DACTINOMYCIN injection, powder, lyophilized, for solution
For Healthcare Providers >

1. Patient Information
2. Manufactured For:
3. Manufactured By:

Patient Information ⮝

Secondary Malignancy or Leukemia

Advise patients of the increased risk of secondary malignancies[seeWarnings 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[seeWarnings and Precautions (5.2)].

Myelosuppression

Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection[seeWarnings 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[seeWarnings 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[seeWarnings 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[seeWarnings 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[seeUse 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[seeUse 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
[seeUse in Specific Populations (8.2)].

Manufactured For: ⮝

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured By: ⮝

Mylan Laboratories Limited

Bangalore, India

Novaplus is a registered trademark of Vizient, Inc.

NOVEMBER 2018

1. Dactinomycin For Injection (actinomycin D) Rx Only
2. Indications And Usage
3. Description
4. Clinical Pharmacology
5. Clinical Studies
6. Contraindications
7. Warnings
8. Precautions
9. Adverse Reactions
10. Overdosage
11. Dosage And Administration
12. How Supplied
13. References
14. Principal Display Panel
15. Highlights Of Prescribing Information
16. Recent Major Changes
17. Dosage Forms And Strengths
18. Warnings And Precautions
19. Use In Specific Populations
20. 1 Indications And Usage
21. 2 Dosage And Administration
22. 3 Dosage Forms And Strengths
23. 4 Contraindications
24. 5 Warnings And Precautions
25. 6 Adverse Reactions
26. 8 Use In Specific Populations
27. 11 Description
28. 12 Clinical Pharmacology
29. 13 Nonclinical Toxicology
30. 15 References
31. 16 How Supplied/storage And Handling
32. Package/label Display Panel
33. 1 Indications And Usage
34. 2 Dosage And Administration
35. 3 Dosage Forms And Strengths
36. 4 Contraindications
37. 5 Warnings And Precautions
38. 6 Adverse Reactions
39. 8 Use In Specific Populations
40. 11 Description
41. 12 Clinical Pharmacology
42. 13 Nonclinical Toxicology
43. 15 References
44. 16 How Supplied/storage And Handling

Dactinomycin For Injection (actinomycin D) Rx Only  ⮝

WARNING

Dactinomycin for injection should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents.

This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Due to the toxic properties of dactinomycin (e.g., corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently. Dactinomycin is extremely corrosive to soft tissue. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms.

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 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)

Description ⮝

Dactinomycin is one of the actinomycins, a 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 the amino acid content of the peptide side chains. The empirical formula is C 62H 86N 12O 16 and the structural formula is:

Dactinomycin is a sterile, yellow to orange lyophilized powder for injection by the intravenous route or by regional perfusion after reconstitution. Each vial contains 0.5 mg (500 mcg) of dactinomycin and 20.0 mg of mannitol.

Clinical Pharmacology ⮝

Action: Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases.

Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implants. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.

Pharmacokinetics and Metabolism: Results of a study in patients with malignant melanoma indicate that dactinomycin ( 3H actinomycin D) is minimally metabolized, is concentrated in nucleated cells, and does not penetrate the blood-brain barrier. Approximately 30% of the dose was recovered in urine and feces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.

Clinical Studies ⮝

A wide variety of single agent and combination chemotherapy regimens with Dactinomycin for injection have been studied. Because chemotherapeutic regimens are constantly changing, the decision to employ Dactinomycin for injection should be directly supervised by physicians familiar with current oncologic practices and new advances in therapy.

Wilms Tumor: The neoplasm responding most frequently to Dactinomycin for injection is Wilms tumor. Data from the National Wilms Tumor Studies (NWTS-1, NWTS-2, NWTS-3 and NWTS-4) support the use of Dactinomycin in Wilms tumor. The NWTS-3 evaluated results in 1,439 patients randomized to various regimens incorporating Dactinomycin (see table below).

