PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action dactinomycin for injection can cause fetal harm when administered to 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 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.DataAnimal DataDactinomycin 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/m2.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:oSecondary Malignancy and Leukemia [see Warnings and Precautions (5.1)]oVeno-occlusive Disease [see Warnings and Precautions (5.2)]oExtravasation [see Warnings and Precautions (5.3)]oMyelosuppression [see Warnings and Precautions (5.4)]oImmunizations [see Warning and Precautions (5.5)]oSevere Mucocutaneous Reactions [see Warnings and Precautions (5.6)]oRenal Toxicity [see Warnings and Precautions (5.7)]oHepatotoxicity [see Warnings and Precautions (5.8)]oPotentiation 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Infections: infections including sepsis with fatal outcomeHematologic: anemia, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia, disseminated intravascular coagulationImmune system: hypersensitivityMetabolism and nutrition: anorexia, hypocalcemia, tumor lysis syndromeNervous system: peripheral neuropathyOcular: optic neuropathyVascular: thrombophlebitis, hemorrhageRespiratory, thoracic and mediastinal: pneumonitis, pneumothoraxGastrointestinal: nausea, vomiting, abdominal pain, diarrhea, constipation, gastrointestinal ulceration, cheilitis, dysphagia, esophagitis, ulcerative stomatitis, ascites, proctitis, mucositisHepatobiliary: liver function test abnormalities, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive diseaseDermatologic: alopecia, rash, dermatitis, acne, erythema multiforme, Stevens Johnson Syndrome, radiation recall, toxic epidermal necrolysisMusculoskeletal and connective tissue: myalgia, growth retardationRenal and urinary: renal impairment, renal failureGeneral: fatigue, fever, malaise. oSecondary Malignancy and Leukemia [see Warnings and Precautions (5.1)]. oVeno-occlusive Disease [see Warnings and Precautions (5.2)]. oExtravasation [see Warnings and Precautions (5.3)]. oMyelosuppression [see Warnings and Precautions (5.4)]. oImmunizations [see Warning and Precautions (5.5)]. oSevere Mucocutaneous Reactions [see Warnings and Precautions (5.6)]. oRenal Toxicity [see Warnings and Precautions (5.7)]. oHepatotoxicity [see Warnings and Precautions (5.8)]. oPotentiation 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 (6)To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dactinomycin is 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, to times per week, for 18 weeks, at doses (based on body surface area) 0.5 times the clinical dose of 1,250 mcg/m2.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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dactinomycin for injection is 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 radiolabeled dactinomycin (3H actinomycin D) were assessed in three adult patients with malignant melanoma.Distribution3H actinomycin is concentrated in nucleated cells and does not penetrate the blood-brain barrier.EliminationExcretionFollowing administration of radiolabeled dactinomycin, approximately 30% was recovered in urine and feces in one week. Specific PopulationsPediatric PatientsPublished studies and population analyses in patients <= 21 years of age with cancer report trend of increasing systemic dactinomycin clearance with increasing body weight.Drug Interaction StudiesPublished in vitro studies report that dactinomycin may be substrate of the P-glycoprotein and OATP1B3 transporter systems.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Dactinomycin USP is one of the actinomycins, group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in amino acid content of the peptide side chains. The empirical formula is C62H86N12O16 and the structural formula is:Dactinomycin for Injection, USP is sterile, yellow to orange, lyophilized powder for injection by intravenous route or by regional perfusion after reconstitution. Each vial contains 0.5 mg (500 mcg) of dactinomycin USP and 20 mg of mannitol.. structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oWilms Tumor: The recommended dose is 45 mcg/kg intravenously once every to weeks for up to 26 weeks, as part of multi-agent combination chemotherapy regimen. (2.1)oRhabdomyosarcoma: The recommended dose is 15 mcg/kg intravenously once daily for days every to weeks for up to 112 weeks, as part of multi-agent combination chemotherapy regimen. (2.2)oEwing Sarcoma: The recommended dose is 1250 mcg/m2 intravenously once every weeks for 51 weeks, as part of multi-agent combination chemotherapy regimen. (2.3)oMetastatic Nonseminomatous Testicular Cancer: The recommended dose is 1000 mcg/m2 intravenously every weeks, as part of cisplatin-based, multi-drug chemotherapy regimen. (2.4)oGestational Trophoblastic Neoplasia:oNon-metastatic and Low-risk Metastatic Disease: The recommended dose is 12 mcg/kg intravenously daily for days, as single agent. (2.5)oHigh-risk Metastatic Disease: The recommended dose is 500 mcg intravenously on Days and every weeks for up to weeks, as part of multi-agent combination chemotherapy regimen. (2.5)oRegional Perfusion in Locally Recurrent and Locoregional Solid Malignancies:oLower Extremity or Pelvis: The recommend dose is 50 mcg/kg once with melphalan. (2.6)oUpper Extremity: The recommended dose is 35 mcg/kg once with melphalan. (2.6) oWilms Tumor: The recommended dose is 45 mcg/kg intravenously once every