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dacarbazine
Dacarbazine is an imidazole carboxamide derivative with structural similarity to certain purines; however, its primary mode of action appears to be alkylation of nucleic acids. Inhibition of DNA synthesis, by acting as a purine analogue and interacting with sulfhydryl groups, is also possible. Dacarbazine is cell cycle non-specific.
Liver. Pharmacokinetics may be more than dose-dependent at high doses (>1200 mg/m2) due to decreased renal clearance; metabolism may also be saturated at this level.
| Cross blood brain barrier? | < 15 % |
| PPB | < 5 % |
Metabolized by hepatic microsomal enzyme oxidation system.
| Active metabolites | Yes |
| Inactive metabolites |
Yes, including amino imidazole carboxamide (AIC; major) |
Excreted in urine via renal tubular secretion.
| Urine |
20-50% unchanged, 12-24% as AIC |
| Half-life |
Terminal t½: 0.5 to 3.5 hours |
- Palliative therapy of metastatic malignant melanoma
Other Uses:
- Adrenal cancer (pheochromocytoma)
- Hodgkin lymphoma
- Neuroendocrine tumours
Emetogenic Potential:
Extravasation Potential: Irritant
The incidences for the adverse effects are based on product monographs where available. Incidences marked with "^" are based on the dacarbazine arm in other metastatic melanoma clinical trials.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | ECG changes | D | |||
| Flushing (facial; rare) | I | ||||
| Hypotension (high doses > 850mg/m2) | I | ||||
| Dermatological | Alopecia (rare) | E | |||
| Photosensitivity (rare, more common with large single doses) | I | ||||
| Rash (rare) | I | ||||
| Gastrointestinal | Anorexia (>90%) | E | |||
| Constipation (23%) ^ | E | ||||
| Diarrhea (12%) ^ | I | ||||
| Mucositis (11%) ^ | E | ||||
| Nausea, vomiting (>90%) | I | ||||
| General | Fatigue (31%) ^ | E | |||
| Flu-like symptoms (<10%) | E | ||||
| Hematological | Immunosuppression | E | |||
| Myelosuppression (11%) ^ (neutropenia); may be severe | E | ||||
| Hepatobiliary | Hepatic necrosis (rare) | E | |||
| ↑ LFTs (rare) | E | ||||
| Veno-occlusive disease (rare) | E | ||||
| Hypersensitivity | Hypersensitivity (rarely severe) | I | |||
| Injection site | Injection site reaction (pain / irritation) | I | |||
| Phlebitis (chemical) | I | ||||
| Nervous System | Confusion (rare) | I | |||
| Headache (rare) | E | ||||
| Paresthesia (facial; rare) | E | ||||
| Seizure (rare) | I | ||||
| Ophthalmic | Blurred vision (rare) | E | |||
| Renal | Creatinine increased (impaired renal function; rare) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Anorexia, nausea and vomiting appear to be induced via a CNS mechanism. The use of prophylactic antiemetics is recommended. Nausea and vomiting may last 1-12h but tend to subside after the first few days of treatment. In rare cases, this may require drug discontinuation.
A flu-like syndrome consisting of fever, myalgia and malaise may occur, especially after large, single doses. These symptoms occur in less than 10% of patients, starting 2-7 days after treatment and lasting for 7-21 days. This syndrome may recur on subsequent treatments.
Hepatotoxicity, including fatal cases, has occurred during dacarbazine treatment. It was usually seen during the second cycle; some cases have been preceded by mild, transient hepatic toxicity after the first cycle.
Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.
Dosage in myelosuppression:
Modify according to protocol by which patient is being treated. If significant hematological toxicity occurs, consider hold or discontinuation of therapy.
