Dactinomycin – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Good evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis.

The capacity of actinomycins to bind with double-helical DNA is responsible for their biological activity and cytotoxicity. X-ray studies of a crystalline complex between dactinomycin and deoxyguanosine permitted formulation of a model that appears to explain the binding of the drug to DNA. The planar phenoxazone ring intercalates between adjacent guaninecytosine base pairs of DNA, while the polypeptide chains extend along the minor groove of the helix. The summation of these interactions provides great stability to the dactinomycin-DNA complex, and as a result of the binding of dactinomycin, the transcription of DNA by RNA polymerase is blocked. The DNA-dependent RNA polymerases are much more sensitive to the effects of dactinomycin than are the DNA polymerases. In addition, dactinomycin causes single-strand breaks in DNA, possibly through a free-radical intermediate or as a result of the action of topoisomerase II

or

Dactinomycin is an antineoplastic antibiotic. The drug has bacteriostatic activity, particularly against gram-positive organisms, but its cytotoxicity precludes its use as an anti-infective agent. Although the exact mechanism(s) of action has not been fully elucidated, the drug appears to inhibit DNA-dependent RNA synthesis by forming a complex with DNA by intercalating with guanine residues and impairing the template activity of DNA. Protein and DNA synthesis are also inhibited but less extensively and at higher concentrations of dactinomycin than are needed to inhibit RNA synthesis. Dactinomycin is immunosuppressive and also possesses some hypocalcemic activity similar to plicamycin.

Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.

Indications

  • Antineoplastic; Anti-Bacterial Agents; Nucleic Acid Synthesis Inhibitors; Protein Synthesis Inhibitors
  • For the treatment of Wilms’ tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma, and metastatic, nonseminomatous testicular cancer as part of a combination chemotherapy and/or multi-modality treatment regimen.
  • Daptomycin is indicated for the treatment of complicated skin and skin structure infections (cSSSI) in patients one year of age and older. It is also indicated for the treatment of Staphylococcus aureus bloodstream infections (bacteremia) in patients one year of age and older, including in adult patients with right-sided infective endocarditis.[rx]
  • Dactinomycin is an intravenously administered, antineoplastic antibiotic that is used in the treatment of solid tumors in children and choriocarcinoma in adult women.
  • Dactinomycin, as part of a combination chemotherapy and/or multi-modality treatment regimen, is indicated for the treatment of Wilms’ tumor, childhood rhabdomyosarcoma, Ewing’s sarcoma and metastatic, nonseminomatous testicular cancer.
  • Dactinomycin is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.
  • Dactinomycin, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.
  • Complicated Skin and Skin Structure Infection
  • Staphylococcus Aureus Bloodstream Infections (BSI; Bacteremia)

Use in Cancer

Dactinomycin is approved to be used alone or with other drugs to treat:

Dactinomycin is also being studied in the treatment of other types of cancer.

Contraindications

  • Serious rash.
  • New primary malignancy.
  • Anemia, bone marrow suppression, geriatric, neutropenia, thrombocytopenia.
  • Herpes infection, infection.
  • Extravasation.
  • Children, hepatotoxicity, infants, sinusoidal obstruction syndrome (SOS), veno-occlusive disease (VOD)
  • Radiation therapy.
  • shingles
  • a bad infection
  • low blood counts due to bone marrow failure
  • anemia
  • decreased blood platelets
  • low levels of white blood cells
  • low levels of a type of white blood cell called neutrophils
  • a blood clot in a vein of the liver
  • liver problems
  • ascites
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • infection caused by the varicella zoster virus
  • exposure to the chickenpox

Dosage

Strengths: 0.5 mg

 Wilms’ Tumor

  • As part of a multi-agent combination chemotherapy regimen: 45 mcg/kg IV over 10 to 15 minutes once every 3 to 6 weeks for up to 26 weeks
  • For the treatment of Wilms tumor as part of a multi-phase combination chemotherapy regimen

Rhabdomyosarcoma

  • As part of a multi-agent combination chemotherapy regimen: 15 mcg/kg IV over 10 to 15 minutes once daily for 5 days every 3 to 9 weeks for up to 112 weeks
  • For the treatment of rhabdomyosarcoma as part of a multi-phase combination chemotherapy regimen

