SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 6 DRUG INTERACTIONS 7 DOSAGE AND ADMINISTRATION 8 OVERDOSAGE 10 ACTION AND CLINICAL PHARMACOLOGY 10 SPECIAL HANDLING INSTRUCTIONS 12 DOSAGE FORMS, COMPOSITION AND PACKAGING 13

PART II: SCIENTIFIC INFORMATION 14

PART III: CONSUMER INFORMATION. 20

Pr COSMEGEN(r) FOR INJECTION

Dactinomycin for Injection PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

COSMEGEN should only be administered under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. COSMEGEN is:

COSMEGEN is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning; DOSAGE FORMS, COMPOSITION AND PACKAGING, and SPECIAL HANDLING INSTRUCTIONS). As with all antineoplastic agents, COSMEGEN is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any body system, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with COSMEGEN. The possibility of an anaphylactoid reaction should be borne in mind. Particular caution is necessary when administering COSMEGEN in the first two months after irradiation for the treatment of right-sided Wilms' tumor, since hepatomegaly and elevated SGOT levels have been noted. Nausea and vomiting due to COSMEGEN make it necessary to give this drug intermittently. 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 hemopoietic depression appears during therapy, these drugs should be discontinued until the patient has recovered.

An increased incidence of gastrointestinal toxicity and marrow suppression has been reported when COSMEGEN was given with radiation therapy. Severe reactions may ensue if high doses of both COSMEGEN and radiation therapy are used or if the patient is particularly sensitive to such combined therapy (see DRUG INTERACTIONS).

Recent reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as COSMEGEN. 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 injection 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 vivo including human fibroblasts and leucocytes, and HELA cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.

Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months (see ADVERSE REACTION, Hepatic).

Pregnant Women: COSMEGEN is a Category D drug and may cause fetal harm when administered to a pregnant woman29. Dactinomycin has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50-100 mcg/kg intravenously9,

29. If COSMEGEN 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 fetus29. Women of childbearing potential must be warned to avoid becoming pregnant29.

Sexual Function/Reproduction

Adequate fertility studies have not been published, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.

Nursing Women:

It is not known whether COSMEGEN 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 as to discontinue nursing and/or to discontinue taking the drug, weighing the risks and benefits of the drug to the mother.

Pediatrics:

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

Geriatrics: Clinical studies of COSMEGEN 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 to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients10. 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.

There are side effects associated with this product that may affect some patients' ability to drive or operate machinery. For a complete list of side effects that may affect some patients' ability to drive, see ADVERSE REACTIONS.

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

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Fatal outcomes have been reported coincident with the use of COSMEGEN. With the exception of nausea and vomiting, toxic effects usually do not become apparent until two to four days after a course of therapy is stopped, and may not be maximal until one to two weeks have elapsed. However, adverse reactions are usually reversible on discontinuance of therapy. They include the following:

Gastrointestinal

: Anorexia, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal ulceration, proctitis. 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, thrombocytopenia, pancytopenia, reticulopenia, neutropenia and febrile neutropenia. A complete blood count should be done frequently to detect severe hemopoietic depression. If results are markedly decreased, the drug should be withheld to allow marrow recovery. This often takes up to three weeks. Hepatic: Liver toxicity including liver function test abnormalities, ascites, hepatomegaly, hepatitis and hepatic failure with reports of death11, 12, 13. Hepatic veno-occlusive disease, which may be associated with intravascular clotting disorder and multi-organ failure, has been reported in patients receiving COSMEGEN as part of a multidrug chemotherapy regimen. Lung: Pneumonitis31.

Oral: .

Cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis

Dermatologic

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

Soft Tissues:

Dactinomycin is extremely corrosive. If an 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.

Miscellaneous: Malaise, fatigue, lethargy, fever, myalgia, hypocalcemia, growth retardation, infection)14-16, 32.

DRUG INTERACTIONS

Since COSMEGEN is not highly protein bound and is not highly metabolized in the liver, pharmacokinetic interactions which would cause changes in drug blood levels by competitive binding to serum albumin or liver enzymes are not likely. Because for some indications COSMEGEN is used in combination with various therapeutics, the potential for interactions should always be considered. It may not always be clear if a change in response is due to one or the other therapies, or if the reason for the change is due to pharmacological or pharmacokinetic factors. Some drugs which may be used concomitantly with COSMEGEN appear to potentiate the effects, for example, other cytotoxic drug therapies, especially those with similar pharmacological effects, and medications causing blood dyscrasia. Because all interactions are not predictable, patients must be monitored very carefully during therapy1, 24, 30.