to weeks for up to 26 weeks, as part of multi-agent combination chemotherapy regimen. (2.1). oRhabdomyosarcoma: The recommended dose is 15 mcg/kg intravenously once daily for days every to weeks for up to 112 weeks, as part of multi-agent combination chemotherapy regimen. (2.2). oEwing Sarcoma: The recommended dose is 1250 mcg/m2 intravenously once every weeks for 51 weeks, as part of multi-agent combination chemotherapy regimen. (2.3). oMetastatic Nonseminomatous Testicular Cancer: The recommended dose is 1000 mcg/m2 intravenously every weeks, as part of cisplatin-based, multi-drug chemotherapy regimen. (2.4). oGestational Trophoblastic Neoplasia:. oNon-metastatic and Low-risk Metastatic Disease: The recommended dose is 12 mcg/kg intravenously daily for days, as single agent. (2.5)oHigh-risk Metastatic Disease: The recommended dose is 500 mcg intravenously on Days and every weeks for up to weeks, as part of multi-agent combination chemotherapy regimen. (2.5). oHigh-risk Metastatic Disease: The recommended dose is 500 mcg intravenously on Days and every weeks for up to weeks, as part of multi-agent combination chemotherapy regimen. (2.5). oRegional Perfusion in Locally Recurrent and Locoregional Solid Malignancies:. oLower Extremity or Pelvis: The recommend dose is 50 mcg/kg once with melphalan. (2.6). oUpper 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 multi-agent combination chemotherapy regimen, is 45 mcg/kg intravenously once every to weeks for up to 26 weeks.. 2.2 Recommended Dosage for Rhabdomyosarcoma The recommended dose of dactinomycin for injection, as part of multi-agent combination chemotherapy regimen, is 15 mcg/kg intravenously once daily for days every to weeks for up to 112 weeks.. 2.3 Recommended Dosage for Ewing Sarcoma The recommended dose of dactinomycin for injection, as part of multi-agent combination chemotherapy regimen, is 1,250 mcg/m2 intravenously once every weeks for 51 weeks.. 2.4 Recommended Dosage for Metastatic Nonseminomatous Testicular Cancer The recommended dose of dactinomycin for injection, as part of cisplatin-based, multi-agent combination chemotherapy regimen, is 1,000 mcg/m2 intravenously once every 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 single agent.The recommended dose of dactinomycin for injection, as part of multi-agent combination chemotherapy regimen, for high-risk metastatic disease is 500 mcg intravenously on Days and every weeks for up to 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 oDactinomycin for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1oVisually inspect the vials for particulate matter and discoloration, whenever solution and container permit.PreparationoReconstitute each vial by adding 1.1 mL of Sterile Water for Injection without preservative using aseptic techniques.oThe reconstituted product should be clear, gold-colored solution at concentration of 500 mcg/mL.oFurther dilute the reconstituted product with 5% Dextrose Injection or 0.9% Sodium Chloride Injection to yield concentrations greater than 10 mcg/mL.oStore at room temperature for no more than hours from reconstitution to completion of injection or infusion. Discard after hours.oDactinomycin for injection does not contain preservative. Discard any unused portions.AdministrationoAdminister the diluted reconstituted product intravenously over 10 to 15 minutes.oDo not use in-line filters with cellulose ester membrane.Management of ExtravasationoDiscontinue dactinomycin for injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation.oManage confirmed or suspected extravasation as follows:oTerminate the injection or infusion immediately and restart in another vein.oIntermittent application of ice to the site for 15 minutes times daily for days [see Warnings and Precautions (5.3)].. oDactinomycin for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1oVisually inspect the vials for particulate matter and discoloration, whenever solution and container permit.. oDactinomycin for injection is cytotoxic drug. Follow applicable special handling and disposal procedures.1. oVisually inspect the vials for particulate matter and discoloration, whenever solution and container permit.. oReconstitute each vial by adding 1.1 mL of Sterile Water for Injection without preservative using aseptic techniques.. oThe reconstituted product should be clear, gold-colored solution at concentration of 500 mcg/mL.. oFurther dilute the reconstituted product with 5% Dextrose Injection or 0.9% Sodium Chloride Injection to yield concentrations greater than 10 mcg/mL.. oStore at room temperature for no more than hours from reconstitution to completion of injection or infusion. Discard after hours.. oDactinomycin for injection does not contain preservative. Discard any unused portions.. oAdminister the diluted reconstituted product intravenously over 10 to 15 minutes.. oDo not use in-line filters with cellulose ester membrane.. oDiscontinue dactinomycin for injection for burning or stinging sensation or other evidence indicating perivenous infiltration or extravasation.. oManage confirmed or suspected extravasation as follows:oTerminate the injection or infusion immediately and restart in another vein.oIntermittent application of ice to the site for 15 minutes times daily for days [see Warnings and Precautions (5.3)].. oTerminate the injection or infusion immediately and restart in another vein.. oIntermittent application of ice to the site for 15 minutes times daily for days [see Warnings and Precautions (5.3)].

