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Cosmegen

Generic Name: Dactinomycin
Class: Antineoplastic Agents
VA Class: AN200
CAS Number: 50-76-0

Warning(s)

  • Powder and solution are highly toxic (e.g., corrosive, carcinogenic, mutagenic, teratogenic).100 (See Toxicity and Adequate Patient Monitoring under Cautions.)

  • Handle and administer with care; avoid inhalation of dust or vapors and contact with skin or mucous membranes, especially the eyes.100 (See IV Administration under Dosage and Administration.)

  • Avoid exposure during pregnancy.100 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Highly corrosive to soft tissue; severe damage to soft tissues if extravasation occurs.100 Contracture of the arms has been reported.100 (See Local Effects under Cautions.)

  • Administer only under the supervision of a qualified clinician experienced in the use of cancer chemotherapeutic agents.100

Introduction

Antineoplastic agent; an actinomycin antibiotic produced by Streptomyces parvullus.100

Uses for Cosmegen

Wilms’ Tumor

In children with Wilms’ tumor, used in combination regimens (e.g., with vincristine with or without doxorubicin) as an adjunct to surgery with or without radiation therapy.100 101 103 The best combination or sequential therapy to achieve maximum response and duration of survival has not been established and comparative efficacy is continually being evaluated.100 103

Generally should not be administered concomitantly with radiation therapy in the treatment of Wilms’ tumor.100 103 (See Toxicity Potentiation with Concomitant Radiation Therapy under Cautions.)

Rhabdomyosarcoma

Component of various chemotherapeutic regimens as an adjunct to surgery with or without radiation therapy; however, the best combination or sequential therapy to achieve maximum response and duration of survival has not been established and comparative efficacy is continually being evaluated.100 101 103 104

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Ewing’s Sarcoma

Has been used in combination chemotherapy for treatment of Ewing’s sarcoma;100 however, other regimens currently are preferred.101 105

Trophoblastic Neoplasms

Treatment (alone or as a component of various chemotherapeutic regimens) of trophoblastic neoplasms (choriocarcinoma, chorioadenoma destruens) in women.100 101 106

Dactinomycin alone is generally reserved for patients whose tumors develop resistance or do not respond to methotrexate or in patients with impaired hepatic or renal function with increased risk of methotrexate toxicity.106

Combination therapy with methotrexate and cyclophosphamide (MAC regimen) has been used for treatment of metastatic gestational trophoblastic tumors that are refractory to single-drug therapy.101 106

Combination therapy with etoposide, methotrexate, cyclophosphamide, and vincristine (EMA-CO) is commonly used in patients with poor-prognosis metastatic gestational trophoblastic tumors.101 106

Testicular Cancer

Used in combination with vinblastine, bleomycin, cyclophosphamide, and cisplatin (VAB-6) for the treatment of advanced nonseminomatous testicular carcinoma.100 107 The best combination or sequential therapy has not been established and comparative efficacy is continually being evaluated.107

Solid Tumors

Used alone or in combination with other chemotherapeutic agents by regional isolation perfusion as an adjunct to surgery or as palliative therapy alone in the treatment of locally recurrent or locoregional solid tumors (sarcomas, carcinomas, and adenocarcinomas).100

Ovarian Germ Cell Tumors

Component of alternative chemotherapeutic regimens for ovarian germ cell tumors.101 102

Cosmegen Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.100

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion (preferred) or IV injection.100 May also be adminstered by regional isolation perfusion.100

Do not administer IM, sub-Q, or orally.100

Avoid extravasation; extremely irritating to tissues.100 Pain and burning or stinging sensation during IV administration may be a symptom, but extravasation may occur without these symptoms and even when blood returns well on aspiration of the infusion needle.100 If manifestations of extravasation occur, immediately stop administration and restart at another site; apply ice intermittently to affected area for 15 minutes 4 times daily for 3 days. 100 Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation recommended.100 Blistering, ulceration, and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.100 (See Local Effects under Cautions.)

