Cosmegen Information
Cosmegen (Dactinomycin) Warning
Cosmegen (Dactinomycin) ® (dactinomycin for injection) should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.
This drug is 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. Due to the toxic properties of dactinomycin (e.g., 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 intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms.
Cosmegen (Dactinomycin) Description
Dactinomycin is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in the amino acid content of the peptide side chains. The empirical formula is CHNO and the structural formula is:
Cosmegen (Dactinomycin) is a sterile, yellow to orange lyophilized powder for injection by the intravenous route or by regional perfusion after reconstitution. Each vial contains 0.5 mg (500 mcg) of dactinomycin and 20.0 mg of mannitol.
Cosmegen (Dactinomycin) Clinical Pharmacology
Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implants. 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.
Cosmegen (Dactinomycin) Clinical Studies
A wide variety of single agent and combination chemotherapy regimens with Cosmegen (Dactinomycin) have been studied. Because chemotherapeutic regimens are constantly changing, the decision to employ Cosmegen (Dactinomycin) should be directly supervised by physicians familiar with current oncologic practices and new advances in therapy.
It should be noted that the complete results from NWTS 4 have not yet been published. Changes in NWTS 4 and NWTS 5 have consisted of alterations in duration as well as dose intensity of Cosmegen (Dactinomycin) . As a consequence, appropriate consultation with physicians experienced in the management of Wilms' tumor should be sought.
Cosmegen (Dactinomycin) was included in all arms as a standard component of the treatment regimen; thus, comparative data are not available from this study. Nevertheless, it does provide information on treatment outcomes in a large group of closely studied patients. For treatment purposes, patients were stratified according to clinical group, histologic subtype, and site of disease. Patients in most strata were randomized, but clinical group I patients with favorable histology were not randomized and treated according to a single regimen.
Cosmegen (Dactinomycin) Indications And Usage
Cosmegen (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.
Cosmegen (Dactinomycin) is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.
Cosmegen (Dactinomycin) , as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.
Cosmegen (Dactinomycin) Contraindications
Hypersensitivity to any component of this product.
Cosmegen (Dactinomycin) should not be given at or about the time of infection with chickenpox or herpes zoster because of the risk of severe generalized disease which may result in death.
Cosmegen (Dactinomycin) Warnings
Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Cosmegen (Dactinomycin) . Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
Cosmegen (Dactinomycin) Pregnancy Category D
Cosmegen (Dactinomycin) may cause fetal harm when administered to a pregnant woman. Cosmegen (Dactinomycin) has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50 100 mcg/kg (approximately 0.5 - 2 times the maximum recommended daily human dose on a body surface area basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential must be warned to avoid becoming pregnant.
Cosmegen (Dactinomycin) General
This drug is and both powder and solution must be handled and administered with care (see and ). Since Cosmegen (Dactinomycin) is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling Cosmegen (Dactinomycin) . Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse (see ).
As with all antineoplastic agents, Cosmegen (Dactinomycin) is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with Cosmegen (Dactinomycin) . The possibility of an anaphylactoid reaction should be borne in mind.
It is extremely important to observe the patient daily for toxic side effects when combination chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.
Particular caution is necessary when administering Cosmegen (Dactinomycin) within two months of irradiation for the treatment of right-sided Wilms' tumor, since hepatomegaly and elevated AST levels have been noted. In general, Cosmegen (Dactinomycin) should not be concomitantly administered with radiotherapy in the treatment of Wilms' tumor unless the benefit outweighs the risk.
Cosmegen (Dactinomycin) Laboratory Tests
Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving Cosmegen (Dactinomycin) . Renal, hepatic, and bone marrow functions should be assessed frequently.
Cosmegen (Dactinomycin)
Cosmegen (Dactinomycin) Carcinogenesis, Mutagenesis, Impairment Of Fertility
Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Cosmegen (Dactinomycin) . Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.
The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors occurred in male F344 rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week for 18 weeks. The first tumor appeared at 23 weeks.
Dactinomycin has been shown to be mutagenic in a number of test systems and including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat. Adequate fertility studies have not been reported, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.
(See .)
Cosmegen (Dactinomycin) Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cosmegen (Dactinomycin) , a decision should be made as to discontinuation of nursing and/or drug, taking into account the importance of the drug to the mother.
Cosmegen (Dactinomycin) Pediatric Use
The greater frequency of toxic effects of Cosmegen (Dactinomycin) in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.
Cosmegen (Dactinomycin) Geriatric Use
Clinical studies of Cosmegen (Dactinomycin) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13 year period suggests that administration of Cosmegen (Dactinomycin) to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Cosmegen (Dactinomycin) Adverse Reactions
Toxic effects (excepting nausea and vomiting) usually do not become apparent until two to four days after a course of therapy is stopped, and may not peak until one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:
Cosmegen (Dactinomycin) Overdosage
Dactinomycin was lethal to mice and rats at intravenous doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended daily human dose on a body surface area basis, respectively). The oral LD of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively.
