Usage
Dactinomycin is an antineoplastic antibiotic primarily used in combination chemotherapy regimens for treating various pediatric and adult cancers. These include:
- Wilms’ tumor: A type of kidney cancer that primarily affects children.
- Rhabdomyosarcoma: A soft tissue sarcoma.
- Ewing sarcoma: A type of bone cancer.
- Metastatic nonseminomatous testicular cancer: Cancer that has spread from the testicles to other parts of the body.
- Gestational trophoblastic neoplasia: A rare group of tumors that form inside a woman’s uterus after conception.
- Locally recurrent or locoregional solid malignancies: Palliative or adjunctive regional perfusion.
Pharmacological Classification: Antineoplastic Antibiotic.
Mechanism of Action: Dactinomycin intercalates into DNA, inhibiting RNA and DNA synthesis, ultimately leading to cell death.
Alternate Names
Brand Names: Cosmegen
How It Works
Pharmacodynamics: Dactinomycin exerts its cytotoxic effects by intercalating into the DNA double helix, specifically binding to guanine residues. This interaction interferes with DNA-dependent RNA polymerase, effectively inhibiting RNA synthesis. The subsequent inhibition of protein synthesis leads to cell cycle arrest and apoptosis.
Pharmacokinetics:
- Absorption: Administered intravenously (IV) or via regional perfusion.
- Distribution: Widely distributed to tissues, with high concentrations in the liver, kidneys, and spleen. Limited penetration of the blood-brain barrier.
- Metabolism: Minimal metabolism.
- Elimination: Primarily excreted in the bile and to a lesser extent in urine.
Mode of Action: Intercalation into DNA, inhibiting RNA and DNA synthesis.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Directly binds to DNA. Inhibits RNA polymerase.
Elimination Pathways: Primarily biliary excretion; some renal excretion.
Dosage
Standard Dosage
Adults: Dosage varies widely depending on the specific cancer type and treatment regimen. Refer to specific protocols. Common adult doses include 0.012-0.015 mg/kg IV daily for 5 days in combination chemotherapy and 1.25 mg/m² IV in various schedules.
Children: Dosages are usually calculated based on body weight or body surface area. Refer to specific protocols. Children older than 6-12 months can receive similar doses to adults but lower doses are recommended for infants under 12 months.
Special Cases:
- Elderly Patients: Start at the lower end of the dosing range due to increased risk of myelosuppression.
- Patients with Renal Impairment: No dose adjustment is typically necessary.
- Patients with Hepatic Dysfunction: Dose reduction may be required in moderate to severe hepatic impairment (consider a 33-50% reduction in hyperbilirubinemia).
- Patients with Comorbid Conditions: Individualized dosing based on the specific comorbidity and its impact on drug metabolism and clearance.
Clinical Use Cases
Dactinomycin is not typically used in situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in cancer chemotherapy regimens administered in specialized oncology settings.
Dosage Adjustments
Dose reductions are often necessary when combining dactinomycin with radiation therapy or other chemotherapy agents due to increased toxicity risks. Adjust dosages for hepatic dysfunction and consider age-related changes in the elderly.
Side Effects
Common Side Effects
- Nausea and vomiting
- Hair loss
- Myelosuppression (decreased blood cell counts)
- Stomatitis (inflammation of the mouth)
- Diarrhea
- Anorexia (loss of appetite)
- Fatigue
- Skin reactions (rash, hyperpigmentation)
Rare but Serious Side Effects
- Hepatic veno-occlusive disease (especially in children under 4 years old)
- Secondary malignancies (e.g., leukemia)
- Severe myelosuppression
- Sepsis
- Anaphylaxis
- Severe skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome)
- Renal failure
Long-Term Effects
- Increased risk of secondary malignancies
- Potential for long-term damage to organs like the liver and kidneys
Adverse Drug Reactions (ADR)
Severe myelosuppression, anaphylaxis, hepatic veno-occlusive disease, secondary malignancies, sepsis.
