DRUG NAME

DACTINOMYCIN :

SYNONYM(S): Actinomycin D

COMMON TRADE NAME(S): COSMEGEN(r)

CLASSIFICATION

Antitumour antibiotic :

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION

[1,2,3] :

Dactinomycin is a derivative of Streptomyces parvulus. At low concentrations, dactinomycin inhibits DNA- primed RNA synthesis by intercalating with guanine residues of DNA. At higher concentrations, it also inhibits DNA synthesis. Interstrand and DNA-protein cross-links may also occur. Dactinomycin is considered to be cell cycle phase-nonspecific.

PHARMACOKINETICS

[3,4,5,6,7,8] :

Oral Absorption poorly absorbed from gastrointestinal tract
Distribution rapid entry into nucleated cells (bone marrow > plasma), crosses placenta
cross blood brain barrier? no
Vd no information found
PPB 5%
Metabolism 15% eliminated by hepatic metabolism
active metabolite(s) no
inactive metabolite(s) yes
Excretion 15% as intact drug in feces in 1 week
urine 15% as intact drug in 1 week
t1/2 36-48 hours prolonged with hepatic dysfunction
Cl no information found

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Dactinomycin

USES

[1,2,3,4,9,10] :

SPECIAL PRECAUTIONS

[4] :

Less frequent uses include: Germ cell tumours Kaposi's sarcoma Melanoma

Optic nerve glioma Osteogenic sarcoma

Dactinomycin has been shown to be teratogenic and carcinogenic in animal studies. Its safe use in pregnancy and its effects on fertility have not been established. Breast feeding is not recommended due to the potential secretion into breast milk.

SIDE EFFECTS

[4,8,10,11,12,13] :

ORGAN SITE SIDE EFFECT ONSET
dermatologic flushing of face, torso I
alopecia (rare, mild-moderate) E
acute superficial folliculitis of face and trunk (rare) E
radiation recall reaction (rare) I
extravasation hazard (refer to Appendix 2) VESICANT I
gastrointestinal nausea and vomiting (onset 1-6 hours, duration 4-20 hours) I
anorexia I
diarrhea (30%) E
stomatitis (30%) E
hematologic myelosuppression , nadir 14-21 days, recovery 21-25 days E
immunosuppression E
hepatic elevated liver function tests E
ascites, liver enlargement E
hypersensitivity Type I (anaphylactoid), (rare) I
fever I
chills I
injection site pain, phlebitis I

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ORGAN SITE SIDE EFFECT ONSET
neoplastic second primary tumours (rare) L
renal/metabolic hypocalcemia (rare) I

Dose-limiting side effects are underlined.

I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)

The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected.

Dactinomycin has the potential to enhance radiation injury to tissues. While often called radiation recall reactions, the timing of the radiation may be before, concurrent with or even after the administration of the dactinomycin. Recurrent injury to a previously radiated site may occur weeks to months following radiation.

Hepatotoxicity has occurred in children with Wilm's tumour. This may manifest as increased AST (SGOT) and bilirubin levels, ascites and liver enlargement. In some cases, thrombocytopenia may accompany hepatotoxicity. Factors associated with severe hepatotoxicity include concurrent administration of other hepatotoxic agents, especially halogenated anesthetics; using single-dose dactinomycin as opposed to a 5 day regimen; doses of dactinomycin >=60 mcg/kg; and radiation.

INTERACTIONS

[12] :

AGENT EFFECT MECHANISM MANAGEMENT
halogenated inhalation anesthetics (eg, enflurane, halothane) increased hepatotoxicity additive caution

SOLUTION PREPARATION AND COMPATIBILITY

[4,8,14,15,16,17] :

For basic information on solution preparation and compatibility, see Chemotherapy Chart in Appendix.

PARENTERAL ADMINISTRATION

[3,7,8,18,19] :

BCCA administration guideline noted in bold, italics
Subcutaneous not used due to corrosive nature
Intramuscular not used due to corrosive nature
Direct intravenous Preferred method due to need for frequent monitoring for signs of extravasation. Via small (21 or 23) gauge needle into tubing of running IV, over 1-5 minutes. Push slowly so that drip of IV solution does not stop or reverse. Check for blood return before administration and after every 2-3 mL of drug. If no blood return, stop the injection and assess the IV site. Flush with 20 mL NS or D5W after administration to clear any remaining drug from tubing.
Intermittent infusion in D5W or NS over 10-15 minutes
Continuous infusion not used due to corrosive nature

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Dactinomycin

Intraperitoneal not used due to corrosive nature
Intrapleural not used due to corrosive nature
Intrathecal not used due to corrosive nature
Intra-arterial in 150-500 mL for isolated limb perfusion by intra-arterial injection has been done with or without concomitant hyperthermia or radiation
Intravesical no information available on this route

DOSAGE GUIDELINES

[3,4,5,6,7,8,16,20,21,22] :

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.