DOSAGE FORMS & STRENGTHS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating dactinomycin for injection [see Use in Specific Population (8.1)]. ContraceptionDactinomycin for injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].FemalesAdvise females of reproductive potential to use effective contraception during treatment with dactinomycin for injection and for at least months after the final dose.MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with dactinomycin for injection and for months after the final dose [see Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of dactinomycin for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

RECENT MAJOR CHANGES SECTION.

oDosage and Administration, Recommended Dosage for Wilms Tumor (2.1) 8/2018oDosage and Administration, Recommended Dosage for Ewing Sarcoma (2.3) 8/2018. oDosage and Administration, Recommended Dosage for Wilms Tumor (2.1) 8/2018. oDosage and Administration, Recommended Dosage for Ewing Sarcoma (2.3) 8/2018.

REFERENCES SECTION.

15 REFERENCES 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html 1.OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

SPL UNCLASSIFIED SECTION.

1.1 Wilms Tumor Dactinomycin for injection is indicated for the treatment of adult and pediatric patients with Wilms tumor, as part of multi-phase, combination chemotherapy regimen.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Dactinomycin for injection, USP is lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold or yellow to orange colored and essentially free from visible particles. Dactinomycin for injection, USP is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin USP and 20 mg of mannitol.NDC 67457-928-02: 0.5 mg/vial in mL single-dose vial; individually boxedStorage: Store at 20o to 25oC (68o to 77oF); [see USP Controlled Room Temperature]. Protect from light and humidity.Special Handling: 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 teratogenic. Due to the drugs toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended 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 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 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).

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Secondary Malignancy or LeukemiaAdvise patients of the increased risk of secondary malignancies [see Warnings and Precautions (5.1)].Veno-occlusive DiseaseAdvise patients about the symptoms of VOD and to seek medical attention if they develop new onset jaundice, abdominal distention, or right upper quadrant pain [see Warnings and Precautions (5.2)].MyelosuppressionAdvise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection [see Warnings and Precautions (5.4)].Severe Mucocutaneous ReactionsAdvise patients of the risk of severe mucocutaneous reactions and to contact their health care provided for new skin lesions, mouth sores or oropharyngeal lesions [see Warnings and Precautions (5.5)].Renal Toxicity or HepatotoxicityAdvise patients of the need for periodic laboratory testing to monitor for renal toxicity and hepatotoxicity [see Warnings and Precautions (5.7, 5.8)].Potentiation of Radiation Toxicity and Radiation RecallAdvise patients of the risk of increased radiation-induced gastrointestinal, myelosuppression and skin toxicity [see Warnings and Precautions (5.9)].Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of 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 for injection and for 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 for injection and for months after final dose [see Use in Specific Populations (8.3) ].LactationAdvise females not to breastfeed during treatment with dactinomycin for injection and for 14 days after the final dose [see Use in Specific Populations (8.2)].Manufactured for:Mylan Institutional LLCRockford, IL 61103 U.S.A.Manufactured by:Mylan Laboratories LimitedBangalore, India Novaplus is registered trademark of Vizient, Inc.NOVEMBER 2018.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 for injection, 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Dactinomycin for injection is cytotoxic actinomycin that binds DNA and inhibits RNA synthesis. The cytotoxic activity of dactinomycin has been demonstrated in animal models of different human cancers.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Dactinomycin is 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, to times per week, for 18 weeks, at doses (based on body surface area) 0.5 times the clinical dose of 1,250 mcg/m2.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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel NDC 67457-928-02Dactinomycin for Injection, USP 500 mcg (0.5 mg)/vialFor Preparation of Intravenous SolutionsCAUTION: CYTOTOXIC AGENTLyophilizedSingle-Dose VialRx ONLYNovaplus. carton.

