Cosmegen (Page 3 of 3)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

COSMEGEN 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 ( 3 H actinomycin D) were assessed in three adult patients with malignant melanoma.

Distribution

3 H 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 2.

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

COSMEGEN (dactinomycin for injection) for intravenous use is supplied as a sterile, amorphous yellow to orange, lyophilized powder in a single-dose vial. Each COSMEGEN vial (NDC 55292-811-55) 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 COSMEGEN from light and humidity.

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

COSMEGEN is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

17 PATIENT COUNSELING INFORMATION

Secondary Malignancy or Leukemia

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

Veno-occlusive Disease

Advise patients about the symptoms of VOD and to seek medical attention if they develop new onset jaundice, abdominal distention, or right upper quadrant pain [see Warnings and Precautions ( 5.2)] .

Myelosuppression

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

Severe Mucocutaneous Reactions

Advise patients of the risk of severe mucocutaneous reactions and to contact their health care provided for new skin lesions, mouth sores or oropharyngeal lesions [see Warnings and Precautions ( 5.5)] .

Renal Toxicity or Hepatotoxicity

Advise patients of the need for periodic laboratory testing to monitor for renal toxicity and hepatotoxicity [see Warnings and Precautions ( 5.7, 5.8)] .

Potentiation of Radiation Toxicity and Radiation Recall

Advise patients of the risk of increased radiation-induced gastrointestinal, myelosuppression and skin toxicity [see Warnings and Precautions ( 5.9)] .

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.10), Use in Specific Populations ( 8.1)] .

Advise females of reproductive potential to use effective contraception during treatment with COSMEGEN 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 COSMEGEN and for 3 months after final dose [see Use in Specific Populations ( 8.3)] .

Lactation

Advise females not to breastfeed during treatment with COSMEGEN and for 14 days after the final dose [see Use in Specific Populations ( 8.2)] .

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

Manufactured for: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.

COSMEGEN is a registered trademark of Recordati Rare Diseases Inc.

PX 2092/5

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 55292-811-55 12 Single Dose Vials
Cosmegen ® for Injection
(dactinomycin for injection)
500 mcg (0.5 mg)
Store at 20-25ºC (68-77ºF).
See USP controlled room temperature.
Protect from light and humidity.
RECORDATI RARE DISEASES GROUP
R x only
Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany
For: Recordati Rare Diseases Inc., Lebanon, NJ 08833, U.S.A.
® Trademark of Recordati Rare Diseases Inc.

Cosmegen carton
(click image for full-size original)
COSMEGEN
dactinomycin injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55292-811
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DACTINOMYCIN (DACTINOMYCIN) DACTINOMYCIN 0.5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:55292-811-55 12 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 1 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (55292-811-55)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA050682 12/10/1964
Labeler — RECORDATI RARE DISEASES, INC. (181699406)
Establishment
Name Address ID/FEI Operations
Baxter Oncology GmbH 344276063 manufacture (55292-811)

Revised: 01/2021 RECORDATI RARE DISEASES, INC.

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