Dosage with Toxicity:
|
Toxicity |
Action1 |
Dose |
|
Grade 3 (with fever or systemic infection) or Grade 4 hematological toxicity |
Hold |
↓ 25% |
|
Grade 3 non-hematological |
Hold |
↓ 25%; discontinue if recurs after 2 dose reductions |
|
Grade 4 non-hematological |
Discontinue |
Not applicable
|
Adjustment required, no details found
|
Creatinine Clearance (mL/min) |
Dose* |
|
>50 |
100% of dose |
|
30-50 |
75% of dose |
|
10-30 |
50% or discontinue |
|
<10 |
discontinue |
* modified from Kintzel et al 1995
Safety and efficacy not established.
Safety and efficacy not established.
-
Administration of concentrated dacarbazine solutions may cause severe perivenous pain; therefore, it is recommended to give dacarbazine as a diluted IV infusion.
-
Extreme care should be taken to avoid extravasation as this may result in tissue damage and severe pain.
-
May be mixed in normal saline or D5W bag (250 to 1000 mL), depending on the regimen.
- Infuse over 30 to 120 minutes; refer to the institutional guidelines for infusion duration.
- Keep dacarbazine vials refrigerated (2 to 8ºC); protect the undiluted drug, infusion bags and tubing from light.
- patients with known hypersensitivity to dacarbazine and any component of its formulation
- patients who have previously had severe myelosuppression.
- Dacarbazine is a moderate immunosuppressive agent. Avoid the use of live vaccines during treatment and for at least 3 months after the last dose. Response to inactivated vaccines may be decreased.
Other Drug Properties:
-
Carcinogenicity:
Yes
-
Mutagenicity:
Yes
-
Teratogenicity:
Yes
Dacarbazine is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during therapy and for at least 6 months after treatment cessation.
-
Breastfeeding:
Breast feeding is not recommended due to the potential secretion into breast milk.
-
Fertility effects:
Probable
Dacarbazine is metabolized by CYP1A1, CYP1A2 and CYP2E1.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Interleukin-2 | ↑ dacarbazine clearance | Unknown | Clinical significance is uncertain; increased dose of dacarbazine may be required. |
| Fotemustine | Fatal Acute Respiratory Distress Syndrome | Unknown | Caution |
| levodopa | ↓ response to levodopa | Unknown | Caution in patients stabilized on levodopa; dosage adjustments of levodopa may be required |
| Phenytoin, phenobarbital and other drugs inducing hepatic oxidase enzymes. | ↑ metabolism of dacarbazine | Induction of hepatic microsomal enzyme oxidation system | Caution; monitor carefully |
| CYP1A2 inhibitors (e.g., atazanavir, ciprofloxacin, fluvoxamine) | ↓ metabolism of dacarbazine | Inhibition of CYP1A2 enzymes | Caution; monitor carefully and consider therapy modification. |
| CYP2E1 inhibitors (e.g., ritonavir, fluoxetine) | ↓ metabolism of dacarbazine | Inhibition of CYP2E1 enzymes | Caution; monitor carefully and consider therapy modification. |
| Mercaptopurine allopurinol, azathioprine | ↑ activity of these drugs | Dacarbazine inhibits xanthine oxidase | Theoretical risk; monitor carefully |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline and before each cycle |
Liver function tests |
Baseline and as clinically indicated |
Renal function tests |
Baseline and as clinically indicated |
Clinical toxicity assessment including GI, infection, bleeding, hypersensitivity, skin, injection site reactions, flu-like symptoms |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Bedikian AY, Millward M, Pehamberge H, et al. Bcl-2 Antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the oblimersen melanoma study group. J Clin Oncol 2006; 24(29): 4738-45.
Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA)
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
Kintzel PE and Dorr RT. Anticancer Drug Renal Toxicity and Elimination: Dosing Guidelines for Altered Renal Function. Cancer Treat Rev 1995; 21(1): 33-64.
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1020-2.
Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18(1): 158-166.
Product Monograph: Dacarbazine for injection. Pfizer Canada, January 25, 2019.
Robert C, Dummer R, Gutzmer R, et al. Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. Lancet Oncol 2013 Jul;14(8):733-40.
Summary of Product Characteristics: Dacarbazine. medac GmbH, March 2017.
April 2020 Updated pharmacokinetics, indications, adverse effects, administration guidelines, special precautions, and monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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