L = Dactinomycin and vincristine (10 weeks) EE = Dactinomycin and vincristine (26 weeks) DD = Dactinomycin, doxorubicin, and vincristine (65 weeks) DD1 = Dactinomycin, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (1000 rads) DD2 = Dactinomycin, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (2000 rads) DD-RT = Dactinomycin, doxorubicin, and vincristine (65 weeks) preceded by radiation therapy (dose according to age) K = Dactinomycin and vincristine (65 weeks) K1 = Dactinomycin and vincristine (65 weeks) preceded by radiation therapy (1000 rads) K2 = Dactinomycin and vincristine (65 weeks) preceded by radiation therapy (2000 rads) J = Dactinomycin, doxorubicin, cyclophosphamide, and vincristine (65 weeks)
The Third National Wilms' Tumor Study
Stage	Regimen	4-Year Relapse Free Survival (%)	4-Year Overall Survival (%)
I (favorable histology)	L EE	89.0 91.8	95.6 97.4
II (favorable histology)	DD DD2 K K2	87.9 86.9 87.4 90.1	93.6 89.6 91.1 94.9
III (favorable histology)	DD1 DD2 K1 K2	82.0 85.9 71.4 76.8	90.9 86.7 85.2 85.1
IV (favorable histology)	DD-RT J	71.9 77.9	78.4 86.6
I-III (unfavorable histology)	DD-RT J	67.1 62.4	68.3 68.4
IV (unfavorable histology)	DD-RT J	58.3 52.9	58.3 52.3

It should be noted that the complete results from NWTS-4 have not yet been published. Changes in NWTS-4 and NWTS-5 have consisted of alterations in duration as well as dose intensity of Dactinomycin. As a consequence, appropriate consultation with physicians experienced in the management of Wilms tumor should be sought.

Childhood Rhabdomyosarcoma: The Third Intergroup Rhabdomyosarcoma Study (IRS-III) studied 1,062 previously untreated pediatric patients and young adults ( 21 years of age) and compared outcomes amongst a number of treatment regimens.

Dactinomycin was included in all arms as a standard component of the treatment regimen; thus, comparative data are not available from this study. Nevertheless, it does provide information on treatment outcomes in a large group of closely studied patients. For treatment purposes, patients were stratified according to clinical group, histologic subtype, and site of disease. Patients in most strata were randomized, but clinical group I patients with favorable histology were not randomized and treated according to a single regimen.

VA = vincristine/Dactinomycin VADRC = vincristine/doxorubicin/cyclophosphamide VAC = vincristine/Dactinomycin/cyclophosphamide CDDP = Cisplatin VP-16 = Etoposide RT = radiation therapy
The Third Intergroup Rhabdomyosarcoma Study
Group	Number of Arms	Chemotherapy Regimen	5-Year Progression Free Survival (%) (mean SEM)	5-Year Overall Survival (%) (mean SEM)
I (favorable histology)	1 (non randomized)	cyclic sequential VA (1 year)	83 3	93 2
II (favorable histology, excluding orbit, head and paratesticular sites)	2 (randomized)	VA, doxorubicin and RT (1 year) VA and RT (1 year)	77 6 56 10	89 5 54 13
III (excluding special pelvic, orbit, scalp, parotid, oral cavity, larynx, oropharynx and cheek)	3 (randomized)	pulsed VAC and RT (2 years) pulsed VADRC-VAC, CDDP and RT (2 years) pulsed VADRC-VAC, CDDP, VP-16 and RT (2 years)	70 6 62 5 56 4	70 6 63 5 64 5
IV (all)	3 (randomized)	pulsed VAC and RT (2 years) pulsed VADRC-VAC, CDDP and RT (2 years) pulsed VADRC-VAC, CDDP, VP-16 and RT (2 years)	27 8 27 8 30 6	27 6 31 6 29 7

Metastatic Nonseminomatous Testicular Cancer: Combinations of vinblastine, cyclophosphamide, Dactinomycin, bleomycin and cisplatin (VAB-6 regimen) have been employed in the treatment of metastatic nonseminomatous testicular cancer. In a retrospective analysis of 142 evaluable patients with primary advanced stage II or clinical stage III testicular cancer 112 (79%) achieved a complete response (CR) after treatment with VAB-6 alone or in combination with surgery. Relapses were uncommon (12%) and 117 of 166 patients (71%) were categorized as alive without evidence of disease during the four years covered by the study.

Ewing s Sarcoma: Dactinomycin in conjunction with vincristine, doxorubicin, cyclophosphamide and radiotherapy has been used in the management of both metastatic and non-metastatic Ewing s sarcoma. Of 120 previously untreated patients with non-metastatic disease treated with Dactinomycin as part of maintenance therapy in the United Kingdom Children s Cancer Study Group Ewing s Tumor Study (ET-1), 49 (41%) were free of disease at 5 years and 53 (44%) were alive at 5 years. Outcomes in regional and metastatic disease for previously untreated patients administered Dactinomycin resulted in 31 of 44 patients (70%) achieving a CR after a median time on study of 83 weeks. Eight of 44 (18%) patients achieved a partial response (PR) and the remaining 5 (11%) demonstrated no response to the regimen.