Halogenated inhalation anesthetics (e.g. enflurane, halothane) may increase hepatoxicity when combined with dactinomycin17. This combination should be used cautiously.

Live vaccines (Bacillus Calmette Guerin, measles, mumps, poliovirus, rotavirus, rubella, smallpox, typhoid, varicella, yellow fever) should not be administered to patients that are immunocompromised by chemotherapeutic agents, such as dactinomycin, as this may lead to an increased risk of infection by the live vaccine. The decreased immune response may allow the live vaccine to produce infection, which can sometimes be fatal.

Dactinomycin can potentiate the effects of radiation therapy. Erythema from previous radiation therapy may be reactivated by dactinomycin alone, especially with brief intervals between dactinomycin and radiotherapy, but even with an interval of several months between therapies. Normal skin as well as the buccal and pharyngeal mucosa may show early erythema. When dactinomycin and radiotherapy are administered in combination, a radiation dose smaller than usual causes erythema and vesiculation. These skin sequelae progress more rapidly through the stages of tanning and desquamation. Healing may occur in 4 to 6 weeks rather than 2 to 3 months. If high doses of both dactinomycin and radiation therapy are used, or if the patient is particularly sensitive to the combined therapy, severe reactions may occur. This potentiation of radiation effect represents a special problem when the radiotherapy involves 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 COSMEGEN and radiation therapy are used or if the patient is particularly sensitive to such combined therapy. Particular caution is necessary when administering COSMEGEN 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 should not be concomitantly administered with radiotherapy in the treatment of Wilms' tumor unless the benefit outweighs the risk1, 11-13, 24.

COSMEGEN may interfere with bioassay procedures for the determination of antibacterial drug levels.

DOSAGE AND ADMINISTRATION

Parenteral Product:

COSMEGEN is not for oral 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. Careful calculation of the dosage should be performed prior to administration of each dose.

Intravenous Use

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 other chemotherapy or radiation therapy is used concomitantly or has been used previously. The dosage of COSMEGEN is calculated in micrograms (mcg). The dose intensity per 2-week cycle should not exceed 15 mcg/kg or 400-600 mcg/m2/day of body surface 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. 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 45 mcg/kg have been administered intravenously in various combinations and schedules with other chemotherapeutic agents17.

Regimens of 15 mcg/kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents15.

Regimens of 1.25 mg/m2 have been administered intravenously in various combinations and schedules with other chemotherapeutic agents14, 18, 19.

12 mcg/kg intravenously daily for five days as a single agent. 500 mcg intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin21, 22.

COSMEGEN is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning, DOSAGE FORMS, COMPOSITION AND PACKAGING, and SPECIAL HANDLING INSTRUCTIONS). 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 or 0.5 mg dactinomycin 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 solution of Dextrose Injection 5 percent of 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 COSMEGEN solution.

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)8. The oral LD50 of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively8. 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. 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.

ACTION AND CLINICAL PHARMACOLOGY

Very little pharmacokinetic data is available given the state of analytical methodologies during the time of development along with the ethics of dosing healthy populations with cytotoxic agents; conduct of studies in very ill persons must be ethically well founded as well. Once considerable knowledge about the therapeutic efficacy and safety of dactinomycin was established, later pursuit of pharmacokinetic studies has not been warranted.

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. Experimental evidence indicates that dactinomycin acts by forming complexes with deoxyribonucleic acid (DNA) and selectively inhibiting the DNA-directed synthesis of ribonucleic acid (RNA). Dactinomycin is thought to inhibit protein synthesis by inhibiting the synthesis of messenger RNA. Dactinomycin inhibits DNA synthesis but at much higher concentrations than are required to inhibit RNA synthesis26. Dactinomycin is a potent antiproliferative agent. Therefore, as for other agents with similar mechanisms of action, it greatly affects rapidly dividing cells, both malignant and nonmalignant. This accounts for its effectiveness in counteracting tumors, and also for the common adverse events, for example, the hematological disturbances26.