Prepare and handle cautiously (by trained nonpregnant personnel); use protective equipment (e.g., latex gloves, protective eyewear) and wash hands after removal of latex gloves.100 Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.100 If drug powder or solution comes in contact with skin or mucosa, immediately irrigate affected area with water for ≥15 minutes; flush affected eye(s) with water or saline for ≥15 minutes and obtain prompt ophthalmologic consultation.100 Remove contaminated clothing and shoes; destroy clothing and and thoroughly clean shoes before reuse.100 (See Toxicity and Adequate Patient Monitoring under Cautions.)

Administer desired dose directly into any suitable vein or preferably into tubing or sidearm of a freely flowing IV infusion to reduce the risk of severe local reactions.100 (See Local Effects under Cautions.)

Following injection, flush vein with the running IV solution for 2–5 minutes and/or inject 5–10 mL of IV solution into sidearm to flush any remaining drug from the tubing.a

For direct IV injection, withdraw dose from the vial with one sterile needle and use another sterile needle for injection into vein.100

Do not use an inline cellulose ester membrane filter during administration.a

Reconstitution

Use strict aseptic technique since drug product contains no preservative.100

Reconstitute vial containing 500 mcg of dactinomycin powder with 1.1 mL of sterile water for injection without preservatives, to provide a solution containing 500 mcg/mL.100

Do not use diluents with preservatives (benzyl alcohol or parabens) which may cause precipitation.100

Dilution

Reconstituted solution may be added to IV infusions of 0.5% dextrose or 0.9% sodium chloride injection.100

Rate of Administration

For direct IV injection, administer desired dose over a few minutes directly into any suitable vein.a

Regional Isolation Perfusion

Techniques for administration by regional isolation perfusion may vary; consult specialized references.100

Administration Risks

Possible systemic and local adverse effects associated with drug that escapes into systemic circulation (e.g., myelosuppression, increased susceptibility to infection, impaired wound healing, ulceration of GI mucosa, absorption of toxic products accompanying extensive tumor destruction, edema of extremity, soft tissue damage, venous thrombosis).100 (See Major Toxicities under Cautions.)

Dosage

Calculate dosage carefully before administration of each dose.100

Base dosage on the clinical and hematologic response, patient tolerance, and other chemotherapy or irradiation being used.100

Base dosage on body surface area in obese or edematous patients.100

Consult published protocols for dosages in combination regimens and method and sequence of administration.100

Pediatric Patients

Wilms’ Tumor
IV

Children >6 months of age: 15 mcg/kg daily for 5 days administered in various combinations and schedules with other chemotherapeutic agents.100

Rhabdomyosarcoma
IV

Children >6 months of age: 15 mcg/kg daily for 5 days administered in various combinations and schedules with other chemotherapeutic agents.100

Ewing’s Sarcoma
IV

Children >6 months of age: 15 mcg/kg daily for 5 days administered in various combinations and schedules with other chemotherapeutic agents.100

Adults

Trophoblastic Neoplasms
Monotherapy
IV

12 mcg/kg daily for 5 days.100

Combination Therapy
IV

500 mcg on days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide, and cisplatin.100 110

Testicular Cancer
IV

1000 mcg/m2 on day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.100

Solid Tumors
IV (Regional Isolation Perfusion)

Dosage by regional isolation perfusion may vary; consult specialized references.100

Pelvis or lower extremity: Usual dose is 50 mcg/kg.100

Upper extremity: Usual dose is 35 mcg/kg.100

Consider dosage reduction in obese patients or those who have received prior chemotherapy or irradiation.100

Prescribing Limits

Pediatric Patients

IV

Maximum 15 mcg/kg daily or 400–600 mcg/m2 IV daily for 5 days for each 2-week course of therapy.100

Adults

IV

Maximum 15 mcg/kg daily or 400–600 mcg/m2 IV daily for 5 days for each 2-week course.100

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.100

Renal Impairment

No specific dosage recommendations at this time.100

Geriatric Patients

Start at lower end of dosage range because of age-related decreases in hepatic, renal, or cardiac function and concomitant disease and drug therapy.100

Cautions for Cosmegen

Contraindications

  • Current or recent infection with chickenpox or herpes zoster.100 (See Immunosuppression under Cautions.)

