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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 C ₆₂ H ₈₆ N ₁₂ O ₁₆ and the structural formula is:

COSMEGEN is a sterile, yellow 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.

Action

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 palliative treatment of certain types of cancer.

and Metabolism

Results of a study in patients with malignant melanoma indicate that dactinomycin ( ³ H actinomycin D) is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. Approximately 30% of the dose was recovered in urine and feces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.

Wilms' Tumor

The neoplasm responding most frequently to COSMEGEN is Wilms' tumor. With low doses of both dactinomycin and radiotherapy, temporary objective improvement may be as good as and may last longer than with higher doses of each given alone. In the National Wilms' Tumor study, combination therapy with dactinomycin and vincristine together with surgery and radiotherapy, was shown to have significantly improved the prognosis of patients in groups II and III. Dactinomycin and vincristine were given for a total of seven cycles, so that maintenance therapy continued for approximately 15 months.

Postoperative radiotherapy in group I patients and optimal combination chemotherapy for those in group IV are unsettled issues. About 70 percent of lung metastases have disappeared with an appropriate combination of radiation, dactinomycin and vincristine.

Rhabdomyosarcoma

Temporary regression of the tumor and beneficial subjective results have occurred with dactinomycin in rhabdomyosarcoma which, like most soft tissue sarcomas, is comparatively radio-resistant.

Several groups have reported successful use of cyclophosphamide, vincristine, dactinomycin and doxorubicin hydrochloride in various combinations. Effective combinations have included vincristine and dactinomycin; vincristine, dactinomycin and cyclophosphamide (VAC therapy) and all four drugs in sequence. At present, the most effective treatment for children with inoperable or metastatic rhabdomyosarcoma has been VAC chemotherapy. Two-thirds of these children were doing well without evidence of disease at a median time of three years after diagnosis.

Carcinoma of Testis and Uterus

The sequential use of dactinomycin and methotrexate, along with meticulous monitoring of human chorionic gonadotropin levels until normal, has resulted in survival in the majority of women with metastatic choriocarcinoma. Sequential therapy is used if there is:

1. Stability in gonadotropin titers following two successive courses of an agent.
2. Rising gonadotropin titers during treatment.
3. Severe toxicity preventing adequate therapy.

In patients with nonmetastatic choriocarcinoma, dactinomycin or methotrexate or both, have been used successfully, with or without surgery.

Dactinomycin has been beneficial as a single agent in the treatment of metastatic nonseminomatour testicular carcinoma when used in cycles of 500 mcg/day for five consecutive days, every 6-8 weeks for periods of four months or longer.

Other Neoplasms

Dactinomycin has been given intravenously or by regional perfusion, either alone or with other antineoplastic compounds or x-ray therapy, in the palliative treatment of Ewing' sarcoma and sarcoma botryoides. For nonmetastatic Ewing' sarcoma, promising results were obtained when dactinomycin (45 mcg/m ² ) and cyclophosphamide (1200 mg/ m ² ) were given sequentially and with radiotherapy, over an 18 month period. Those with metastatic disease remain the subject of continued investigation with a more aggressive chemotherapeutic regimen employed initially.

Temporary objective improvement and relief of pain and discomfort have followed the use of dactinomycin usually in conjunction with radiotherapy for sarcoma botryoides. This palliative effect ranges from transitory inhibition of tumor growth to a considerable but temporary regression in tumor size.

COSMEGEN (Dactinomycin for Injection)

and Radiation Therapy

Much evidence suggests that dactinomycin potentiates the effects of x-ray therapy. The converse also appears likely; i.e., dactinomycin may be more effective when radiation therapy also is given.

With combined dactinomycin-radiation therapy, the normal skin, as well as the buccal and pharyngeal mucosa, show early erythema. A smaller than usual x-ray dose when given with dactinomycin causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous x-ray therapy may be reactivated by dactinomycin alone, even when irradiation occurred many months earlier, and especially when the interval between the two forms of therapy is brief. This potentiation of radiation effect represents a special problem when the irradiation treatment area includes the mucous membrane. When irradiation is directed toward the nasopharynx, the combination may produce severe oropharyngeal mucositis. Severe reactions may ensue if high doses of both dactinomycin and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.

Because of this potentiating effect, dactinomycin may be tried in radio-sensitive tumors not responding to doses of x-ray therapy that can be tolerated. Objective improvement in tumor size and activity may be observed when lower, better tolerated doses of both types of therapy are employed.

COSMEGEN (Dactinomycin for Injection)

and Perfusion Technic

Dactinomycin alone or with other antineoplastic agents has also been given by the isolation-perfusion technic, either as palliative treatment or as an adjunct to resection of a tumor. Some tumors considered resistant to chemotherapy and radiation therapy may respond when the drug is given by the perfusion technic. Neoplasms in which dactinomycin has been tried by this technic include various types of sarcoma, carcinoma, and adenocarcinoma.

In some instances tumors regressed, pain was relieved for variable periods, and surgery made possible. On other occasions, however, the outcome has been less favorable. Nevertheless, in selected cases, the drug by perfusion may provide more effective palliation than when given systemically.

