1.1 Wilms Tumor

COSMEGEN is indicated for the treatment of adult and pediatric patients with Wilms tumor, as part of a multi-phase, combination chemotherapy regimen.

1.2 Rhabdomyosarcoma

COSMEGEN is indicated for the treatment of adult and pediatric patients with rhabdomyosarcoma, as part of a multi-phase, combination chemotherapy regimen.

1.3 Ewing Sarcoma

COSMEGEN is indicated for the treatment of adult and pediatric patients with Ewing sarcoma, as part of a multi-phase, combination chemotherapy regimen.

1.4 Metastatic Nonseminomatous Testicular Cancer

COSMEGEN is indicated for the treatment of adult and pediatric patients with metastatic, nonseminomatous testicular cancer, as part of a multi-phase, combination chemotherapy regimen.

1.5 Gestational Trophoblastic Neoplasia

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

1.6 Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies

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

2.1 Recommended Dosage for Wilms Tumor

The recommended dose of COSMEGEN, as part of a multi-agent combination chemotherapy regimen, is 45 mcg/kg intravenously once every 3 to 6 weeks for up to 26 weeks.

2.2 Recommended Dosage for Rhabdomyosarcoma

The recommended dose of COSMEGEN, as part of a multi-agent combination chemotherapy regimen, is 15 mcg/kg intravenously once daily for 5 days every 3 to 9 weeks for up to 112 weeks.

2.3 Recommended Dosage for Ewing Sarcoma

The recommended dose of COSMEGEN, as part of a multi-agent combination chemotherapy regimen, is 1250 mcg/m 2 intravenously once every 3 weeks for 51 weeks.

2.4 Recommended Dosage for Metastatic Nonseminomatous Testicular Cancer

The recommended dose of COSEMGEN, as part of a cisplatin-based, multi-agent combination chemotherapy regimen, is 1000 mcg/m 2 intravenously once every 3 weeks for 12 weeks.

2.5 Recommended Dosage for Gestational Trophoblastic Neoplasia

The recommended dose of COSEMEGEN for nonmetastatic and low-risk metastatic disease is 12 mcg/kg intravenously daily for five days as a single agent.

The recommended dose of COSEMEGEN, as part of a multi-agent combination chemotherapy regimen, for high-risk metastatic disease is 500 mcg intravenously on Days 1 and 2 every 2 weeks for up to 8 weeks.

2.6 Recommended Dosage for Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies

The recommended dose of COSMEGEN, in combination with melphalan, is 50 mcg/kg once for lower extremity or pelvis.

The recommended dose of COSMEGEN, in combination with melphalan, is 35 mcg/kg once for upper extremity.

Calculate the dose for obese or edematous patients based on ideal body weight.

2.7 Preparation and Administration

• COSMEGEN is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1
• Visually inspect the vials for particulate matter and discoloration, whenever solution and container permit.

Preparation

• Reconstitute each vial by adding 1.1 mL of Sterile Water for Injection without preservative using aseptic techniques.
• The reconstituted product should be a clear, gold-colored solution at a concentration of 500 mcg/mL.
• Further dilute the reconstituted product with 5% Dextrose Injection or 0.9% Sodium Chloride Injection to yield concentrations greater than 10 mcg/mL.
• Store at room temperature for no more than 4 hours from reconstitution to completion of injection or infusion. Discard after 4 hours.
• COSMEGEN does not contain a preservative. Discard any unused portions.

Administration

• Administer the diluted reconstituted product intravenously over 10 to 15 minutes.
• Do not use in-line filters with a cellulose ester membrane.

Management of Extravasation

• Discontinue COSMEGEN for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation.
• Manage confirmed or suspected extravasation as follows:
• Terminate the injection or infusion immediately and restart in another vein.
• Intermittent application of ice to the site for 15 minutes 4 times daily for 3 days [see Warnings and Precautions ( 5.3)].

5.1 Secondary Malignancy or Leukemia

The risk of developing secondary malignancies, including leukemia, is increased following treatment with COSMEGEN.

5.2 Veno-occlusive Disease

Severe and fatal hepatic veno-occlusive disease (VOD) can occur with COSMEGEN. Risk factors for the development of VOD include age younger than 4 years or concomitant radiotherapy. After treatment with COSMEGEN, monitor frequently for signs and symptoms of VOD; these include elevations in AST, ALT, total bilirubin, hepatomegaly, weight gain, or ascites. If patients develop VOD, considering delaying next dose of COSMEGEN. Resume, reduce dose or permanently discontinue based on severity of reaction and disease being treated.

5.3 Extravasation

Extravasation of COSMEGEN can result in severe local tissue injury manifesting as blistering, ulcerations and persistent pain requiring wide excision surgery followed by split-thickness skin grafting. If any signs or symptoms of extravasation occur, immediately interrupt the injection or infusion. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days [see Dosage and Administration ( 2.7)] . Observe closely and consult plastic surgery if necessary based on severity of reaction.

