Dactinomycin

Dactinomycin is an antineoplastic agent belonging to the pharmacological class of antibiotics.

Actinomycin D and Actinomycin C1 are the synonyms of Dactinomycin.

The FDA approved Dactinomycin for treating various types of cancers, including Wilms' tumour, rhabdomyosarcoma, Ewing sarcoma, and gestational trophoblastic neoplasia.

Dactinomycin is poorly absorbed from the GI tract, widely distributed to different tissues, metabolized very little, and excreted in bile and urine.

Dactinomycin's most common side effects include nausea, vomiting, mouth ulcers and loss of appetite.

Dactinomycin is available as a powder for injection.

The molecule is available in India, the United States, Canada, China, countries within the European Union, Australia, Japan and South Korea.

Dactinomycin is an antineoplastic agent belonging to the pharmacological class of antibiotics.

Dactinomycin is an immunosuppressive agent that forms stable complexes with DNA through intercalation. It selectively inhibits DNA-dependent RNA synthesis while inhibiting protein and DNA synthesis to a lesser extent.

Primary uses:

Gestational trophoblastic tumour

Rhabdomyosarcoma

Wilms’ tumour

Other uses:

Ewing’s sarcoma

Malignant Germ Cell Tumors of the Ovary (Off-label)

Malignant melanoma

Testicular cancer

• Testicular cancer: Testicular cancer can be effectively treated with dacinomycin, primarily when the cancer has spread and is not seminomatous. Dactinomycin inhibits the growth and/or kills cancer cells as part of a multiphase combination chemotherapy regimen; in men, it also prevents cancer cells from multiplying. Preventing DNA synthesis and the cell cycle eventually causes cancer cells to be destroyed or inhibited. Consequently, it helps those who have testicular cancer have better outcomes.
• Wilms' tumour: The most common kidney cancer in children is wilms' tumor, commonly referred to as nephroblastoma. Dactinomycin is administered in combination with other medications or therapeutic approaches, such as surgery, radiation therapy, or chemotherapy, contingent on the patient's condition and the cancer's stage or severity. Dactinomycin acts an integral part in the overall management of Wilms' tumor by interfering with the process of DNA synthesis and preventing cell proliferation.
• Rhabdomyosarcoma: Mostly affecting children and adolescents, rhabdomyosarcoma is a rare cancer that develops from skeletal muscle cells. Pediatric patients with Rhabdomyosarcoma have a markedly better prognosis when treated with Dactinomycin because it effectively inhibits the spread and growth of cancer cells by interfering with DNA synthesis and preventing cell proliferation.
• Gestational trophoblastic neoplasia: A rare tumour called gestational trophoblastic disease (GTD) develops inside the uterus from tissue that forms following successful sperm and egg fusion in a female. Dactinomycin is administered to kill these tumour cells and stop them from growing further by interfering with DNA synthesis and disrupting the cell cycle. Dactinomycin also inhibits the growth and multiplication of trophoblastic cells, which provides the overall effectiveness of the treatment.
• Ewing's sarcoma: A tumour called Ewing's sarcoma develops in the soft tissue surrounding the bones, such as the cartilage or nerves. Young adults and children usually get affected. Dactinomycin inhibits DNA synthesis, which stops the growth of cancer cells and aids in treating Ewing's sarcoma. It can be administered either by itself or in addition to other medications.

Dactinomycin is indicated in the following health conditions:

• For Wilms tumour, use as part of a multiphase, combination chemotherapy regimen.
• For rhabdomyosarcoma, use as part of a multiphase, combination chemotherapy regimen.
• For Ewing sarcoma, use as part of a multiphase, combination chemotherapy regimen.
• For postmenarchal patients with gestational trophoblastic neoplasia, use as a single agent or as part of a combination chemotherapy regimen.
• For metastatic, nonseminomatous testicular cancer, use as part of a multiphase, combination chemotherapy regimen.
• For locally recurrent or locoregional solid malignancies, use as an adjunctive regional perfusion or component of palliative.

Parenterally: Administer the IV diluted reconstituted product over a 10-to 15-minute period. Abstain from IM or SC administration, and do not use an in-line cellulose ester membrane filter. Stop the injection or infusion immediately and restart in another vein if extravasation is confirmed or suspected. If there are any indications of extravasation or perivenous infiltration, like burning, stop. Apply sporadic ice to the area for fifteen minutes every day for three days. Depending on the severity of the reaction, closely monitor and seek counsel from plastic surgery if necessary.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Patients can actively manage side effects by altering their diet while receiving Dactinomycin treatment. Include foods high in nutrients, like leafy greens, fruits and whole grains. For the best possible treatment results, it is also imperative to refrain from smoking and drinking alcohol, as well as to avoid processed meats, fast food, fried foods, refined carbohydrates, and salty snacks.

The dietary restriction should be individualized as per patient requirements.

• Secondary Malignancy or Leukemia: Treatment increases the risk of secondary malignancies.
• Veno-occlusive Disease (VOD): Severe or fatal VOD may occur. Monitor for signs, delay the next dose if VOD develops, and adjust treatment based on severity.
• Extravasation: Severe local tissue injury may result. Immediately interrupt injection, apply ice to the site, and take appropriate measures if extravasation occurs.
• Myelosuppression: Closely monitor blood cell counts before each cycle and delay the next dose if severe myelosuppression persists.
• Immunizations: Avoid live viral vaccines before or during treatment.
• Severe Mucocutaneous Reactions: Steven-Johnson syndrome and Toxic Epidermal Necrolysis can occur. Permanently discontinue if severe mucocutaneous reactions develop.
• Renal Toxicity: Monitor creatinine and electrolytes frequently during therapy.
• Hepatotoxicity: Abnormalities in liver function can occur. Monitor liver enzymes before and during therapy.
• Potentiation of Radiation Toxicity and Radiation Recall: Lower the dose by 50% during concurrent radiation. Use extreme caution when administering within 2 months of radiation therapy.
• Embryo-Fetal Toxicity: Dactinomycin can cause fetal harm. Advise patients of the potential risk and recommend effective contraception during treatment.

