e, 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.

se caution when administering within two months of radiation. ( 5.9 ) embryo-fetal toxicity: can cause fetal harm. advise patients of the potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 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 )] .

ays 1 and 2 every 2 weeks for up to 8 weeks, as part of a multi-agent combination chemotherapy regimen. ( 2.5 ) regional perfusion in locally recurrent and locoregional solid malignancies: lower extremity or pelvis: the recommend dose is 50 mcg/kg once with melphalan. ( 2.6 ) upper extremity: the recommended dose is 35 mcg/kg once with melphalan. ( 2.6 ) 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 )].

rom a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. infections: infections including sepsis with fatal outcome hematologic : anemia, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia, disseminated intravascular coagulation immune system: hypersensitivity metabolism and nutrition: anorexia, hypocalcemia, tumor lysis syndrome nervous system: peripheral neuropathy ocular: optic neuropathy vascular: thrombophlebitis, hemorrhage respiratory, thoracic and mediastinal: pneumonitis, pneumothorax gastrointestinal: nausea, vomiting, abdominal pain, diarrhea, constipation, gastrointestinal ulceration, cheilitis, dysphagia, esophagitis, ulcerative stomatitis, ascites, proctitis, mucositis hepatobiliary: liver function test abnormalities, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive disease dermatologic: alopecia, rash, dermatitis, acne, erythema multiforme, stevens johnson syndrome, radiation recall, toxic epidermal necrolysis musculoskeletal and connective tissue: myalgia, growth retardation renal and urinary: renal impairment, renal failure general: fatigue, fever, malaise common adverse reactions are: infection, alopecia, rash, dysphagia, fatigue, fever, nausea, vomiting, anemia, neutropenia, thrombocytopenia, mucositis, and hepatotoxicity ( 6 ) to report suspected adverse reactions, contact recordati rare diseases at 1-800-575-8374 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

cidence 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.

clinical dose of 1250 mcg/m 2 .

ght. drug interaction studies published in vitro studies report that dactinomycin may be a substrate of the p-glycoprotein and oatp1b3 transporter systems.

n of radiation toxicity and radiation recall advise patients of the risk of increased radiation-induced gastrointestinal, myelosuppression and skin toxicity [see warnings and precautions ( 5.9 )] . embryo-fetal toxicity advise females of reproductive potential of the potential risk to a fetus. advise females to inform their healthcare provider of a known or suspected pregnancy [see warnings and precautions ( 5.10 ), use in specific populations ( 8.1 )] . advise females of reproductive potential to use effective contraception during treatment with cosmegen and for 6 months after final dose [see use in specific populations ( 8.3 )] . advise male patients with female partners of reproductive potential to use effective contraception during treatment with cosmegen and for 3 months after final dose [see use in specific populations ( 8.3 )] . lactation advise females not to breastfeed during treatment with cosmegen and for 14 days after the final dose [see use in specific populations ( 8.2 )] . manufactured by: baxter oncology gmbh, 33790 halle/westfalen, germany manufactured for: recordati rare diseases inc., lebanon, nj 08833, u.s.a. cosmegen is a registered trademark of recordati rare diseases inc. px 2092/5