ilms tumor, as part of a multi-phase, combination chemotherapy regimen. 1.2 rhabdomyosarcoma dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin. 5.2 veno-occlusive disease severe and fatal hepatic veno-occlusive disease (vod) can occur with dactinomycin. risk factors for the development of vod include age younger than 4 years or concomitant radiotherapy. after treatment with dactinomycin for injection, 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 dactinomycin. resume, reduce dose or permanently discontinue based on severity of reaction and disease being treated. 5.3 extravasation extravasation of dactinomycin for injection 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 dactinomycin for injection. 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 dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin for injection. permanently discontinue dactinomycin for injection in patients who experience a severe mucocutaneous reaction. 5.7 renal toxicity abnormalities of renal function can occur with dactinomycin for injection. monitor creatinine and electrolytes frequently during dactinomycin for injection therapy. 5.8 hepatotoxicity hepatotoxicity can occur with dactinomycin for injection. monitor ast, alt, alkaline phosphatase, and bilirubin prior to and during dactinomycin for injection therapy. 5.9 potentiation of radiation toxicity and radiation recall dactinomycin for injection can increase radiation-induced gastrointestinal toxicity, myelosuppression, or erythema and vesiculation of the skin or buccal and pharyngeal mucosa. reduce the dose of dactinomycin for injection by 50% during concomitant radiation. radiation recall, affecting previously treated radiation fields, can occur in patients who receive dactinomycin for injection after prior radiation therapy. although the risk can occur with distant radiation exposure, the risk appears highest when dactinomycin for injection is administered within two months of prior radiation. 5.10 embryo-fetal toxicity based on findings from animal studies and its mechanism of action, dactinomycin for injection 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 dactinomycin for injection 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 dactinomycin for injection and for 3 months after the final dose [see use in specific populations (8.1 , 8.3) ] .

n days 1 and 2 every 2 weeks for up to 8 weeks, as part of a multiagent combination chemotherapy regimen. ( 2.5 ) regional perfusion in locally recurrent and locoregional solid malignancies: o lower extremity or pelvis: the recommend dose is 50 mcg/kg once with melphalan. ( 2.6 ) o 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 dactinomycin for injection, 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 dactinomycin for injection, 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 dactinomycin for injection, as part of a multi-agent combination chemotherapy regimen, is 1,250 mcg/m 2 intravenously once every 3 weeks for 51 weeks. 2.4 recommended dosage for metastatic nonseminomatous testicular cancer the recommended dose of dactinomycin for injection, as part of a cisplatin-based, multi-agent combination chemotherapy regimen, is 1,000 mcg/m 2 intravenously once every 3 weeks for 12 weeks. 2.5 recommended dosage for gestational trophoblastic neoplasia the recommended dose of dactinomycin for injection for nonmetastatic and low-risk metastatic disease is 12 mcg/kg intravenously daily for five days as a single agent. the recommended dose of dactinomycin for injection, 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 dactinomycin for injection, in combination with melphalan, is 50 mcg/kg once for lower extremity or pelvis. the recommended dose of dactinomycin for injection, 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 o dactinomycin for injection is a cytotoxic drug. follow applicable special handling and disposal procedures. 1 o 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. • dactinomycin for injection 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 dactinomycin for injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation. • manage confirmed or suspected extravasation as follows: o terminate the injection or infusion immediately and restart in another vein. o intermittent application of ice to the site for 15 minutes 4 times daily for 3 days [see warnings and precautions (5.3) ].

se some of these reactions were reported voluntarily from 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 auromedics pharma llc at 1-866-850-2876 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

mbryotoxicity at doses (based on body surface area) as low as 0.2 times the clinical dose of 1,250 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 dactinomycin, advise women not to breastfeed during treatment with dactinomycin for injection 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 dactinomycin [see use in specific population (8.1) ]. contraception dactinomycin 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 dactinomycin 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 dactinomycin 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 dactinomycin have not been established in pediatric patients undergoing regional perfusion for locally recurrent or locoregional solid malignancies. 8.5 geriatric use clinical studies of dactinomycin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

clinical dose of 1,250 mcg/m 2 .

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

ed for the preparation of dactinomycin for injection 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 class ii laminar flow biological safety cabinet. 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. 1-4 accidental contact measures: 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). the vial stopper is not made with natural rubber latex.

tion 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 dactinomycin 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 dactinomycin and for 3 months after final dose [see use in specific populations (8.3) ]. lactation advise females not to breastfeed during treatment with dactinomycin and for 14 days after the final dose [see use in specific populations (8.2) ]. distributed by: auromedics pharma llc 279 princeton-hightstown rd. e. windsor, nj 08520 manufactured by: mylan laboratories limited bangalore, india novaplus is a registered trademark of vizient inc. revised: november 2021 dactinomycin-figure-3