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Dactinomycin

Pronunciation: DAK-tin-oh-MYE-sin
Class: Antineoplastic agent

Trade Names

Cosmegen
- Injection, lyophilized powder for solution 500 mcg

Pharmacology

Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvulus . It binds DNA and inhibits messenger RNA synthesis.

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Pharmacokinetics

Distribution

Concentrated in nucleated cells. Does not penetrate the blood-brain barrier.

Metabolism

Minimally metabolized.

Elimination

Approximately 30% recovered in urine and feces in 1 wk; half-life is approximately 36 h.

Indications and Usage

Treatment of Wilms tumor, childhood rhabdomyosarcoma, Ewing sarcoma, and metastatic nonseminomatous testicular cancer as part of combination chemotherapy and/or multimodality treatment regimen; palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies as a component of regional perfusion; treatment of gestational trophoblastic neoplasia as a single agent or as part of a combination chemotherapy regimen.

Contraindications

Infection with chickenpox or herpes zoster; hypersensitivity to any component of the product.

Dosage and Administration

Ewing Sarcoma/Wilms Tumor
Adults and children older than 6 mo

IV 15 mcg/kg/day for 5 days with other chemotherapeutic agents. Repeat in 3 wk (adults) or 3 to 6 wk (children) if necessary (max dose, 15 mcg/kg/day for 5 days per 2-wk cycle).

Gestational Trophoblastic Neoplasia
Adults

IV 12 mcg/kg/day for 5 days as a single agent; as a combination regimen, 500 mcg on days 1 and 2 with etoposide, methotrexate, leucovorin (folinic acid), vincristine, cyclophosphamide, and cisplatin. Repeat in 3 wk if necessary (max dose, 15 mcg/kg/day for 5 days per 2-wk cycle).

Metastatic Nonseminomatous Testicular Cancer
Adults and children older than 6 mo

IV 1,000 mcg/m 2 on day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin. Repeat in 3 wk (adults) or 3 to 6 wk (children) if necessary.

Rhabdomyosarcoma
Adults and children older than 6 mo

IV 15 mcg/kg/day for 5 days with other chemotherapeutic agents. Repeat in 3 wk (adults) or 3 to 6 wk (children) if necessary (max dose, 15 mcg/kg/day for 5 days per 2-wk cycle).

Solid Malignancies
Adults and children older than 6 mo

IV The dosage schedules and the technique itself vary from one investigator to another; therefore, the published literature should be consulted for details. In general, for lower extremity or pelvis, administer 50 mcg/kg; for upper extremity, administer 35 mcg/kg (max dose, 15 mcg/kg/day for 5 days per 2-wk cycle).

General Advice

  • Administer by IV push injection, IV sidearm, or regional perfusion only.
  • The dosage varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy.
  • Nausea and vomiting, which may occur early during the first few hours after administration, may be alleviated by giving antiemetics.
  • It may be advisable to use lower doses in obese patients or when previous chemotherapy or radiation therapy has been employed. Calculate the dosage for obese or edematous patients on the basis of surface area to more closely relate dosage to lean body mass.
  • Dactinomycin is highly toxic. Handle and administer with extreme care. Diligently follow institutional and National Institutes of Health (NIH) procedures for handling, administration, and disposal of anticancer drugs. Wear appropriate protective equipment when preparing and administering dactinomycin. Avoid inhalation of dust or vapors and contact with skin, mucous membranes, and eyes.
  • If accidental skin or mucous membrane contact occurs, immediately irrigate the affected area with copious amounts of water for at least 15 min while removing contaminated clothing and shoes. Destroy contaminated clothing and thoroughly clean shoes before reuse.
  • If accidental eye contact occurs, immediately institute irrigation with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution for at least 15 min. Prompt ophthalmic evaluation should follow irrigation.
  • The NIH presently recommends that the preparation of injectable antineoplastic drugs should be performed in a class II laminar flow biological safety cabinet.
  • Reconstitute powder for injection with 1.1 mL of sterile water for injection (without preservative). Mix thoroughly to obtain complete dissolution. Resulting solution contains 500 mcg/mL (0.5 mg/mL) of dactinomycin.
  • Do not reconstitute powder for injection using diluents with preservatives that can cause precipitation of dactinomycin. Use of water containing preservatives (benzyl alcohol or parabens) results in the formation of a precipitate.
  • Reconstituted solution should be a clear, golden-colored solution.
  • Add prescribed dose or reconstituted solution directly to infusion solution of dextrose 5% or sodium chloride injection or to the tubing of a running IV infusion.
  • If medication is to be given directly into a vein without the use of an infusion, use the “2-needle technique” to reduce risk of tissue damage. Reconstitute and withdraw the calculated dose from the vial with 1 sterile needle. Use another sterile needle for direct injection into the vein.
  • Do not use in-line filters made of cellulose, which can remove dactinomycin.
  • If extravasation occurs, severe damage to soft tissue will occur. In at least one instance, this has led to contracture of the arms. Care in the administration of dactinomycin will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions, such as urticaria and erythematous streaking. Extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle.

