COSMEGEN, 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 is indicated as a single agent, or as part of a combination chemotherapy regimen, for the treatment of gestational trophoblastic neoplasia.

COSMEGEN, as a component of regional perfusion, is indicated for the palliative and/or adjunctive treatment of locally recurrent or locoregional solid malignancies.

Toxic reactions due to COSMEGEN are frequent and may be severe (see ADVERSE REACTIONS), thus limiting in many instances the amount that may be administered. However, the severity of toxicity varies markedly and is only partly dependent on the dose employed.

The dosage of COSMEGEN varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when additional chemotherapy or radiation therapy is used concomitantly or has been used previously.

The dosage for COSMEGEN 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/ m²/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 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 and are on a per cycle basis.

Regimens of 15 mcg/kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents have been utilized in the treatment of Wilms' tumor¹, rhabdomyosarcoma² and Ewing's sarcoma.^5,6

1000 mcg/m² intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.³

12mcg/kg intravenously daily for five days as a single agent.⁷ 500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.⁸

The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details. In general, the following doses are suggested: 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.

This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning and HOW SUPPLIED, Special Handling). Since COSMEGEN 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. 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 HOW SUPPLIED, Special Handling.)

Reconstitute COSMEGEN by adding 1.1 mL of Sterile Water for Injection (without preservative) using aseptic precautions. The resulting solution of COSMEGEN 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 is a clear, gold-colored solution.

Once reconstituted, the solution of COSMEGEN 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 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 for Injection, results in the formation of a precipitate.

Partial removal of COSMEGEN 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 solution.

Care in the administration of COSMEGEN will reduce the chance of perivenous infiltration (see boxed warning and ADVERSE REACTIONS). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of COSMEGEN, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 minutes q.i.d. for 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.⁹

No. 3298- COSMEGEN for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear and gold-colored. COSMEGEN for Injection is supplied as follows:

NDC 0006-3298-22 in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from light and humidity.

Animal studies have shown dactinomycin to be corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic. Due to the drug's toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of COSMEGEN for parenteral administration. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a ClassII laminar flow biological safety cabinet.¹⁰ Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments and shoe covers. Additional body garments should be used based upon the task being performed (e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapors and dust. Appropriate techniques should be used to remove potentially contaminated clothing.

Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered.^11-16

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 PRECAUTIONS, General and DOSAGE AND ADMINISTRATION, Preparation of Solution for Intravenous Administration).

1. D'Angio, G.J.; et al: Treatment of Wilms' Tumor: Results of the Third National Wilms' Tumor Study, Cancer 64: 349-360, 1989.

2. Crist, W.; et al: The Third Intergroup Rhabdomyosarcoma Study, J. Clin. Oncol. 13: 610-630, 1995.

3. Vugrin, D.; et al: VAB-6 Combination Chemotherapy in Disseminated Cancer of the Testis, Ann. Intern. Med. 95: 59-61, 1981.

4. Bosl, G.J.; et al: VAB-6: An Effective Chemotherapy Regimen for Patients With Germ-Cell Tumors, J. Clin. Oncol. 4: 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, 33: 1061-1069, 1997.

6. Vietti, T.J.; et al: Multimodal Therapy in Metastatic Ewing's Sarcoma: An Intergroup Study, Nat. Cancer Inst. Monogr. 56: 279-284, 1981.

7. Osathanondh, R.; et al: Actinomycin D as the Primary Agent for Gestational Trophoblastic Disease, Cancer, 36: 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. 98: 550-557, 1991.

9. Rudolph, R.; Larson, D.L.: Etiology and Treatment of Chemotherapeutic Agent Extravasation Injuries: A Review, J. Clin. Oncol. 5: 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, 253: 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 1: 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. 47: 1033-1049, 1990.

16. Controlling Occupational Exposure to Hazardous Drugs (OSHA Work-Practice Guidelines), Am. J. Health-Syst. Pharm. 53: 1669-1685, 1996.

MERCK & CO., INC. , Whitehouse Station, NJ 08889, USA, Issued August 2004, Printed in USA, Revised 08/17/2005

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