeks (Middleton 2000)

Medullary thyroid cancer, advanced (off-label use): IV: 200 mg/m² once daily for 5 days every 6 weeks (in combination with fluorouracil and streptozocin) or 600 mg/m² once daily for 2 days every 3 or 4 weeks (in combination with cyclophosphamide and vincristine) or 250 mg/m² over 15 to 30 minutes once daily for 5 days every 4 weeks (in combination with fluorouracil) (Orlandi 1994; Schlumberger 1995; Wu 1994).

Pancreatic neuroendocrine tumors, advanced (off-label use): IV: 850 mg/m² over 60 to 90 minutes on day 1 every 4 weeks (Ramanathan 2001).

Pheochromocytoma, malignant (off-label use): IV: 600 mg/m² once daily for 2 days every 3 or 4 weeks (in combination with cyclophosphamide and vincristine) (Huang 2008).

Soft tissue sarcoma, advanced (off-label use): IV:

AD regimen: 250 mg/m²/day as a continuous infusion for 4 days every 3 weeks (total of 1,000 mg/m²/cycle) (in combination with doxorubicin) (Antman 1993) or 187.5 mg/m²/day as a continuous infusion for 4 days every 3 weeks (total of 750 mg/m²/cycle) (in combination with doxorubicin) (Zalupski 1991)

MAID regimen: 250 mg/m²/day as a continuous infusion for 4 days every 3 weeks (total of 1,000 mg/m²/cycle) (in combination with mesna, doxorubicin, and ifosfamide) (Antman 1993; Antman 1998)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: For oncology uses, details concerning dosing in combination regimens should also be consulted. Dacarbazine (any dose) is associated with a high emetic potential (Dupuis 2011); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2013).

Hodgkin lymphoma, high-risk: Limited data available: ABVD regimen: Children and Adolescents: IV: 375 mg/m² over 30 to 60 minutes on Days 1 and 15 of a 28-day treatment cycle for 2 to 6 cycles in combination with doxorubicin, vinblastine, and bleomycin (Hutchinson 1998)

Melanoma, high-risk: Limited data available: Children ≥10 years and Adolescents: IV: 800 mg/m² over 1 hour on Day 1 only after vinblastine and in combination with cisplatin, interferon alfa-2b every 21 days for 3 cycles (Flaherty 2014)

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

The manufacturer recommends reconstituting 100 mg and 200 mg vials with 9.9 mL and 19.7 mL SWFI, respectively, to a concentration of 10 mg/mL; some institutions may use different standard dilutions (eg, 20 mg/mL). Further dilute for infusion in D5W or NS.

Canadian labeling: Reconstitute the 600 mg vial with 59.1 mL SWFI; further dilute with 150 or 250 mL D5W or NS.

Administration

Dacarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Hesketh 2017; Roila 2016).

IV: Infuse over 15 to 60 minutes; rapid infusion may cause severe venous irritation. Other infusion durations have been reported; refer to literature and/or regimen for infusion details (may vary by protocol).

Dacarbazine is an irritant; local reactions may occur (Perez Fidalgo 2012). Monitor infusion site.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Protect from light. Extended storage information for intact vials at room temperature may be available; contact product manufacturer to obtain current recommendations. According to the manufacturer, the reconstituted solution (in the vial) should be used within 72 hours if refrigerated and 8 hours if at room temperature; however, additional stability data indicates the reconstituted solution may be stable for 24 hours at room temperature (20°C) and 96 hours refrigerated (4°C) when protected from light (El Aatmani 2002). Following dilution for infusion (in D5W or NS), solutions may be stored for up to 24 hours refrigerated (4°C) or for up to 8 hours at normal room conditions (dacarbazine is light sensitive).

Drug Interactions

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Fotemustine: May enhance the adverse/toxic effect of Dacarbazine. Specifically, the risk for pulmonary toxicity (adult acute respiratory distress syndrome) may be increased. Management: Do not administer fotemustine and dacarbazine simultaneously, particularly with high doses of dacarbazine. An interval of 1 week should be left between the last dose of fotemustine and the first dose of dacarbazine. Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

SORAfenib: May decrease the serum concentration of Dacarbazine. Sorafenib may also increase the concentration of dacarbazine's active metabolite. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Frequency not always defined.

Central nervous system: Infusion-site pain

Dermatologic: Alopecia

Gastrointestinal: Nausea and vomiting (>90%), anorexia

Hematologic & oncologic: Bone marrow depression (onset: 5 to 7 days; nadir: 7 to 10 days; recovery: 21 to 28 days), leukopenia, thrombocytopenia

<1%, postmarketing, and/or case reports: Anaphylaxis, anemia, diarrhea, dysgeusia, eosinophilia, erythema, facial flushing, facial paresthesia, flu-like symptoms (fever, myalgia, malaise), hepatic necrosis, increased liver enzymes (transient), paresthesia, renal function test abnormality, skin photosensitivity, skin rash, urticaria, venous obstruction (hepatic vein)

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: May occur following dacarbazine administration.
• Bone marrow suppression: [US Boxed Warning]: Bone marrow suppression is the most common toxicity; leukopenia and thrombocytopenia may be severe; may result in treatment delays or discontinuation; anemia may also occur. Monitor CBC with differential. The onset for leukopenia is ~14 days (range: 10 to 30 days) and the duration is ~1 to 3 weeks. The onset for thrombocytopenia is ~18 days (range: 12 to 30 days) and the duration is ~1 to 3 weeks.
• Carcinogenic/teratogenic: [US Boxed Warning]: Studies have demonstrated this agent to be carcinogenic and/or teratogenic when used in animals.
• Extravasation: Dacarbazine is an irritant; local reactions may occur (Perez Fidalgo 2012). According to the manufacturer, extravasation may result in tissue damage and severe pain.
• Gastrointestinal toxicity: Dacarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).
• Hepatic effects: [US Boxed Warning]: Hepatic necrosis has been reported. Hepatotoxicity may be accompanied with hepatic vein thrombosis and hepatocellular necrosis; may be fatal. Hepatotoxicity usually occurs with combination chemotherapy, but may occur with dacarbazine alone.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; half-life is increased, monitor for toxicity and consider dosage reduction.
• Renal impairment: Use with caution in patients with renal impairment; half-life is increased, monitor for toxicity and consider dosage reduction.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Experienced physician: [US Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician. Carefully evaluate the potential benefits of therapy against the risk for toxicity. Adequate laboratory facilities should be available for appropriate monitoring.

Monitoring Parameters

CBC with differential, liver function

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

[US Boxed Warning]: Studies have demonstrated this agent to be carcinogenic and/or teratogenic when used in animals.

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team). In general, if chemotherapy is indicated, it should be avoided during in the first trimester, there should be a 3-week time period between the last chemotherapy dose and anticipated delivery, and chemotherapy should not be administered beyond week 33 of gestation (Peccatori 2013). An international consensus panel has published guidelines for hematologic malignancies during pregnancy. Dacarbazine is a component of the ABVD regimen, which is used for the treatment of Hodgkin lymphoma. If treatment cannot be deferred until after delivery in patients with early stage Hodgkin lymphoma, ABVD may be administered safely and effectively in the latter phase of pregnancy (based on limited data); for patients with advanced-stage disease, ABVD can be administered in the second and third trimesters (Lishner 2016).

Patient Education

What is this drug used for?

• It is used to treat cancer.

Frequently reported side effects of this drug

• Lack of appetite
• Hair loss
• Nausea
• Vomiting
• Flushing
• Numbness or tingling of face

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Loss of strength and energy
• Severe injection site redness, pain, burning, swelling, blisters, or sores
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.