Gestational Trophoblastic Neoplasia: Single agent Dactinomycin has been used in the management of nonmetastatic gestational trophoblastic neoplasia. In a series of 31 patients with nonmetastatic disease, complete and sustained remissions were achieved with Dactinomycin alone in 94% of treated patients. Alternating combination regimens incorporating Dactinomycin in conjunction with etoposide, methotrexate, vincristine and cyclophosphamide (EMA-CO regimen) have also been used in the treatment of poor prognosis gestational trophoblastic neoplasia. Administration of EMA-CO to 148 women with poor prognosis gestational trophoblastic neoplasia resulted in 110 (80%) complete and 25 (18%) partial responses after a mean follow-up of 50.4 months. Overall survival during the study period was 85% and relapses were uncommon (5.4%). Meticulous monitoring of beta-hCG (human chorionic gonadotropin) must be incorporated into the treatment regimen.

Regional Perfusion in Locally Recurrent and Locoregional Solid Malignancies: Dactinomycin, as a component of regional perfusion, has been administered as palliative treatment and as an adjunct to tumor resection in the management of locally recurrent and locoregional sarcomas, carcinomas and adenocarcinomas.

Contraindications ⮝

None. (4)

Warnings ⮝

Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Dactinomycin. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

Pregnancy Category D: Dactinomycin may cause fetal harm when administered to a pregnant woman. Dactinomycin has been shown to cause malformations and embryotoxicity in rat, rabbit, and hamster when given in doses of 50-100 mcg/kg (approximately 0.5-2 times the maximum recommended daily human dose on a body surface area basis). If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential must be warned to avoid becoming pregnant.

Precautions ⮝

General: This drug is HIGHLY TOXIC and both powder and solution must be handled and administered with care (see boxed warning and HOW SUPPLIED, Special Handling). Since Dactinomycin is extremely corrosive to soft tissues, it is intended for intravenous use. Inhalation of dust or vapors and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Appropriate protective equipment should be worn when handling Dactinomycin. 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 HOW SUPPLIED, Special Handling).

As with all antineoplastic agents, Dactinomycin is a toxic drug and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most commonly the hematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with Dactinomycin. The possibility of an anaphylactoid reaction should be borne in mind.

It is extremely important to observe the patient daily for toxic side effects when combination chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe hematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.

Veno-occlusive Disease: Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months. (See ADVERSE REACTIONS, Hepatic.)

Dactinomycin for Injection and Radiation Therapy: An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combined therapy incorporating Dactinomycin for injection and radiation. Moreover, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema. A smaller than usual radiation dose administered in combination with Dactinomycin causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous radiation therapy may be reactivated by Dactinomycin alone, even when radiotherapy was administered many months earlier, and especially when the interval between the two forms of therapy is brief. This potentiation of radiation effect represents a special problem when the radiotherapy involves the mucous membrane. When irradiation is directed toward the nasopharynx, the combination may produce severe oropharyngeal mucositis. Severe reactions may ensue if high doses of both Dactinomycin and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.

Particular caution is necessary when administering Dactinomycin for injection within two months of irradiation for the treatment of right-sided Wilms tumor, since hepatomegaly and elevated AST levels have been noted. In general, Dactinomycin should not be concomitantly administered with radiotherapy in the treatment of Wilms tumor unless the benefit outweighs the risk.

Dactinomycin for Injection and Regional Perfusion Therapy: Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of hematopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include edema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.

Laboratory Tests: Many abnormalities of renal, hepatic, and bone marrow function have been reported in patients with neoplastic diseases receiving Dactinomycin. Renal, hepatic, and bone marrow functions should be assessed frequently.

Drug/Laboratory Test Interactions: Dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Reports indicate an increased incidence of second primary tumors (including leukemia) following treatment with radiation and antineoplastic agents, such as Dactinomycin. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors occurred in male F344 rats given intraperitoneal injections of 50 mcg/kg, 2 to 5 times per week for 18 weeks. The first tumor appeared at 23 weeks.

Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.

Adequate fertility studies have not been reported, although, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.

Pregnancy: Pregnancy Category D

(See WARNINGS.)

