Dactinomycin

Dactinomycin for injection is an actinomycin indicated for the treatment of: adult and pediatric patients with Wilms tumor, as part of a multi-phase, combination chemotherapy regimen. ( 1.1 ) adult and pediatric patients with rhabdomyosarcoma, as part of a multiphase, combination chemotherapy regimen. ( 1.2 ) adult and pediatric patients with Ewing sarcoma, as part of a multi-phase, combination chemotherapy regimen. ( 1.3 ) adult and pediatric patients with metastatic, nonseminomatous testicular cancer, as part of a multi-phase, combination chemotherapy regimen. ( 1.4 ) post-menarchal patients with gestational trophoblastic neoplasia, as a single agent or as part of a combination chemotherapy regimen. ( 1.5 ) adult patients with locally recurrent or locoregional solid malignancies, as a component of palliative or adjunctive regional perfusion. ( 1.6 )

1.1 Wilms Tumor Dactinomycin for injection 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 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.

For injection: 500 mcg as a sterile, amorphous yellow to orange, lyophilized powder in a single-dose vial. For injection: 500 mcg as a lyophilized powder in a single-dose vial. ( 3 )

None. None. ( 4 )

Secondary Malignancy or Leukemia: Increased risk of secondary malignancies following treatment. ( 5.1 ) Veno-occlusive Disease: Can cause severe or fatal VOD. Monitor for elevations in AST, ALT, total bilirubin, hepatomegaly, weight gain, or ascites. Consider delaying next dose. ( 5.2 ) Extravasation: Immediately interrupt the injection or infusion and apply ice. ( 2.7 , 5.3 ) Myelosuppression: Monitor blood cell counts before each cycle. Delay next dose if severe myelosuppression has not improved. ( 5.4 ) Immunizations: Vaccination with live viral vaccines is not recommended before or during treatment. ( 5.5 ) Severe Mucocutaneous Reactions: Discontinue treatment ( 5.6 ) Renal Toxicity: Monitor creatinine and electrolytes frequently. ( 5.7 ) Hepatotoxicity: Monitor transaminases, alkaline phosphatase and bilirubin prior to and during treatment. ( 5.8 ) Potentiation of Radiation Toxicity and Radiation Recall: Reduce dose by 50% during concomitant radiation. Use 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) ] .

The following serious adverse reactions are described elsewhere in the labeling:

• Secondary Malignancy and Leukemia [see Warnings and Precautions (5.1) ]
• Veno-occlusive Disease [see Warnings and Precautions (5.2) ]
• Extravasation [see Warnings and Precautions (5.3) ]
• Myelosuppression [see Warnings and Precautions (5.4) ]
• Immunizations [see Warning and Precautions (5.5) ]
• Severe Mucocutaneous Reactions [see Warnings and Precautions (5.6) ]
• Renal Toxicity [see Warnings and Precautions (5.7) ]
• Hepatotoxicity [see Warnings and Precautions (5.8) ]
• Potentiation of Radiation Toxicity and Radiation Recall [see Warnings and Precautions (5.9) ] Common adverse reactions are: infection, alopecia, rash, dysphagia, fatigue, fever, nausea, vomiting, anemia, neutropenia, thrombocytopenia, mucositis, and hepatotoxicity. The following adverse reactions have been identified in clinical studies or postmarketing reports. Because 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 Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action dactinomycin 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 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.

Dactinomycin 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.