  • Known hypersensitivity to dactinomycin or any ingredient in the formulation.100

Warnings/Precautions

Warnings

Carcinogenic Effects

Secondary malignancies (e.g., leukemias) reported in patients receiving dactinomycin in combination with radiation therapy.100 Long-term observation for occurrence of secondary malignancy is necessary in patients receiving combined modality treatment for cancer.100

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.100 Avoid pregnancy during therapy.100 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.100

Immunosuppression

Do not administer at or near the time of infection with chickenpox or herpes zoster.100 Risk of severe and possibly fatal generalized disease.100

Concurrent administration of live virus vaccines not recommended.100

Sensitivity Reactions

Hypersensitivity Reactions

Possible serious hypersensitivity reactions, including anaphylaxis. 100

Major Toxicities

Hematologic Effects

Risk of dose-limiting myelosuppression, manifested primarily by leukopenia and thrombocytopenia; anemia, pancytopenia, reticulopenia, agranulocytosis, and aplastic anemia also may occur.100 a

Leukocyte and platelet nadirs generally occur 14–21 days following completion of a course of therapy.a Leukocyte and platelet counts usually return to normal levels within 21–25 days.100

Monitor hematologic function frequently.100 If severe myelosuppression develops, discontinue therapy until blood counts return to an acceptable level;100 administer supportive therapy, anti-infectives for complicating infections, and blood product transfusions as indicated.a

Use with extreme caution in patients with impaired bone marrow function.a

GI Effects

Nausea and vomiting; generally occur within hours of administration and last up to 24 hours.100 a Antiemetics may be effective in preventing or treating nausea and vomiting.100 a

Risk of stomatitis or diarrhea; if stomatitis or diarrhea develops, discontinue therapy until symptoms resolve. 100

Hepatic Effects

Potentially fatal hepatic failure and hepatic veno-occlusive disease reported.100 Veno-occlusive disease may be associated with intravascular clotting disorder and multiorgan failure and may be fatal, particularly in children <4 years of age.100

Abnormal liver function tests, ascites, hepatomegaly, and hepatitis reported.100

Local Effects

Extravasation may produce severe local tissue damage, necrosis, cellulitis, phlebitis, and inflammation; contracture of the arms reported.100 a Follow precautions to avoid extravasation.100 (See IV Administration under Dosage and Administration.)

Epidermolysis, erythema, and edema, sometimes severe, reported with regional limb perfusion.100

General Precautions

Toxicity and Adequate Patient Monitoring

Highly toxic drug with a low therapeutic index; therapeutic response is not likely to occur without some evidence of toxicity.100 a Handle and administer cautiously; administer only under the supervision of qualified clinician experienced in the use of cancer chemotherapy agents.100 (See IV Administration under Dosage and Administration.)

Closely observe patient and frequently assess bone marrow, hepatic, and renal function.100

Toxicity Potentiation with Concomitant Radiation Therapy

Appears to potentiate effects of radiation therapy.100 Severe reactions possible if high doses of both dactinomycin and radiation are used or if patient is especially sensitive to such combination therapy.100

Increased incidence of GI toxicity (e.g., severe oropharyngeal mucositis) and myelosuppression reported.100

Erythema at the site of irradiation may occur early in normal skin and buccal and pharyngeal mucosa and may be followed rapidly by hyperpigmentation and/or edema, desquamation, vesiculation, and rarely necrosis.100 a

Possible reactivation of radiation effects (e.g., erythema) in previously irradiated tissues.100

Hepatomegaly, elevated serum AST concentrations, and ascites reported in the first 2 months after radiation therapy in patients with right-sided Wilms’ tumor; administer dactinomycin with particular caution in the first 2 months after radiation therapy.100 a Do not administer concomitantly with radiation therapy for treatment of Wilms’ tumor unless benefit outweighs risk.100 103

Specific Populations

Pregnancy

Category D.100 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether dactinomycin is distributed into human milk.100 Discontinue nursing or the drug.100

Pediatric Use

Increased incidence of adverse effects in infants; use only in infants older than 6–12 months of age.100

Increased incidence of fatal veno-occlusive disease in children <4 years of age.100 (See Hepatic Effects under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.100

