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Dactinomycin

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

DactinomycinSynonyms: Actinomycin C1; Actinomycin D; Dactinomicina; Dactinomycinum; Daktinomycin; Daktinomysiini; Meractinomycin; NSC-3053
BAN: Dactinomycin
USAN: Dactinomycin
INN: Dactinomycin [rINN (en)]
INN: Dactinomicina [rINN (es)]
INN: Dactinomycine [rINN (fr)]
INN: Dactinomycinum [rINN (la)]
INN: Дактиномицин [rINN (ru)]
Chemical name: N2.1,N2´.1´-(2-Amino-4,6-dimethyl-3-oxo-3H-phenoxazine-1,9-diyldicarbonyl)bis[threonyl-d-valylprolyl(N-methylglycyl)(N-methylvaline) 1.5–3.1-lactone]
Molecular formula: C62H86N12O16 =1255.4
CAS: 50-76-0
ATC code: L01DA01
Read code: y02k6; y07eX

Description. Dactinomycin is an antineoplastic antibiotic produced by Streptomyces parvulus and other species of Streptomyces.

Cactinomycin (actinomycin C; HBF-386; NSC-18268) is a mixture of dactinomycin (actinomycin D) (10%), actinomycin C2 (45%), and actinomycin C3 (45%) produced by Streptomyces chrysomallus.

Pharmacopoeias. In China, International, Japan, Poland, and US.

The United States Pharmacopeia 31, 2008 (Dactinomycin). A bright red, somewhat hygroscopic, crystalline powder, affected by light and heat. It has a potency of not less than 950 and not more than 1030 micrograms/mg, calculated on the dried basis. Soluble in water at 10° and slightly soluble in water at 37°; freely soluble in alcohol; very slightly soluble in ether. Store at a temperature not exceeding 40° in airtight containers. Protect from light.

Adsorption. Dactinomycin binds to cellulose ester filters, and such filtration should be avoided. Although it has been suggested that significant amounts of drug may be adsorbed to glass or plastic, dactinomycin is reportedly compatible with glass and PVC infusion containers, and giving into the tubing of a fast-running intravenous infusion is recommended — see Uses and Administration, below.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

Apart from nausea and vomiting adverse effects are often delayed, beginning 2 to 4 days after the completion of a course of treatment and reaching a maximum after 1 to 2 weeks. Fatalities have occurred. Bone-marrow depression and gastrointestinal effects (particularly stomatitis and diarrhoea) may prove dose-limiting. Bone-marrow depression is apparent 1 to 7 days after therapy and may be manifest first as thrombocytopenia; the nadir of the platelet and white cell counts usually occurs within 14 to 21 days, with recovery in 21 to 25 days. Other adverse effects include oral and gastrointestinal effects such as cheilitis, oesophagitis, gastrointestinal ulceration, and proctitis; fever, malaise, hypocalcaemia, erythema, myalgia, alopecia, pneumonitis, and kidney and liver abnormalities. Anaphylactoid reactions have occurred. Dactinomycin is very irritant and extravasation results in severe tissue damage.

The effects of radiotherapy are enhanced by dactinomycin and severe reactions may follow the use of high doses. Erythema and pigmentation of the skin may occur in areas previously irradiated. An increase in incidence of second primary tumours has been seen in patients treated with radiation and dactinomycin.

Dactinomycin should not be given to patients with varicella or herpes zoster, as severe and even fatal systemic disease may occur. Its use is best avoided in infants under 1 year as they are reported to be highly susceptible to the toxicity of dactinomycin. Blood counts and renal and hepatic function should be monitored frequently

Effects on the liver. Although doses less than about 50 micrograms/kg or 1.5 mg/m do not seem to be associated with an unacceptable degree of hepatotoxicity, giving dactinomycin as a single dose of 60 micrograms/kg (about 1.8 mg/m) every 3 weeks to children with Wilms’ tumour was associated with a high incidence of severe hepatotoxicity; reduction of the dose to 45 micrograms/kg every 3 weeks reduced this incidence to levels comparable with a standard regimen of 15 micrograms/kg daily for 5 successive days. Others have not seen such a high incidence of hepatotoxicity with doses of 60 micrograms/kg (despite some raised liver enzyme values), but in this case the high dose was given only every 6 weeks In general, dactinomycin should be given with caution to children with a history of antecedent liver damage, including abdominal irradiation or recent halothane anaesthesia.

