DACTINOMYCIN injection, powder, lyophilized, for solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
DACTINOMYCIN (UNII: 1CC1JFE158) (DACTINOMYCIN - UNII:1CC1JFE158)
Available from:
X-GEN Pharmaceuticals, Inc.
Administration route:
INTRAVENOUS
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
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. Dactinomycin for injection is indicated for the treatment of adult and pediatric patients with rhabdomyosarcoma, as part of a multi-phase, combination chemotherapy regimen. 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. 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. 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. Dactinomycin for injection is indicated for the treatment of adult patients with locally recurrent or locoregional s
Product summary:
Dactinomycin for injection for intravenous use is supplied as a sterile, amorphous yellow to orange, lyophilized powder in a single-dose vial. Each Dactinomycin for injection vial (NDC 39822-2100-2) 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 from light and humidity. Store the reconstituted Dactinomycin for injection at room temperature for no more than 4 hours from reconstitution to completion of administration [see Dosage and Administration (2.7)] . Dactinomycin for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 NDC Single Vial Cartons NDC 39822-2100-2
Authorization status:
Abbreviated New Drug Application
Authorization number:
39822-2100-1, 39822-2100-2

DACTINOMYCIN- dactinomycin injection, powder, lyophilized, for solution

X-GEN Pharmaceuticals, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Dactinomycin for Injection safely and

effectively. See full prescribing information for Dactinomycin for Injection.

Dactinomycin for Injection for intravenous use

Initial U.S. Approval: 1964

Rx Only

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

INDICATIONS AND USAGE

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 multi-phase, 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)

DOSAGE AND ADMINISTRATION

Wilms Tumor: The recommended dose is 45 mcg/kg intravenously once every 3 to 6 weeks for up to 26 weeks, as part

of a multi-agent combination chemotherapy regimen. (2.1)

Rhabdomyosarcoma: The recommended dose is 15 mcg/kg intravenously once daily for 5 days every 3 to 9 weeks for

up to 112 weeks, as part of a multi-agent combination chemotherapy regimen. (2.2)

Ewing Sarcoma: The recommended dose is 1250 mcg/m intravenously once every 3 weeks for 51 weeks, as part of a

multi-agent combination chemotherapy regimen. (2.3)

Metastatic Nonseminomatous Testicular Cancer: The recommended dose is 1000 mcg/m intravenously every 3

weeks, as part of cisplatin-based, multi-drug chemotherapy regimen. (2.4)

Gestational Trophoblastic Neoplasia:

Non-metastatic and Low-risk Metastatic Disease: The recommended dose is 12 mcg/kg intravenously daily for 5 days,

as a single agent. ( 2.5)

High-risk Metastatic Disease: The recommended dose is 500 mcg intravenously on Days 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)

DOSAGE FORMS AND STRENGTHS

For injection: 500 mcg as a lyophilized powder in a single-dose vial.

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

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)

ADVERSE REACTIONS

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 X-GEN Pharmaceuticals, Inc. at 1-8 66-390-4411 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION

Revised: 2/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

RECENT MAJOR CHANGES

1 INDICATIONS AND USAGE

1.1 Wilms Tumor

1.2 Rhabdomyosarcoma

1.3 Ewing Sarcoma

1.4 Metastatic Nonseminomatous Testicular Cancer

1.5 Gestational Trophoblastic Neoplasia

1.6 Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Wilms Tumor

2.2 Recommended Dosage for Rhabdomyosarcoma

2.3 Recommended Dosage for Ewing Sarcoma

2.4 Recommended Dosage for Metastatic Nonseminomatous Testicular Cancer

2.5 Recommended Dos age for Gestational Trophoblastic Neoplasia

2.6 Recommended Dosage for Regional Perfus ion in Locally Recurrent and Locoregional

Solid Malignancies

2.7 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Secondary Malignancy or Leukemia

5.2 Veno-occlusive Disease

5.3 Extravasation

5.4 Myelosuppression

5.5 Immunizations

5.6 Severe Mucocutaneous Reactions

5.7 Renal Toxicity

5.8 Hepatotoxicity

5.9 Potentiation of Radiation Toxicity and Radiation Recall

5.10 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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.

Sections or subsections omitted from the full prescribing information are not listed.

2 DOSAGE AND ADMINISTRATION

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 1250 mcg/m 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 1000 mcg/m intravenously once every 3 weeks for 12 weeks.

2.5 Recommended Dos age 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 Perfus ion 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

Dactinomycin for injection 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.

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:

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)].

3 DOSAGE FORMS AND STRENGTHS

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

vial.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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 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 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, 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)].

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

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 .

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

H N O and the molecular weight is 1255.42 daltons.

The structural formula of dactinomycin is shown below:

Dactinomycin for injection 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Dactinomycin for injection 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.

12.2 Pharmacodynamics

Dactinomycin exposure-response relationships and the time course of pharmacodynamics response are

unknown.

12.3 Pharmacokinetics

The distribution and excretion of radioloabeled dactinomycin (3H actinomycin D) were assessed in

three adult patients with malignant melanoma.

Distribution

3H actinomycin D is concentrated in nucleated cells and does not penetrate the blood-brain barrier.

Elimination

Excretion

Following administration of radiolabeled dactinomycin, approximately 30% was recovered in urine and

feces in one week.

Specific Populations

Pediatric Patients

Published studies and population analyses in patients ≤ 21 years of age with cancer report a trend of

increasing systemic dactinomycin clearance with increasing body weight.

Drug Interaction Studies

Published in vitro studies report that dactinomycin may be a substrate of the P-glycoprotein and

OATP1B3 transporter systems.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dactinomycin is a 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, 2 to 5 times per week, for 18 weeks, at doses (based on body

surface area) 0.5 times the clinical dose of 1250 mcg/m .

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.

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

Dactinomycin for injection for intravenous use is supplied as a sterile, amorphous yellow to orange,

lyophilized powder in a single-dose vial. Each Dactinomycin for injection vial (NDC 39822-2100-2)

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 from light and humidity.

Store the reconstituted Dactinomycin for injection at room temperature for no more than 4 hours from

reconstitution to completion of administration [see Dosage and Administration (2.7)].

Dactinomycin for injection is a cytotoxic drug. Follow applicable special handling and disposal

procedures. 1

NDC

Single Vial Cartons NDC 39822-2100-2

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)].

Manufactured in Canada

Manufactured for:

X-GEN Pharmaceuticals, Inc.

Big Flats, NY 14814

PRINCIPAL DISPLAY PANEL

NCD 39822-2100-1

Single Dose Vial

Dactinomycin for Injection, USP

500 mcg (0.5 mg) per vial

For Preparation of Intravenous Solutions

Rx only

DACTINOMYCIN

dactinomycin injection, powder, lyophilized, for solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:39 8 22-210 0

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DACTINO MYCIN (UNII: 1CC1JFE158 ) (DACTINOMYCIN - UNII:1CC1JFE158 )

DACTINOMYCIN

0 .5 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

MANNITO L (UNII: 3OWL53L36 A)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:39 8 22-210 0 -

1 in 1 CARTON

0 7/31/20 19

1

NDC:39 8 22-210 0 -

1 mL in 1 VIAL, SINGLE-DOSE; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 39 9 9

0 7/31/20 19

X-GEN Pharmaceuticals, Inc.

Labeler -

X-GEN Pharmaceuticals, Inc. (790169531)

Revised: 11/2019

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