Ewing’s Sarcoma

  • As part of a multi-agent combination chemotherapy regimen: 1250 mcg/m2 IV over 10 to 15 minutes once every 3 weeks for 51 weeks
  • For the treatment of Ewing sarcoma as part of a multi-phase combination chemotherapy regimen

Testicular Cancer

  • As part of a cisplatin-based multi-agent combination chemotherapy regimen: 1000 mcg/m2 IV over 10 to 15 minutes once every 3 weeks for 12 weeks
  • For the treatment of metastatic nonseminomatous testicular cancer as part of a multi-phase combination chemotherapy regimen

Trophoblastic Disease

  • As a single agent for nonmetastatic and low-risk metastatic disease: 12 mcg/kg IV over 10 to 15 minutes daily for 5 days
  • As part of a multi-agent combination chemotherapy regimen for high-risk metastatic disease: 500 mcg IV over 10 to 15 minutes Days 1 and 2 every 2 weeks for up to 8 weeks
  • For the treatment of post-menarchal patients with gestational trophoblastic neoplasia as a single agent or as part of a combination chemotherapy regimen

Solid Tumors

  • In combination with melphalan for lower extremity or pelvis: 50 mcg/kg IV over 10 to 15 minutes once
  • In combination with melphalan for upper extremity: 35 mcg/kg IV once
  • For the treatment of adult patients with locally recurrent or locoregional solid malignancies as a component of palliative or adjunctive regional perfusion

Usual Pediatric Dose

Wilms’ Tumor

  • As part of a multi-agent combination chemotherapy regimen: 45 mcg/kg IV over 10 to 15 minutes once every 3 to 6 weeks for up to 26 weeks
  • For the treatment of Wilms tumor as part of a multi-phase combination chemotherapy regimen

Rhabdomyosarcoma

  • As part of a multi-agent combination chemotherapy regimen: 15 mcg/kg IV over 10 to 15 minutes once daily for 5 days every 3 to 9 weeks for up to 112 weeks
  • For the treatment of rhabdomyosarcoma as part of a multi-phase combination chemotherapy regimen

Ewing’s Sarcoma

  • As part of a multi-agent combination chemotherapy regimen: 1250 mcg/m2 IV over 10 to 15 minutes once every 3 weeks for 51 weeks
  • For the treatment of Ewing sarcoma as part of a multi-phase combination chemotherapy regimen

Testicular Cancer

  • As part of a cisplatin-based multi-agent combination chemotherapy regimen: 1000 mcg/m2 IV over 10 to 15 minutes once every 3 weeks for 12 weeks
  • For the treatment of metastatic nonseminomatous testicular cancer as part of a multi-phase combination chemotherapy regimen

Trophoblastic Disease

  • As a single agent for nonmetastatic and low-risk metastatic disease: 12 mcg/kg IV over 10 to 15 minutes daily for 5 days
  • As part of a multi-agent combination chemotherapy regimen for high-risk metastatic disease: 500 mcg IV over 10 to 15 minutes Days 1 and 2 every 2 weeks for up to 8 weeks
  • For the treatment of post-menarchal pediatric patients with gestational trophoblastic neoplasia as a single agent or as part of a combination chemotherapy regimen

Dose Adjustments

Calculate the dose for obese or edematous patients based on ideal body weight.

Administration advice:

  • Administer the diluted reconstituted product IV over 10 to 15 minutes.
  • Do not use in-line filters with a cellulose ester membrane.

Side Effects

The Most Common

  • Common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. Actinomycin is a vesicant, if extravasation occurs.
  • vomiting
  • stomach pain
  • diarrhea
  • hair loss
  • hives
  • rash
  • difficulty breathing or swallowing
  • nausea
  • extreme tiredness
  • unusual bleeding or bruising
  • sores in the mouth and throat
  • lack of energy
  • loss of appetite
  • pain in the upper right part of the stomach
  • yellowing of the skin or eyes
  • fever, sore throat, ongoing cough and congestion, or other signs of infection
  • unusual bleeding or bruising
  • black and tarry stools
  • red blood in stools

More common

  • Black, tarry stools
  • blood in the urine or stools
  • chills
  • cough
  • diarrhea (continuing)
  • difficulty with swallowing
  • fever
  • heartburn
  • hoarseness
  • lower back or side pain
  • painful or difficult urination
  • pinpoint red spots on the skin
  • sores in the mouth and on the lips
  • stomach pain (continuing)
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • swelling or tenderness in your stomach (upper right side), rapid weight gain;
  • swelling in your arms or legs;
  • dark urine, jaundice (yellowing of the skin or eyes);
  • redness of your skin or the inside of your mouth and throat (if you are also receiving radiation treatment);
  • sores or white patches in or around your mouth, trouble swallowing or talking, dry mouth, bad breath, altered sense of taste;
  • blisters, ulcers, or other skin changes where an injection was given; or
  • low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath.