Adults:

Direct intravenous: 2

q2w: 1.25 mg/m

q3-4w: 1-2 mg/m2 (25-50 mcg/kg)

q4-6w: 400-600 mcg/m2/day (10-15 mcg/kg/day) x 5 days q1-4w: 750-2000 mcg/m2 as a single dose (investigational)

Isolated perfusion:

q3-4w: upper extremity: 35mcg/kg lower extremity or pelvis: 50 mcg/kg

Dosage in myelosuppression:

modify according to protocol by which patient is being treated; if no guidelines

available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure:

no adjustment required

Dosage in hepatic failure:

adjustment required, no details found

Children:

Direct intravenous:

q5-8w: 15 mcg/kg/day x 5 days. Maximum single dose 500 mcg.

q3w: 45 mcg/kg. Maximum single dose 500 mcg.

BIBLIOGRAPHY:

  1. Haskell CM, ed. Cancer treatment, 3rd ed. Philadelphia: WB Saunders Co, 1990.

  2. Chabner BA, Myers CE. Clinical pharmacology of cancer chemotherapy. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 3rd ed. Philadelphia: JB Lippincott Co, 1989.

  3. Riggs CE. Antitumor antibiotics and related compounds. In: Perry MC, ed. The chemotherapy source book. Baltimore: Williams & Wilkins, 1992:330-2.

  4. Krogh CME, ed. Compendium of pharmaceuticals and specialties, 28th ed. Ottawa: Canadian Pharmaceutical Association, 1993:287-8.

  5. Tattersall MHN, et al. Pharmacokinetics of actinomycin D in patients with malignant melanoma. Clin Pharmacol Ther 1975; 17:701-8.

  6. Frei E. The clinical use of actinomycin. Cancer Chemother Rep 1974; 58:49-54.

  7. McEvoy GK, ed. American hospital formulary service: Drug information 1993. Bethesda: American Society of Hospital Pharmacists, 1993.

  8. Dorr RT, Von Hoff DD, eds. Cancer chemotherapy handbook, 2nd ed. Norwalk: Appleton & Lange, 1994:349-54.

  9. Packer RJ, Sutton LN, Bilaniuk LT, et al. Treatment of chiasmic/hypothalmic gliomas of childhood with chemotherapy: An update. Ann Neurol 1988; 23:79-85.

  10. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 1993; 35:43-50.

  11. Raine J, Bowman A, Wallendszus K, et al. Hepatopathy-thrombocytopenia syndrome--A complication of dactinomycin therapy for Wilm's tumor: A report from the United Kingdom Childrens Cancer Study Group. J Clin Oncol 1991; 9:268-73.

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Green DM, Norkool P, Breslow NE, et al. Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: A report from the National Wilms' Tumor Study. J Clin Oncol 1990; 3:1525-30. Jaybose S, Shende A, Lanzkowsky P, et al. Hepatotoxicity of chemotherapy following nephrectomy for right-sided Wilm's tumor. J Pediatr 1976; 88:898-9. Merck Sharp & Dohme International. Cosmegen package insert. Rahway, NJ; 1987. King JC. Guide to parenteral admixtures. St. Louis: KabiVitrum Inc, 1992. Trissel LA. Handbook on injectable drugs, 7th ed. Bethesda: American Society of Hospital Pharmacists, 1992. Trissel LA, Tramonte SM, Grilley BJ. Visual compatibility of ondansetron hydrochloride with selected drugs during simulated Y-site injection. Am J Hosp Pharm 1991; 48:988-92. Altman AJ, Schwartz AD, eds. Malignant diseases of infancy, childhood and adolescence. Philadelphia: WB Saunders Co, 1983:82. Barrett A. Germ cell tumours. In: Voute PA, Barrett A, et al, eds. Cancer in children 2nd Edition. New York: Springer- Verlag, 1986:188. Tournade MF, Lemerle J, Sarrazin D, et al. Tumours of the kidney. In: Voute PA, Barrett A, et al, eds. Cancer in children, 2nd ed. New York: Springer-Verlag, 1986:256. Mauer HM, Beltangady M, Gehan EA, et al. The intergroup rhabdomycosarcoma study-I. A final report. Cancer 1988; 61:209- 20. Mauer HM, Gehan EA, Beltangady M, et al. The intergroup rhabdomyosarcoma study-II. Cancer 1993; 71:1904-22. USP DI Drug information for the health care professional, 12th ed. Rockville: United States Pharmacopeial Convention Inc, 1992:1118-22. USP DI Advice for the patient: Drug information in lay language, 12th ed. Rockville: United States Pharmacopeial Convention Inc, 1992:442-4.