Dacarbazine

L01A - Alkylating agents ATC L01AX04 Small molecule approved 1975 Parenteral Natural product Black-box warning

JFDA label: Dacarbazine Medac 500mg

⚠ Black-Box Warning

Experienced physician:
Bone marrow suppression:
Hepatic effects:
Carcinogenic/teratogenic:

Mechanism of Action

Inhibitor of DNA — DNA inhibitor

Target	Action	Gene / class
DNA efficacy	INHIBITOR

Indications

Approved

Hodgkin lymphoma
Metastatic malignant melanoma

Off-label

Medullary thyroid cancer (advanced)
Pancreatic neuroendocrine tumors (advanced)
Pheochromocytoma (malignant)
Soft-tissue sarcomas (advanced)

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Prior severe myelosuppression Absolute
Hypersensitivity to dacarbazine or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (1)

Not Known Infusion-site pain

Blood and lymphatic system disorders (3)

Not Known Bone marrow depression (onset: 5 to 7 days; nadir: 7 to 10 days; recovery: 21 to 28 days) · leukopenia · thrombocytopenia

Gastrointestinal disorders (2)

Not Known anorexia · Nausea and vomiting

Skin and subcutaneous tissue disorders (1)

Not Known Alopecia

Dosing

Source: Lexicomp

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) Metastatic malignant melanoma: IV: 250 mg/m2 over 30 minutes once daily on days 1 to 5 every 3 weeks (Middleton 2000) Metastatic melanoma (off-label dosing/combinations): IV: CVD regimen: 800 mg/m2 over 60 minutes on day 1 every 3 weeks (in combination with cisplatin and vinblastine) (Atkins 2008; Eton 2002) Biochemotherapy regimen: 800 mg/m2 over 60 minutes on day 1 every 3 weeks (in combination with cisplatin, vinblastine, interleukin-2 and interferon alfa-2b) (Flaherty 2014) 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). Additional data may be necessary to further define the role of dacarbazine in this condition. 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). Additional data may be necessary to further define the role of dacarbazine in this condition. Soft tissue sarcoma, advanced (off-label use): MAID regimen: IV: 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)

(For additional information see "Dacarbazine: Pediatric drug information") Note: Dacarbazine is associated with a high emetic potential; antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011). Hodgkin lymphoma: Children and Adolescents: ABVD regimen: IV: 375 mg/m2 over 30 to 60 minutes on days 1 and 15 every 4 weeks (in combination with doxorubicin, bleomycin, and vinblastine) (Hutchinson 1998)

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling. The following adjustments have been recommended (Kintzel 1995): CrCl 46 to 60 mL/minute: Reduce dose to 80% of usual dose CrCl 31 to 45 mL/minute: Reduce dose to 75% of usual dose CrCl ≤30 mL/minute: Reduce dose to 70% of usual dose

There are no dosage adjustments provided in the manufacturer's labeling. May cause hepatotoxicity; monitor closely for signs of toxicity.

Warnings & Precautions

Source: Lexicomp

Anaphylaxis

May occur following dacarbazine administration.

Bone marrow suppression

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

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

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

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.

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

[US Boxed Warning]: Studies have demonstrated this agent to be carcinogenic and/or teratogenic when used in animals; adverse effects have been observed in animal reproduction studies. Women of reproductive potential should avoid becoming pregnant during treatment. 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

Lactation

It is not known if dacarbazine is excreted in breast milk. Due to the potential for serious adverse reactions in the breast-feeding infant, a decision should be made to discontinue dacarbazine or to discontinue breast-feeding, taking into account the benefits of treatment to the mother.

Monitoring

Clinical pearl	CBC with differential, liver function

Chemistry & Properties

Formula	C6H10N6O
Molecular weight	182.19 g/mol
IUPAC name	4-[(E)-dimethylaminodiazenyl]-1H-imidazole-5-carboxamide
CAS	4342-03-4
PubChem CID	135398738
InChIKey	`FDKXTQMXEQVLRF-ZHACJKMWSA-N`
logP	0.07 (XLogP -0.6)
Polar surface area	99.73 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.51
Lipinski violations	0

SMILES

CN(C)/N=N/c1[nH]cnc1C(N)=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.373 h
Volume of distribution	1.028 L/kg
Protein binding	5.2%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP1A2	Substrate	—
CYP2C8	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Aldesleukin	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Lomitapide	major
Measles virus vaccine live attenuated	major
Mipomersen	major
Mumps virus strain B level jeryl lynn live antigen	major
Nalidixic acid	major
Natalizumab	major
Ozanimod	major
Pexidartinib	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Thalidomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Alefacept	moderate
Alemtuzumab	moderate
Anakinra	moderate
Anthrax vaccine	moderate
Asparaginase Erwinia chrysanthemi	moderate
Asparaginase Escherichia coli	moderate

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Dacarbazine Medac	Vial 500 mg	1 vial	Pharma Care Drug Store	—
Dacarbazine Medac	Vial 200 mg	10 vial	Pharma Care Drug Store	—