Reversible veno-occlusive disease has been seen particularly in children with Wilms’ tumour who have received dactinomycin and vincristine. One study found age of less than 1 year to be a risk factor and a study in children with rhabdomyosarcoma given dactinomycin, vincristine, and eye lop hosp hamide also found that young age (under 3 years) was associated with a greater risk of severe hepatic toxicity. A literature review noted a significant predominance of veno-occlusive disease in right-sided Wilms’ tumour, possibly because the tumour mass could interfere with blood flow in the hepatic veins, which might make the liver more susceptible to the effects of dactinomycin.

Handling. Dactinomycin is irritant; avoid contact with skin and mucous membranes.

Interactions

For a general outline of antineoplastic drug interactions.

Pharmacokinetics

Intravenous doses of dactinomycin are rapidly distributed with high concentrations in bone marrow and nucleated cells. It undergoes only minimal metabolism and is slowly excreted in urine and bile. The terminal plasma half-life is reported to be about 36 hours. It does not cross the blood-brain barrier but is thought to cross the placenta.

In children. A study involving 31 patients aged between 1 and 20 years given dactinomycin in intravenous doses of 0.7 to 1.5 mg/m found that the pharmacokinetics of the drug were variable, but could be described by a 3-compartment model. Peak plasma concentrations varied from 3.2 to 99.2nanograms/mL, and both peak plasma concentration and exposure were inversely related to body-weight. Since there was evidence that exposure was also related to more severe toxicity, younger patients might be at greater risk with a regimen based on surface area; conversely the practice of capping the dose at 2 mg in older patients might result in underdosage.

For evidence that younger patients do experience more liver toxicity with dactinomycin, see Effects on the Liver, above.

Uses and Administration

Dactinomycin is a highly toxic antibiotic with antineoplastic properties. It inhibits the proliferation of cells in a cell-cycle non-specific way by forming a stable complex with DNA and interfering with DNA-dependent RNA synthesis. It may enhance the cytotoxic effects of radiotherapy (see also Adverse Effects, above). Dactinomycin also has immunosuppressant properties.

It has been used, usually with other drugs or radiotherapy, in the treatment of Wilms’ tumour, gestational trophoblastic tumours, nonseminomatous testicular cancer, and sarcomas such as rhabdomyosarcoma and Ewing’s sarcoma.

In the treatment of Wilms’ tumour, childhood rhabdomyosarcoma, or Ewing’s sarcoma, an intravenous dose of 15 micrograms/kg daily for 5 days has been used in combination regimens. In adults, gestational trophoblastic tumours have been treated with 12 micrograms/kg daily for 5 days as a single agent, or 500 micrograms on days 1 and 2 of combination regimens. Metastatic nonseminomatous testicular cancer has been treated with 1 mg/m on day 1 of combination regimens. The dose intensity for adults or children should not exceed 15 micrograms/kg or 400 to 600 micrograms/m daily for 5 days per 2-week cycle, and lower doses may need to be used in some chemotherapy combinations or with radiotherapy. Using a regional perfusion technique to localise the drug has permitted the use of higher doses, 50 micrograms/kg being suggested for an isolated lower extremity or pelvis and 35 micrograms/kg for an upper extremity.

Great care must be taken to avoid extravasation and it should be given, for preference, into the tubing of a fast-running intravenous infusion. Platelet and white cell counts should be performed frequently to detect bone-marrow depression; if either count shows a marked decrease the drug should be withheld until recovery occurs, which may take up to 3 weeks (see also Bone-marrow Depression.

Preparations

The United States Pharmacopeia 31, 2008: Dactinomycin for Injection.

Proprietary Preparations

Argentina: Cosmegen;

Australia: Cosmegen;

Austria: Cosmegen;

Belgium: Lyovac Cosmegen;

Brazil: Cosmegen;

Canada: Cosmegen;

Finland: Cosmegen;

France: Cosmegen;

Germany: Lyovac Cosmegen;

Greece: Cosmegen;

Hong Kong: Cosmegen;

India: Dacmozen;

Ireland: Cosmegen;

Italy: Cosmegen;

Malaysia: Cosmegen ;

Mexico: Ac-De;

The Netherlands: Lyovac Cosmegen;

Norway: Cosmegen;

New Zealand: Cosmegen;

Philippines: Cosmegen; Trepar;

Singapore: Cosmegen;

Sweden: Cosmegen;

Switzerland: Cosmegen;

Thailand: Cosmegen ; Lyovac Cosmegen;

Turkey: Cosmegen;

United Kingdom (UK): Cosmegen;

United States of America (US and USA): Cosmegen.

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