Dactinomycin - Drug Monograph

Introduction

Dactinomycin (also known as actinomycin D) is a cytotoxic antibiotic derived from Streptomyces parvulus. First isolated in the 1940s, it represents one of the earliest chemotherapeutic agents used in oncology. Dactinomycin is a potent antineoplastic agent primarily used in the treatment of various pediatric cancers and gestational trophoblastic neoplasia. It is classified as an antitumor antibiotic and is typically administered intravenously under careful medical supervision due to its significant toxicity profile.

Mechanism of Action

Dactinomycin exerts its cytotoxic effects through intercalation into DNA between guanine-cytosine base pairs. This binding inhibits DNA-dependent RNA synthesis by interfering with RNA polymerase activity. The drug preferentially binds to double-stranded DNA, preventing transcription and ultimately inhibiting protein synthesis. Additionally, dactinomycin causes single-strand DNA breaks through free radical formation and is cell cycle-specific, with greatest activity during the G1 phase and minimal effects during the S phase.

Indications

FDA-approved indications include:

• Wilms' tumor (as part of combination therapy)
• Rhabdomyosarcoma and other soft tissue sarcomas
• Ewing's sarcoma
• Gestational trophoblastic neoplasia
• Testicular carcinoma (nonseminomatous)
• Regional perfusion for locally recurrent or metastatic disease to extremities

Dactinomycin is also used off-label for certain ovarian germ cell tumors and as a component of some conditioning regimens prior to hematopoietic stem cell transplantation.

Dosage and Administration

• 15 mcg/kg/day IV for 5 days every 3-4 weeks
• Alternative: 400-600 mcg/m²/day for 5 days
• For gestational trophoblastic neoplasia: 12 mcg/kg/day IV for 7-10 days

• Administer IV push over 2-3 minutes or IV infusion over 10-15 minutes
• Extravasation can cause severe tissue damage - ensure patent venous access
• Dose reduction required for hepatic impairment or bone marrow suppression
• Renal impairment does not typically require dose adjustment

• Pediatric: Dosing based on body surface area or weight
• Geriatric: Use with caution due to increased susceptibility to toxicity
• Hepatic impairment: Reduce dose by 50% for bilirubin 3.1-5 mg/dL; avoid if bilirubin >5 mg/dL

Pharmacokinetics

Contraindications

• Hypersensitivity to dactinomycin or any component of the formulation
• Patients with recent exposure to chickenpox or herpes zoster (risk of severe generalized disease)
• Pregnancy (except for treatment of gestational trophoblastic neoplasia)
• Breastfeeding
• Patients with vaccination with live vaccines within 2-4 weeks

Warnings and Precautions

• Extravasation may cause severe soft tissue damage
• Highly toxic and potentially fatal
• Must be administered by experienced personnel in appropriate settings

• Bone marrow suppression: Monitor blood counts regularly
• Hepatotoxicity: May cause liver enzyme elevations and veno-occlusive disease
• Gastrointestinal toxicity: Severe nausea, vomiting, and mucositis common
• Secondary malignancies: Potential risk of development of secondary cancers
• Reproductive toxicity: May cause infertility; advise fertility preservation options
• Recall phenomenon: Skin reactions at previous radiation sites may occur

Drug Interactions

• Live vaccines: Increased risk of vaccine-related infections
• Other myelosuppressive agents: Enhanced bone marrow toxicity
• Radiation therapy: Enhanced radiation effects and recall reactions
• Phenytoin: Reduced phenytoin absorption leading to decreased efficacy
• Warfarin: Potential increased anticoagulant effect

Adverse Effects

• Nausea and vomiting (90%)
• Bone marrow suppression (anemia, leukopenia, thrombocytopenia)
• Mucositis/stomatitis (70%)
• Alopecia (30%)
• Fatigue/malaise
• Anorexia

• Severe myelosuppression
• Hepatotoxicity (elevated LFTs, veno-occlusive disease)
• Extravasation injury with tissue necrosis
• Anaphylactoid reactions
• Secondary malignancies
• Sepsis in neutropenic patients

Monitoring Parameters

• Complete blood count (weekly during therapy)
• Liver function tests (before each cycle)
• Renal function
• Electrolytes and nutritional status
• Signs/symptoms of infection
• Injection site for extravasation
• Tumor response assessment
• Pregnancy testing in women of childbearing potential

• Vital signs
• IV site patency
• Acute hypersensitivity reactions

Patient Education

• Report any signs of infection (fever, chills, sore throat)
• Immediately report pain, redness, or swelling at injection site
• Expect hair loss, which is usually reversible after treatment
• Use effective contraception during and for several months after treatment
• Maintain good oral hygiene to manage mucositis
• Stay hydrated and report persistent nausea/vomiting
• Avoid exposure to people with infections
• Do not receive live vaccines without consulting oncology team
• Report unusual bleeding or bruising
• Discuss fertility preservation options before treatment

References

1. FDA Prescribing Information: Dactinomycin for Injection 2. NCCN Guidelines: Pediatric Cancers (Version 2.2023) 3. Chabner BA, et al. Chemotherapy of Neoplastic Diseases. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. 4. Pinkel D. Actinomycin D in Childhood Cancer. Pediatrics. 1959;23:342-347. 5. National Cancer Institute. Dactinomycin - Cancer Drug Information. 6. EMA Assessment Report: Dactinomycin 7. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023. 8. Truong PT, et al. The safety and efficacy of dactinomycin in the treatment of solid tumors. Expert Opin Drug Saf. 2018;17(7):729-737.