Contraindications
- Hypersensitivity to dactinomycin
- Active chickenpox or herpes zoster infection
Drug Interactions
- Radiation therapy: Increased toxicity, especially within two months of radiation treatment, particularly when involving the liver.
- Live vaccines: Decreased effectiveness of the vaccine and increased risk of infection.
- Drugs that cause myelosuppression: Additive myelosuppressive effects.
- Hepatotoxic drugs: Increased risk of liver damage.
- Anticoagulants: Possible altered anticoagulant effects. Careful monitoring is recommended.
- CYP450 interactions: Minimal metabolism by CYP450 enzymes, so direct CYP450 interactions are less of a concern.
Pregnancy and Breastfeeding
Pregnancy Safety Category: D
Fetal risks: Dactinomycin is teratogenic and can cause fetal harm. It should not be used during pregnancy. Effective contraception is essential for both men and women during and after treatment.
Breastfeeding: Dactinomycin is contraindicated during breastfeeding due to the potential for secretion into breast milk.
Drug Profile Summary
- Mechanism of Action: Intercalates into DNA, inhibiting RNA and DNA synthesis.
- Side Effects: Nausea, vomiting, hair loss, myelosuppression, stomatitis, diarrhea, increased risk of infection. Serious side effects include hepatic veno-occlusive disease and secondary malignancies.
- Contraindications: Hypersensitivity, active chickenpox or herpes zoster infection, pregnancy.
- Drug Interactions: Radiation therapy, live vaccines, myelosuppressive drugs, hepatotoxic drugs.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies widely depending on indication and regimen. Consult specific protocols.
- Monitoring Parameters: Complete blood counts, liver function tests, renal function tests.
Popular Combinations
Dactinomycin is frequently used in combination chemotherapy regimens with other antineoplastic agents, tailored to the specific cancer being treated. Examples include combinations with vincristine, doxorubicin, cyclophosphamide, and cisplatin.
Precautions
- General Precautions: Monitor for signs of myelosuppression, hepatic toxicity, and other adverse effects.
- Specific Populations: See above under Dosage/Special Cases.
- Lifestyle Considerations: Advise patients on managing side effects such as nausea, vomiting, and fatigue.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Dactinomycin?
A: Dactinomycin dosing is highly variable and dependent on the indication, patient age and body weight, other medications given as part of the chemotherapy regime, and whether given as an infusion or bolus. The usual dosages for the various indications have been described earlier and should be referred to.
Q2: How is Dactinomycin administered?
A: Intravenously (IV), either as a bolus injection or a short infusion, or through regional perfusion.
Q3: What are the major side effects to watch for?
A: Myelosuppression (monitor blood counts), hepatic toxicity (monitor liver function), nausea and vomiting, stomatitis, and alopecia.
Q4: Is Dactinomycin safe during pregnancy or breastfeeding?
A: No, Dactinomycin is contraindicated in pregnancy and breastfeeding due to its teratogenic effects and potential secretion into breast milk.
Q5: What are the key drug interactions with Dactinomycin?
A: Radiation therapy increases toxicity. Live vaccines are less effective and may pose an infection risk. Concurrent use with other myelosuppressive or hepatotoxic drugs increases those respective risks.
Q6: How does Dactinomycin interact with other chemotherapy drugs?
A: Interactions vary depending on the specific drugs. Additive myelosuppression is a common concern.
Q7: What should be monitored in patients receiving Dactinomycin?
A: Complete blood counts, liver function tests, and renal function tests are essential for monitoring for toxicity. Also monitor for signs of infection and other adverse effects.
Q8: What are the signs of Dactinomycin extravasation, and how is it managed?
A: Extravasation can cause severe tissue damage. Signs include pain, swelling, redness, and blistering at the injection site. Management involves stopping the infusion immediately, aspirating any remaining drug, applying cold compresses, and possibly administering an antidote (e.g., dimethyl sulfoxide) as per local protocols.
Q9: What patient education is important regarding Dactinomycin?
A: Educate patients about potential side effects, the importance of reporting any adverse effects, and the need for reliable contraception during and after treatment.
