PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 42658-008-01** Vial Label**

Dactinomycin for injection, USP

500 mcg per vial


NDC 42658-008-01** Inner carton**

Dactinomycin for injection, USP

500 mcg per vial


4 CONTRAINDICATIONS

None.

6 ADVERSE REACTIONS

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

RECENT MAJOR CHANGES

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

3 DOSAGE FORMS AND STRENGTHS

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and its mechanism of action, dactinomycin for injection 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 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 Testing

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

Contraception

Dactinomycin for injection 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 for injection 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 for injection 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 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.

11 DESCRIPTION

Dactinomycin is an actinomycin. Dactinomycin is produced by Streptomyces parvullus. The chemical name is 8-amino-N-(2-amino-4,6-dimethyl-3-oxo- phenoxazin-1-yl)carbonyl-N'-[8-amino-4,6-dimethyl-7-oxo-9-[[3,6,10-trimethyl-7,14-bis(1-methylethyl)-2,5,8,12,15-pentaoxo-9-oxa-3,6,13,16-tetrazabicyclo[14.3.0]nonadec-11-yl]carbamoyl]phenoxazin-1-yl]carbonyl-4,6-dimethyl-7-oxo-N,N'-bis[3,6,10-trimethyl-7,14-bis(1-methylethyl)-2,5,8,12,15-pentaoxo-9-oxa-3,6,13,16 tetrazabicyclo[14.3.0]nonadec-11-yl]-1,9-bis[[3,6,10-trimethyl-7,14-bis(1-methylethyl)-2,5,8,12,15-pentaoxo-9-oxa-3,6,13,16-tetrazabicyclo[14.3.0] nonadec-11-yl]carbamoyl]phenoxazine-1,9-dicarboxamide. The molecular formula is C 62H 86N 12O 16 and the molecular weight is 1255.42 daltons. The structural formula of dactinomycin is shown below:


Dactinomycin for Injection USP for intravenous use is a sterile, amorphous yellow to orange, lyophilized powder in a single-dose vial. Each vial contains 500 mcg of dactinomycin and 20 mg of mannitol.

15 REFERENCES

1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

16 HOW SUPPLIED/STORAGE AND HANDLING

Dactinomycin for Injection USP for intravenous use is supplied as a sterile, amorphous yellow to orange, lyophilized powder in a single-dose vial. Each Dactinomycin for Injection USP vial (NDC 42658-008-01) contains 0.5 mg of dactinomycin and 20 mg of mannitol.

Store at 20 to 25ºC (68 to 77ºF); excursions permitted between 15 to 30ºC (59 to 86ºF) [see USP Controlled Room Temperature].

Protect Dactinomycin for Injection USP from light and humidity.

Store the reconstituted Dactinomycin for Injection USP at room temperature for no more than 4 hours from reconstitution to completion of administration [see Dosage and Administration ( 2.7)] .

Dactinomycin for Injection USP is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

17 PATIENT COUNSELING INFORMATION

Secondary Malignancy or Leukemia

Advise patients of the increased risk of secondary malignancies [see Warnings and Precautions ( 5.1)] .

Veno-occlusive Disease

Advise 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)] .

Myelosuppression

Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection [see Warnings and Precautions ( 5.4)] .

Severe Mucocutaneous Reactions

Advise 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 Hepatotoxicity

Advise 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 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 for injection 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 for injection and for 3 months after final dose [see Use in Specific Populations ( 8.3)] .

Lactation

Advise 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)] .

Distributed by:

Hisun Pharmaceuticals USA, Inc.

Bridgewater, NJ 08807 USA

Manufactured in China