Preclinical and clinical pharmacokinetic and pharmacodynamic data prior to marketing dactinomycin are limited. Due to limitations in analytical methodologies, pharmacokinetic data were not systematically studied prior to use in clinical treatment at the time this product was developed. This was justified by the seriousness of the indications and the lack of alternative therapies. Most of the available data are from the post-marketing period. Distribution: Dactinomycin is rapidly distributed into the tissues from the bloodstream. It is concentrated in nucleated cells (bone marrow, tumor cells), and has poor penetration into red blood cells and cerebrospinal fluid (does not cross the blood-brain barrier). Based upon results from nonclinical studies, dactinomycin might cross the blood-placenta barrier. It is unknown if dactinomycin is distributed into breast milk27, 29. Metabolism: Results of a study in patients with malignant melanoma indicate that dactinomycin (3H 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. Elimination: After a single intravenous injection of dactinomycin, approximately 85% of the drug is cleared from the blood in two minutes33. Approximately 12-20% is recovered in the urine and 50-90% is excreted in the bile within 24 hours33. The plasma half-life of dactinomycin may be prolonged with hepatic dysfunction24, 27. The urinary and fecal excretion was prolonged and only about 30 percent of the dose of actinomycin was recovered in 9 days. It is thought that the long persistence of dactinomycin in nucleated cells which are not proliferating probably is responsible for the observed interaction with radiation; the dactinomycin could be interfering with the cellular ability to repair radiation damage. Thus, special precautions must be taken when combining radiation with COSMEGEN therapy, and are addressed in the product labeling27.

After single or multiple IV doses, dactinomycin is rapidly distributed into and extensively bound to body tissues. Results of a study in patients with malignant melanoma receiving 3H- dactinomycin indicate that dactinomycin is minimally metabolized, is concentrated in nucleated cells, and does not appreciably penetrate the blood-brain barrier (<10%). Plasma concentrations of 3H-dactinomycin decrease rapidly within 2 hours and then decline slowly with a half-life of approximately 36 hours. Approximately 30% of the dose is recovered in urine and feces in one week27.

No specific data are available. Due to the use of concomitant therapies, potential interactions, including the effects of several medications being excreted by the same organs, must be considered within each indication.

Renal Impairment:

No specific data are available regarding dactinomycin administration to patients with renal impairment. Dactinomycin is excreted in the urine unchanged only to an extent of about 15% over 1 week; therefore, dosage adjustment would not necessarily be required with renal impairment.

Hepatic Impairment:

No specific data are available regarding COSMEGEN administration to patients with hepatic impairment. Although dactinomycin undergoes minimal hepatic metabolism, dose reduction of dactinomycin with moderate or severe hepatic dysfunction may be considered. Some clinicians recommend reduction of dosage by one third or one half in patients with hyperbilirubinemia.

Gender:

No studies are available exploring any differences depending on gender. To date, no differences have been observed during post-marketing surveillance.

Race:

No studies have been done to explore potential differences. To date, no effects indicating differences among races have been observed during post-marketing surveillance.

STORAGE AND STABILITY

Store in a dry place at 25 * C (77 * F); excursions permitted to 15 - 30 * C (59 - 86 * F). Protect from light and humidity.

SPECIAL HANDLING INSTRUCTIONS

Since COSMEGEN is extremely corrosive to soft tissues, it is intended for intravenous use. 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 teratogenic28. Due to the drug's toxic and mutagenic 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. If an extravasation occurs during intravenous use, damage to soft tissues may occur. Avoid exposure during pregnancy20. 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 chemical resistant, impervious gloves, safety goggles, outer garment 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 clothing2. Several other guidelines for proper handling and disposal of antineoplastic drugs have been published and should be considered3-8.

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 reuse8.

DOSAGE FORMS, COMPOSITION AND PACKAGING

COSMEGEN for Injection is a sterile lyophilized powder and is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol. In the dry form the compound is an amorphous yellow powder. The solution is clear and gold-colored.

Route of Administration	Dosage Form / Strength	Clinically Relevant Nonmedical Ingredients
Intravenous	Lyophilized Powder/ 0.5 mg dactinomycin/vial	mannitol

Vial Size	Volume of Diluent to be Added to Vial	Approximate Available Volume	Nominal Concentration per mL
0.5 mg	1.1mL	1.1mL	0.5 mg per mL

Pr Cosmegen(r)

Dactinomycin for Injection

Lyophilized powder for injection containing 500 mcg dactinomycin/vial Actinomycin antibiotic; antineoplastic

Date of Revision:

Control #114738

PART I: HEALTH PROFESSIONAL INFORMATION 3