Dactinomycin by the isolation-perfusion technic offers certain advantages, provided leakage of the drug through the general circulation into other areas of the body is minimal. By this technic the drug is in continuous contact with the tumor for the duration of treatment. The dose may be increased well over that used by the systemic route, usually without adding to the danger of toxic effects. If the agent is confined to an isolated part, it should not interfere with the patient' defense mechanism. Systemic absorption of toxic products from neoplastic tissue can be minimized by removing the perfusate when the procedure is finished.

CONTRAINDICATIONS

If dactinomycin is given at or about the time of infection with chicken pox or herpes zoster, a severe generalized disease, which may result in death, may occur.

PRECAUTIONS

General

COSMEGEN should be administered only under the supervision of a physician 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. Should accidental eye contact occur, copious irrigation with water 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.

As with all antineoplastic agents, 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. The possibility of an anaphylactoid reaction should be borne in mind.

Increased incidence of gastrointestinal toxicity and marrow suppression has been reported when dactinomycin was given with x-ray therapy.

Particular caution is necessary when administering dactinomycin within two months of irradiation for the treatment of right-sided Wilms' tumor, since hepatomegaly and elevated SGOT levels have been noted.

Nausea and vomiting due to dactinomycin make it necessary to give this drug intermittently. It is extremely important to observe the patient daily for toxic side effects when multiple chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hemopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.

Recent reports indicate an increased incidence of second primary tumors following treatment with radiation and anti-neoplastic agents, such as dactinomycin. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

Laboratory Tests

Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic disease and receiving dactinomycin. It is advisable to check renal, hepatic, and bone marrow functions frequently.

Drug/Laboratory Test Interactions

It has been reported that dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.

Carcinogenesis, Mutagenesis,

Impairment of Fertility

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 0.05 mg/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 in vitro and in vivo including human fibroblasts and leucocytes, and HELA cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.

Adequate fertility studies have not been reported.

Pregnancy

Pregnancy Category C.

COSMEGEN has been shown to cause malformations and embryotoxicity in the rat, rabbit and hamster when given in doses of 50-100 mcg/kg intravenously (3-7 times the maximum recommended human dose). There are no adequate and well-controlled studies in pregnant women. COSMEGEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The greater frequency of toxic effects of dactinomycin in infants suggest that this drug should be given to infants only over the age of 6 to 12 months.

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 be maximal before one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:

Miscellaneous:   malaise, fatigue, lethargy, fever, myalgia, proctitis, hypocalcemia.

Oral:   cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis.

Gastrointestinal:   anorexia, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal ulceration, liver toxicity including ascites, hepatomegaly, hepatitis, and liver function test abnormalities. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by giving antiemetics.

Hematologic:   anemia, even to the point of aplastic anemia, agranulocytosis, leukopenia, thrombopenia, pancytopenia, reticulopenia. Platelet and white cell counts should be done daily  to detect severe hemopoietic depression. If either count markedly decreases, the drug should be withheld to allow marrow recovery. This often takes up to three weeks.

Dermatologic:   alopecia, skin eruptions, acne, flare-up of erythema or increased pigmentation of previously irradiated skin.

Soft tissues.   Dactinomycin is extremely corrosive. 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.

OVERDOSAGE

The intravenous LD ₅₀ of COSMEGEN in the rat is 460 mcg/kg.

DOSAGE AND ADMINISTRATION

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

Intravenous Use

The dosage of dactinomycin 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 other chemotherapy or x-ray therapy is used concomitantly or has been used previously.

The dosage for adults or children should not exceed 15 mcg/ kg or 400-600 mcg/square meter of body surface daily intravenously for five days. Calculation of the dosage for obese or edematous patients should be on the basis of surface area in an effort to relate dosage to lean body mass.

Adults:   The usual adult dosage is 500 mcg (0.5 mg) daily intravenously for a maximum of five days.

Children:   In children 15 mcg (0.015 mg) per kilogram of body weight is given intravenously daily for five days. An alternative schedule is a total dosage of 2500 mcg (2.5 mg) per square meter of body surface given intravenously over a one week period.

In both adults and children, a second course may be given after at least three weeks have elapsed, provided all signs of toxicity have disappeared.

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

Once reconstituted, the solution of 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 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 dactinomycin from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.

Since dactinomycin is extremely corrosive to soft tissue, precautions for materials of this nature should be observed.

If the drug is given directly into the vein without the use of an infusion, the "two-needle technic" 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 dactinomycin solution.

Isolation-Perfusion Technic

The dosage schedules and the technic 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.

Complications of the perfusion technic are related mainly to the amount of drug that escapes into the systemic circulation and may consist of hemopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include edema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.

HOW SUPPLIED

No. 3298--COSMEGEN for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow 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

(6505-00-902-1222, 0.5 mg).

Storage

Store at controlled room temperature, 15-30°C (59-86°F). Protect from light, humidity, and excessive heat.

Special Handling

Due to the drug' toxic and mutagenic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of COSMEGEN for parenteral administration. The National Institutes of Health presently recommends that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet and that personnel preparing drugs of this class should wear surgical gloves and a closed front surgical-type gown with knit cuffs.

9000829   Issued February 1997

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