Manifestations of overdose in patients have included nausea, vomiting, diarrhea, mucositis including stomatitis, gastrointestinal ulceration, skin disorders including exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, acute renal failure, and death. No specific information is available on the treatment of overdosage with Cosmegen (Dactinomycin) . Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.
Cosmegen (Dactinomycin) Dosage And Administration
Careful calculation of the dosage should be performed prior to administration of each dose.
The dosage for Cosmegen (Dactinomycin) is calculated in micrograms (mcg). The dose intensity per 2 week cycle for adults or children should not exceed 15 mcg/kg/day or 400 600 mcg/m/day intravenously for five days. Calculation of the dosage for obese or edematous patients should be performed on the basis of surface area in an effort to more closely relate dosage to lean body mass.
A wide variety of single agent and combination chemotherapy regimens with Cosmegen (Dactinomycin) may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with Cosmegen (Dactinomycin) and are on a per cycle basis.
500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.
50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis.
35 mcg (0.035 mg) per kilogram of body weight for upper extremity.
It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.
Reconstitute Cosmegen (Dactinomycin) by adding 1.1 mL of using aseptic precautions. The resulting solution of Cosmegen (Dactinomycin) will contain approximately 500 mcg (0.5 mg) per mL.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. When reconstituted, Cosmegen (Dactinomycin) is a clear, gold-colored solution.
Once reconstituted, the solution of Cosmegen (Dactinomycin) can be added to infusion solutions of Dextrose Injection 5 percent or Sodium Chloride Injection either directly or to the tubing of a running intravenous infusion.
Although reconstituted Cosmegen (Dactinomycin) is chemically stable, the product does not contain a preservative and accidental microbial contamination might result. Any unused portion should be discarded. Use of water containing preservatives (benzyl alcohol or parabens) to reconstitute Cosmegen (Dactinomycin) for Injection, results in the formation of a precipitate.
Partial removal of Cosmegen (Dactinomycin) from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.
If the drug is given directly into the vein without the use of an infusion, the "two-needle technique" should be used. Reconstitute and withdraw the calculated dose from the vial with one sterile needle. Use another sterile needle for direct injection into the vein.
Discard any unused portion of the Cosmegen (Dactinomycin) solution.
Cosmegen (Dactinomycin) How Supplied
Cosmegen (Dactinomycin) for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold-colored and essentially free from visible particles. Cosmegen (Dactinomycin) for Injection is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.
NDC 67386-811-55
Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.
Cosmegen (Dactinomycin) References
1. D'Angio, G.J.; et al: Treatment of Wilms' Tumor: Results of the Third National Wilms' Tumor Study. Cancer : 349-360, 1989.
2. Crist, W.; et al: The Third Intergroup Rhabdomyosarcoma Study. J. Clin. Oncol. : 610-630, 1995.
3. Vugrin, D.; et al: VAB-6 Combination Chemotherapy in Disseminated Cancer of the Testis. Ann. Intern. Med. : 59-61, 1981.
4. Bosl, G.J.; et al: VAB-6: An Effective Chemotherapy Regimen for Patients With Germ-Cell Tumors. J. Clin. Oncol. : 1493-1499, 1986.
5. Craft, A.W.; et al: Long-Term Results from the First UKCCSG Ewing's Tumour Study (ET-1). Eur. J. Cancer : 1061-1069, 1997.
6. Vietti, T.J.; et al: Multimodal Therapy in Metastatic Ewing's Sarcoma: An Intergroup Study. Nat. Cancer Inst. Monogr. : 279-284, 1981.
7. Osathanondh, R.; et al: Actinomycin D as the Primary Agent for Gestational Trophoblastic Disease, Cancer. : 863-866, 1975.
8. Newlands, E.S.; 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. : 550-557, 1991.
9. Rudolph, R.; Larson, D.L.: Etiology and Treatment of Chemotherapeutic Agent Extravasation Injuries: A Review. J. Clin. Oncol. : 1116-1126, 1987.
10. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs, NIH Publication No. 83-2621. For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402.
11. AMA Council Report, Guidelines for Handling Parenteral Antineoplastics. JAMA : 1590-1592, 1985.
12. National Study Commission on Cytotoxic Exposure - Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
13. Clinical Oncological Society of Australia, Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med. J. Australia : 426-428, 1983.
14. Jones, R. B.; et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center, Ca- A Cancer Journal for Clinicians, Sept/Oct, 258-263, 1983.
15. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am. J. Hosp. Pharm. : 1033-1049, 1990.
16. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines). Am. J. Health-Syst. Pharm. : 1669-1685, 1996.
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Revised: September 2009
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