Storage/Stability

Store between 68° and 77°F. Protect from light and humidity. Discard vial within 6 h of the initial needle puncture if opened within an ISO Class 5 biological safety cabinet, or within 1 h of the initial needle puncture if opened outside of such an environment, based on the USP Chapter < 797 > standards. Discard reconstituted solution within 24 h. The final prepared product (which has undergone reconstitution and dilution) must be used within 4 h of initial reconstitution when stored at ambient room temperature.

Drug Interactions

Live vaccines

Live virus vaccines should not be administered during therapy with dactinomycin.

Palifermin

Coadministration of palifermin and dactinomycin within the same 24-h time period may increase the severity and duration of oral mucositis.

Laboratory Test Interactions

Bioassay procedures for the determination of antibacterial drug levels.

Adverse Reactions

CNS

Fatigue; lethargy; malaise.

Dermatologic

Acne; alopecia; erythema multiforme; flare-up of erythema; increased pigmentation of previously irradiated skin; skin eruptions; Stevens-Johnson syndrome, TEN (postmarketing).

GI

Abdominal pain; anorexia; cheilitis; diarrhea; dysphagia; esophagitis; GI ulceration; nausea; proctitis; ulcerative stomatitis; vomiting.

Hepatic

Abnormal LFTs; hepatic failure with reports of death; hepatic veno-occlusive disease that may be associated with intravascular clotting disorder and multiorgan failure; hepatitis; hepatomegaly; liver toxicity including ascites.

Hematologic-Lymphatic

Agranulocytosis; anemia; aplastic anemia; febrile neutropenia; leukopenia; neutropenia; pancytopenia; reticulocytopenia; thrombocytopenia.

Respiratory

Pharyngitis; pneumonitis.

Miscellaneous

Fever; growth retardation; hypocalcemia; infection; myalgia; sepsis, including neutropenic sepsis, with fatal outcome.

Precautions

Warnings

Dactinomycin should be administered only under the supervision of a health care provider who is experienced in the use of cancer chemotherapeutic agents. This drug is highly toxic and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Because of the toxic properties of dactinomycin (eg, corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently.

Dactinomycin is extremely corrosive to soft tissue. If extravasation occurs during IV use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms.


Monitor

Assess renal, hepatic, and bone marrow function at baseline and frequently during therapy. Observe patients frequently for toxic effects (eg, stomatitis, diarrhea, severe hematopoietic depression). Monitor IV injection site for signs or symptoms of extravasation.


Pregnancy

Category D . May cause fetal harm. Avoid use during pregnancy.

Lactation

Undetermined.

Children

Toxicity is increased in infants. Avoid use in infants younger than 6 to 12 mo.

Elderly

Elderly patients have an increased risk of myelosuppression. Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Radiation therapy

With combined dactinomycin-radiation therapy, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema. A smaller than usual radiation dose when given with dactinomycin causes erythema and vesiculation, which progress more rapidly through the tanning and desquamation stages. Erythema from previous radiation therapy may be reactivated by dactinomycin alone, even when irradiation occurred many months earlier, and especially when the interval between the 2 forms of therapy is brief. When the nasopharynx is irradiated, the combination may produce severe oropharyngeal mucositis. Severe reactions may appear if high doses are used or if the patient is particularly sensitive to such combined therapy. Particular caution is necessary when administering dactinomycin within 2 mo of irradiation for the treatment of right-sided Wilms tumor because hepatomegaly and elevated AST levels have been noted. In general, dactinomycin should not be coadministered with radiotherapy in the treatment of Wilms tumor unless the benefit outweighs the risk.

Second primary tumors

Increased incidence (including leukemia) following treatment with radiation and antineoplastic agents.

Toxic effects

Note that toxic effects (with the exception of nausea and vomiting) usually do not become apparent until 2 to 4 days after a course of therapy is stopped, and may not peak until 1 to 2 wk have elapsed.

Veno-occlusive disease

Veno-occlusive disease (primarily hepatic), may result in fatality, particularly in children younger than 48 mo.

Overdosage

Symptoms

Acute renal failure, desquamation and epidermolysis, diarrhea, exanthema, GI ulceration, mucositis including stomatitis, nausea, sepsis (including neutropenic sepsis with fatal outcome and death), severe hematopoietic depression, severe skin disorders including skin exfoliation, veno-occlusive disease, vomiting.

Patient Information

  • Advise patients, families, or caregivers that medication will be prepared and administered by health care providers in a health care setting.
  • Advise women of childbearing potential to avoid becoming pregnant during therapy.
  • Because dactinomycin may lower the ability of the body to fight infection, advise patients to avoid contact with people who have colds or infection.
  • Advise patients, families, or caregivers to immediately report any of the following to their health care provider: rash; hives; difficulty breathing or unexplained shortness of breath; fever, chills, or other signs of infection; sores in mouth; pain, redness, or swelling at injection site.
  • Advise patients to avoid activities that may cause bruising or bleeding while on therapy.
  • Inform patients that dactinomycin may increase their risk of developing other cancers (eg, leukemia) when used with radiation therapy.

Copyright © 2009 Wolters Kluwer Health.

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