Possible increased incidence of myelosuppression compared with younger adults.100

Common Adverse Effects

With IV therapy, myelosuppression, nausea, vomiting, anorexia, abdominal pain, diarrhea, GI ulceration, dysphagia, stomatitis, alopecia, rash, malaise, fatigue, lethargy, liver function test abnormalities, hepatitis, growth retardation, fever, infection, myalgia.100

With regional isolation perfusion, edema of involved extremity, regional soft tissue damage, myelosuppression, infection, impaired wound healing.100

Interactions for Cosmegen

No formal drug interaction studies to date.100

Specific Drugs, Therapies, and Laboratory Tests

Drug

Interaction

Comments

Antibacterial drug concentration bioassay

Possible intereferance with bioassay100

Antineoplastic agents

Possible potentiation of toxicity100

Reduced dactinomycin dosage may be necessary if other chemotherapy is used concomitantly with or prior to dactinomycin100

Radiation therapy

Possible potentiation of GI and hematologic toxicity and radiation effects100

Severe reactions possible; reduced dactinomycin dosage may be necessary if radiation therapy is used concomitantly with or prior to dactinomycin100

Vaccines, live

Potentially hazaradous in immunosuppresed patients, including those undergoing cytotoxic chemotherapy100

Concomitant administration not recommended100

Cosmegen Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from the GI tract.a

Distribution

Extent

Rapidly distributed into tissues, with highest concentrations in bone marrow and nucleated cells (i.e., granulocytes, lymphocytes).a 100 Does not cross the blood-brain barrier.100 a

Appears to cross placenta; not known whether distributed into milk.a 100

Elimination

Metabolism

Minimally metabolized.100

Elimination Route

Excreted in urine and feces; excreted in urine primarily as unchanged drug.a 100

Half-life

Biphasic; terminal half-life is approximately 36 hours.100 a

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).100 Protect from light and humidity; discard any unused portion.100

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Manufacturer states that dactinomycin should not be mixed with diluents containing preservatives (benzyl alcohol or parabens); precipitation reported.100

Solution CompatibilityHID

Compatible

Dextrose 5% in water

Drug Compatibility
Y-Site CompatibilityHID

Compatible

Allopurinol sodium

Amifostine

Aztreonam

Cefepime HCl

Etoposide phosphate

Fludarabine phosphate

Gemcitabine HCl

Granisetron HCl

Melphalan HCl

Ondansetron HCl

Sargramostim

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Filgrastim

Actions

  • Mechanism(s) of antineoplastic action not fully understood; 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.100 a

  • Also inhibits protein and DNA synthesis, but less extensively and at higher concentrations of dactinomycin than are needed to inhibit RNA synthesis.a

  • Cytotoxicity precludes use as an anti-infective agent.a 100

Advice to Patients

  • Risk of alopecia, nausea, vomiting, myelosuppression, and hepatotoxicity.100

  • Importance of patients informing clinicians immediately if any stinging or burning occurs at IV injection site during administration.100

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.100

  • Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.100

  • Importance of informing patients of other important precautionary information.100 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Dactinomycin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

500 mcg

Cosmegen (with mannitol 20 mg)

Merck

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

100. Merck & Co., Inc. Cosmegen for injection (dactinomycin for injection) prescribing information. Whitehouse Station, NJ; 2005 Jun.

101. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. [PubMed 15529105]

102. Ovarian germ cell tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

103. Wilms’ tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

104. Childhood rhabdomyosarcoma. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

105. Ewing’s family of tumors including primitive neuroectodermal tumor (PNET). From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.

106. Gestational trophoblastic tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.

107. Testicular cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Aug.

108. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066]. Fed Regist. 1979; 44:37434-67.

109. Department of Health and Human Services, Food and Drug Administration. Subpart B-Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

110. Newlands ES, Bagshawe KD, Begent RH et al. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol. 1991; 98:550-7. [PubMed 1651757]

a. AHFS drug information 2006. McEvoy GK, ed. Dactinomycin. Bethesda, MD: American Society of Health-System Pharmacists; 2006:1009-11.

HID. Trissel LA. Handbook on injectable drugs. 12th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2003:400-402.

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