The adverse reactions related to Dactinomycin can be categorized as:

• Common Adverse Effects: Myelosuppression, nausea, vomiting, stomatitis, diarrhea, abdominal pain, and localized redness and pain at the injection site.
• Less Common Adverse Effects: Mucositis, anorexia, elevated liver enzymes, fever, and potential allergic responses.
• Rare Adverse Effects: Hematologic toxicities, secondary malignancies, veno-occlusive disease, renal toxicity, and dermatologic reactions such as rash and hyperpigmentation.

Postmarketing Reports:

Serious infections, such as sepsis

Hematologic: pancytopenia, reticulocytopenia, leukopenia, thrombocytopenia, anemia, neutropenia, febrile neutropenia, and disseminated intravascular coagulation.

Immune system: Hypersensitivity

Anorexia, hypocalcemia, and tumour lysis syndrome regarding nutrition and metabolism

Peripheral neuropathy in the neurological system

Ocular: Neuropathy of the optic nerve

Vascular: haemorrhage, thrombophilia

Pneumonia and pneumothorax are respiratory, thoracic, and mediastinal conditions.

Gastrointestinal symptoms include ascites, proctitis, mucositis, cheilitis, dysphagia, esophagitis, ulcerative stomatitis, vomiting, diarrhea, constipation, and abdominal pain.

Hepatobiliary: Abnormal liver function tests, hepatomegaly, hepatitis, fatal reports of hepatic failure, hepatic veno-occlusive disease

Dermatologic conditions include radiation recall, toxic epidermal necrolysis, erythema multiforme, rash, dermatitis, alopecia, and Stevens-Johnson Syndrome.

Myalgia and growth retardation in the musculoskeletal and connective tissue

renal and urinary: renal failure, renal impairment

General: fatigue, fever, and malaise

The clinically relevant drug interactions of Dactinomycin are briefly summarized here.

When used alongside radiation therapy for a right-sided Wilms' tumour, dactinomycin may increase toxicity, especially if given within two months of radiation therapy. Furthermore, it may lessen the efficacy of live vaccinations.

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available, and life is in danger. Positive evidence of prenatal risk in humans.

Pregnant women may experience fetal harm from the medication due to its mechanism of action and results from animal studies.

Pregnant animals administered the drug during the organogenesis phase in animal reproduction studies experienced teratogenic side effects, including malformations, even at doses below the human recommended threshold.

Before starting, confirm if females who are capable of reproducing are pregnant.

Contraception

Fertile women should use reliable contraception both during treatment and for a minimum of six months following the last dosage.

Men who have potential partners who are female: Use reliable contraception during treatment and for three months following the last dosage.

• Nursing Mothers

The presence of dactinomycin or its metabolites in human milk, their effects on the breastfed infant, or their effects on milk production are not well-documented.

• Pediatric Use

As per the FDA, dactinomycin is safe and effective in pediatric patients with Wilms tumour, Ewing sarcoma, rhabdomyosarcoma, and metastatic nonseminomatous testicular cancer. In pediatric postmenarchal patients with gestational trophoblastic neoplasia, it is also established. Its safety and effectiveness have not yet been determined for children receiving regional perfusion for solid tumours.

Dose Adjustment

Wilms Tumor

45 mcg/kg IV every 3 to 6 weeks for a maximum duration of 26 weeks

Rhabdomyosarcoma

15 mg/kg IV on Days 1-5 every 3 to 9 weeks for ua maximum of 112 weeks

Ewing Sarcoma

1250 mcg/m² IV every 3Week for 51 weeks

Gestational Trophoblastic Neoplasms

Nonmetastatic, Low-risk metastatic disease: 12 mcg/kg IV daily for 5 days as a single agent.

High-risk metastatic disease: 500 mcg IV on Day 1 and 2 after every 2 Weeks for a maximum duration of 8 weeks.

Testicular Cancer

As part of a cisplatin-based, multi-agent combination regimen, 1000 mcg/m2 IV once every three weeks for twelve weeks.

Malignant Germ Cell Tumors (Off Label)

As a Palliative treatment

≥14 years old: 300 mcg/m²/day IV for 5 days every 4 weeks (in combination with vincristine and cyclophosphamide) (Slayton 1985)

• Geriatric Use

There were insufficient subjects 65 years of age and older in Dactinomycin clinical trials to assess whether their responses differed from those of younger subjects.

Dose Adjustment in Kidney Impairment Patients:

There is not enough information to determine whether these patients require a change in their dosage of dactinomycin.

Dose Adjustment in Hepatic Impairment Patients:

The use of Dactinomycin in Hepatic Impairment Patients needs to be well-documented.

Pharmacodynamics

It is unknown how exposure to dactinomycin affects response and how long the pharmacodynamics response takes to become apparent.

Pharmacokinetics

• Absorption: Dactinomycin exhibits poor absorption from the gastrointestinal (GI) tract when taken orally.
• Distribution: Dactinomycin spreads rapidly after administration; higher concentrations are seen in nucleated cells and bone marrow. It cannot cross the blood-brain barrier but successfully crosses the placenta, making it accessible during pregnancy. The medication binds extensively to various bodily tissues but weakly to proteins.
• Metabolism: Dactinomycin is not extensively metabolized within the body.
• Excretion: For a week following radiolabeled dactinomycin administration, about 30% of the medication is eliminated through urine and faeces. The half-life of dactinomycin in the terminal plasma is approximately 36 hours.

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