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Dactinomycin, a decision should be made as to discontinuation of nursing and/or drug, taking into account the importance of the drug to the mother.

Pediatric Use: The greater frequency of toxic effects of Dactinomycin in infants suggest that this drug should be administered to infants only over the age of 6 to 12 months.

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. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13-year period suggests that administration of Dactinomycin to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage ⮝

Dactinomycin was lethal to mice and rats at intravenous doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended daily human dose on a body surface area basis, respectively). The oral LD 50 of dactinomycin is 7.8 mg/kg and 7.2 mg/kg in the mouse and rat, respectively.

Manifestations of overdose in patients have included nausea, vomiting, diarrhea, mucositis including stomatitis, gastrointestinal ulceration, severe skin disorders including skin exfoliation, exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome and death. No specific information is available on the treatment of overdosage with Dactinomycin. Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.

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/m2 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/m2 intravenously every 3 weeks, as part of cisplatin-based, multi-drug chemotherapy regimen. (2.4)

Gestational Trophoblastic Neoplasia:

o

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)

o

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:

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)

How Supplied ⮝

Dactinomycin for Injection is a lyophilized powder. In the dry form the compound is an amorphous yellow to orange powder. The solution is clear, gold-colored and essentially free from visible particles. Dactinomycin for Injection is supplied in vials containing 0.5 mg (500 micrograms) of dactinomycin and 20.0 mg of mannitol.

NDC 66993-489-83 Single Dose Vial

NDC 66993-489-35 12 Single Dose Vials

Storage: Store at 20-25 C (68-77 F). 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 drug s toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of Dactinomycin 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).

References ⮝

1. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi_2.html.
3. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO (eds.) 2005. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. (2nd ed) Pittsburgh, PA: Oncology Nursing Society.

Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany

For: Prasco Laboratories, Mason, OH 45040 USA

Revised: May 2014

APX1015

Principal Display Panel ⮝

Manufactured in Canada

Manufactured for:

X-GEN Pharmaceutical, Inc.

Big Flats, NY 14814

NDC 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 Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:39822-2100 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DACTINOMYCIN (UNII: 1CC1JFE158) (DACTINOMYCIN - UNII:1CC1JFE158) DACTINOMYCIN 0.5 mg in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:39822-2100-2 1 in 1 CARTON 07/31/2019 1 NDC:39822-2100-1 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203999 07/31/2019

Labeler - X-GEN Pharmaceuticals, Inc. (790169531)

Revised: 7/2019 Document Id: 0889a20b-658e-4dba-a2e7-65c8b2e5a229 34391-3 Set id: efe03d73-eb11-45ff-a3cb-09a540ed352f Version: 6 Effective Time: 20190731 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

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

Dosage Forms And Strengths ⮝

For injection: 500 mcg as a lyophilized powder in a single-dose vial. (3)

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)

Use In Specific Populations ⮝

Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 4/2019

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.

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 1,250 mcg/m2 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/m2 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)].

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 1,250 mcg/m2.

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 [seeNonclinical 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 USP is one of the actinomycins, a 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 a 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.

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 radiolabeled 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 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.

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 is a 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 2 mL single-dose vial; individually boxed

Storage: Store at 20 to 25 C (68 to 77 F); [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 drug s 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 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).

Package/label Display Panel  ⮝

NDC 67457-928-02

Dactinomycin for Injection, USP

500 mcg (0.5 mg)/vial

For Preparation of Intravenous Solutions

CAUTION: CYTOTOXIC AGENT

Lyophilized

Single-Dose Vial

Rx ONLY

Novaplus

DACTINOMYCIN dactinomycin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:67457-928 Route of Administration INTRAVENOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DACTINOMYCIN (UNII: 1CC1JFE158) (DACTINOMYCIN - UNII:1CC1JFE158) DACTINOMYCIN 0.5 mg in 1 mL

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:67457-928-02 1 in 1 CARTON 06/20/2019 1 1 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA203385 06/20/2019

Labeler - Mylan Institutional LLC (790384502)

Revised: 6/2019 Document Id: c350c9a1-e82c-40f3-a2f7-ae904294b6c4 34391-3 Set id: 0e173ef5-d0f1-41c3-9b64-543195443310 Version: 2 Effective Time: 20190621 Mylan Institutional LLC

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.

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/m2 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/m2 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/m2.

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 C62H86N12O16 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/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.

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 25 C (68 to 77 F); excursions permitted between 15 to 30 C (59 to 86 F) [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