5.4 Myelosuppression

Severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia and anemia, can occur with COSMEGEN. The nadir in neutrophil counts generally occurs 14 to 21 days after administration. Obtain complete blood counts prior to each treatment cycle. Delay next dose of COSMEGEN if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction and disease being treated.

5.5 Immunizations

The safety with live viral vaccines following COSMEGEN has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

5.6 Severe Mucocutaneous Reactions

Severe mucocutaneous reactions, such as Steven-Johnson syndrome and Toxic Epidermal Necrolysis (TEN), can occur with COSMEGEN. Permanently discontinue COSMEGEN in patients who experience a severe mucocutaneous reaction.

5.7 Renal Toxicity

Abnormalities of renal function can occur with COSMEGEN. Monitor creatinine and electrolytes frequently during COSMEGEN therapy.

5.8 Hepatotoxicity

Hepatotoxicity can occur with COSMEGEN. Monitor AST, ALT, alkaline phosphatase, and bilirubin prior to and during COSMEGEN therapy.

5.9 Potentiation of Radiation Toxicity and Radiation Recall

COSMEGEN can increase radiation-induced gastrointestinal toxicity, myelosuppression, or erythema and vesiculation of the skin or buccal and pharyngeal mucosa. Reduce the dose of COSMEGEN by 50% during concomitant radiation.

Radiation recall, affecting previously treated radiation fields, can occur in patients who receive COSMEGEN after prior radiation therapy. Although the risk can occur with distant radiation exposure, the risk appears highest when COSMEGEN is administered within two months of prior radiation.

5.10 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, COSMEGEN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of dactinomycin to pregnant animals during the period of organogenesis was teratogenic, resulting in malformations at doses lower than the recommended human dose.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COSMEGEN and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with COSMEGEN and for 3 months after the final dose [see Use in Specific Populations ( 8.1, 8.3)] .

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, COSMEGEN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . In animal reproduction studies, administration of dactinomycin to pregnant animals during the period of organogenesis was teratogenic, resulting in malformations at doses lower than the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3)] .

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Dactinomycin was teratogenic in animals. Administration of dactinomycin to pregnant rats, rabbits, and hamsters during the period of organogenesis, increased the incidence of fetal malformations and caused embryotoxicity at doses (based on body surface area) as low as 0.2 times the clinical dose of 1250 mcg/m 2.

8.2 Lactation

Risk Summary

There are no data on the presence of dactinomycin or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from COSMEGEN, advise women not to breastfeed during treatment with COSMEGEN and, based on limited published data regarding the dactinomycin half-life, for 14 days after the final dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating COSMEGEN [see Use in Specific Population ( 8.1)].

Contraception

COSMEGEN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1)] .

Females

Advise females of reproductive potential to use effective contraception during treatment with COSMEGEN and for at least 6 months after the final dose.

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with COSMEGEN and for 3 months after the final dose [see Nonclinical Toxicology ( 13.1)] .

8.4 Pediatric Use

The safety and effectiveness of dactinomycin have been established in pediatric patients with Wilms tumor, rhabdomyosarcoma, Ewing sarcoma, and metastatic nonseminomatous testicular cancer .

The safety and effectiveness of dactinomycin have been established in post-menarchal pediatric patients with gestational trophoblastic neoplasia.

The safety and effectiveness of COSMEGEN have not been established in pediatric patients undergoing regional perfusion for locally recurrent or locoregional solid malignancies.

8.5 Geriatric Use

Clinical studies of COSMEGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

COSMEGEN is a cytotoxic actinomycin that binds DNA and inhibits RNA synthesis. The cytotoxic activity of dactinomycin has been demonstrated in animal models of different human cancers.

12.2 Pharmacodynamics

Dactinomycin exposure-response relationships and the time course of pharmacodynamics response are unknown.

12.3 Pharmacokinetics

The distribution and excretion of radioloabeled dactinomycin ( 3H actinomycin D) were assessed in three adult patients with malignant melanoma.

Distribution

3H actinomycin D is concentrated in nucleated cells and does not penetrate the blood-brain barrier.

Elimination

Excretion

Following administration of radiolabeled dactinomycin, approximately 30% was recovered in urine and feces in one week.

Specific Populations

Pediatric Patients

Published studies and population analyses in patients ≤ 21 years of age with cancer report a trend of increasing systemic dactinomycin clearance with increasing body weight.

Drug Interaction Studies

Published in vitro studies report that dactinomycin may be a substrate of the P-glycoprotein and OATP1B3 transporter systems.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dactinomycin is a carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injections. Mesenchymal tumors occurred in male rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week, for 18 weeks, at doses (based on body surface area) 0.5 times the clinical dose of 1250 mcg/m 2.

Dactinomycin was mutagenic in several in vitro and in vivo test systems including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.