Rare

  • Blistering, peeling, or loosening of the skin
  • body aches or pain
  • chapped, red, or swollen lips
  • confusion
  • congestion
  • cough
  • difficulty with breathing
  • difficulty with moving
  • difficulty with swallowing
  • dryness or soreness of the throat
  • flushing or redness of the skin
  • irregular heartbeat
  • joint pain or swelling
  • muscle ache, pains, or stiffness
  • muscle cramps in the hands, arms, feet, legs, or face
  • numbness and tingling around the mouth, fingertips, or feet
  • pain at the injection site
  • runny nose
  • scaling, redness, burning, pain, or other signs of inflammation of the lips
  • seizures
  • slow growth
  • stomach cramps
  • swelling of the feet or lower legs
  • tender, swollen glands in the neck
  • tremor
  • unusually warm skin
  • voice changes
  • yellow eyes or skin

Drug Interaction

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Pregnancy and Lactation

AU TGA pregnancy category: D
US FDA pregnancy category: Not assigned.

Pregnancy

Based on findings from animal studies and its mechanism of action, this drug can cause fetal harm when administered to a pregnant woman.
Verify negative pregnancy status in females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during therapy and for at least 6 months after. Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during therapy and for 3 months after. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Lactation

No information is available on the use of this drug during breastfeeding. Most experts consider breastfeeding contraindicated during maternal antineoplastic therapy. The effects in the nursing infant are unknown. The manufacturer recommends that breastfeeding be discontinued during therapy and for at least 14 days after.

How should this medicine be used?

Dactinomycin comes as a powder to be mixed with liquid to be injected intravenously (into a vein) by a doctor or nurse in a medical facility. The length of treatment depends on the type of cancer you have, the types of other drugs you are taking, and how well your body responds to treatment. Your doctor may need to stop or delay your treatment if you experience certain side effects. Dactinomycin may also be injected by a doctor directly into a specific the part of the body or the organ to treat the area where a tumor is located. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

Dactinomycin is also sometimes used to treat a type of cancer of the ovaries (a cancer that begins in the female reproductive organs where eggs are formed). Talk to your doctor about the risks of using this medication for your condition. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving dactinomycin,

  • tell your doctor and pharmacist if you are allergic to dactinomycin, any other medications, or any of the ingredients in dactinomycin injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take.
  • tell your doctor if you have chickenpox or herpes zoster (shingles). Your doctor will probably not want you to receive dactinomycin injection.
  • tell your doctor if you have previously received or are currently receiving radiation therapy.
  • tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should not become pregnant or breast-feed while you are receiving dactinomycin. If you become pregnant while receiving dactinomycin, call your doctor. Dactinomycin may harm the fetus.
  • do not have any vaccinations without talking to your doctor.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050682s025lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050682s033lbl.pdf
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Dactinomycin
  4. https://pubchem.ncbi.nlm.nih.gov/compound/2019
  5. https://en.wikipedia.org/wiki/Dactinomycin
  6. https://go.drugbank.com/drugs/DB00080
  7. https://medlineplus.gov/druginfo/meds/a682224.html
  8. https://www.mayoclinic.org/drugs-supplements/dactinomycin-intravenous-route/side-effects/drg-20063277?p=1
  9. https://www.drugs.com/mtm/dactinomycin.html
  10. https://www.webmd.com/drugs/2/drug-19921/dactinomycin-intravenous/details/list-contraindications
  11. CAMEO Chemical Reactivity Classification
  12. Dactinomycin [USAN:USP:INN:BAN]
    ChemIDplus Chemical Information Classification
  13. CompTox Chemicals Dashboard Chemical Lists
  14. NCI Thesaurus Tree
  15. The Natural Products Atlas Classification
  16. IARC Classification
  17. LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
  18. PubChem
  19. Nucleic Acid Synthesis Inhibitors
    Protein Synthesis Inhibitors
    Antibiotics, Antineoplastic
  20. NORMAN Suspect List Exchange Classification
  21. NCBI