PEDIATRIC USE SECTION.

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 for injection have not been established in pediatric patients undergoing regional perfusion for locally recurrent or locoregional solid malignancies.

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The distribution and excretion of radiolabeled dactinomycin (3H actinomycin D) were assessed in three adult patients with malignant melanoma.Distribution3H actinomycin is concentrated in nucleated cells and does not penetrate the blood-brain barrier.EliminationExcretionFollowing administration of radiolabeled dactinomycin, approximately 30% was recovered in urine and feces in one week. Specific PopulationsPediatric PatientsPublished studies and population analyses in patients <= 21 years of age with cancer report trend of increasing systemic dactinomycin clearance with increasing body weight.Drug Interaction StudiesPublished in vitro studies report that dactinomycin may be substrate of the P-glycoprotein and OATP1B3 transporter systems.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Advise not to breastfeed. (8.2). oLactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy Risk SummaryBased on findings from animal studies and its mechanism of action dactinomycin for injection can cause fetal harm when administered to 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 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.DataAnimal DataDactinomycin 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/m2.. 8.2 Lactation Risk SummaryThere 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 for injection, 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 TestingVerify the pregnancy status of females of reproductive potential prior to initiating dactinomycin for injection [see Use in Specific Population (8.1)]. ContraceptionDactinomycin for injection can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].FemalesAdvise females of reproductive potential to use effective contraception during treatment with dactinomycin for injection and for at least months after the final dose.MalesBecause of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with dactinomycin for injection and for 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 for injection 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 for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oSecondary Malignancy or Leukemia: Increased risk of secondary malignancies following treatment. (5.1)oVeno-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)oExtravasation: Immediately interrupt the injection or infusion and apply ice. (2.7, 5.3)oMyelosuppression: Monitor blood cell counts before each cycle. Delay next dose if severe myelosuppression has not improved. (5.4)oImmunizations: Vaccination with live viral vaccines is not recommended before or during treatment. (5.5)oSevere Mucocutaneous Reactions: Discontinue treatment (5.6)oRenal Toxicity: Monitor creatinine and electrolytes frequently. (5.7)oHepatotoxicity: Monitor transaminases, alkaline phosphatase and bilirubin prior to and during treatment. (5.8)oPotentiation of Radiation Toxicity and Radiation Recall: Reduce dose by 50% during concomitant radiation. Use caution when administering within two months of radiation. (5.9)oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception. (5.10, 8.1, 8.3). oSecondary Malignancy or Leukemia: Increased risk of secondary malignancies following treatment. (5.1). oVeno-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). oExtravasation: Immediately interrupt the injection or infusion and apply ice. (2.7, 5.3). oMyelosuppression: Monitor blood cell counts before each cycle. Delay next dose if severe myelosuppression has not improved. (5.4). oImmunizations: Vaccination with live viral vaccines is not recommended before or during treatment. (5.5). oSevere Mucocutaneous Reactions: Discontinue treatment (5.6). oRenal Toxicity: Monitor creatinine and electrolytes frequently. (5.7). oHepatotoxicity: Monitor transaminases, alkaline phosphatase and bilirubin prior to and during treatment. (5.8). oPotentiation of Radiation Toxicity and Radiation Recall: Reduce dose by 50% during concomitant radiation. Use caution when administering within two months of radiation. (5.9). oEmbryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to 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 for injection.. 5.2 Veno-occlusive Disease Severe and fatal hepatic veno-occlusive disease (VOD) can occur with dactinomycin for injection. Risk factors for the development of VOD include age younger than 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 for injection. 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, times day for 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 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 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 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 months after the final dose [see Use in Specific Populations (8.1, 8.3)].