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WARNING
COSMEGEN® (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.
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 C62H86N12O16 and the structural formula is:
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COSMEGEN 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.
COSMEGEN is indicated for the treatment of adult and pediatric patients with Wilms tumor, as part of a multi-phase, combination chemotherapy regimen.
COSMEGEN is indicated for the treatment of adult and pediatric patients with rhabdomyosarcoma, as part of a multi-phase, combination chemotherapy regimen.
COSMEGEN is indicated for the treatment of adult and pediatric patients with Ewing sarcoma, as part of a multi-phase, combination chemotherapy regimen.
COSMEGEN is indicated for the treatment of adult and pediatric patients with metastatic, nonseminomatous testicular cancer, as part of a multi-phase, combination chemotherapy regimen.
COSMEGEN 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.
COSMEGEN is indicated for the treatment of adult patients with locally recurrent or locoregional solid malignancies, as a component of palliative or adjunctive regional perfusion.
The recommended dose of COSMEGEN, 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.
The recommended dose of COSMEGEN, 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.
The recommended dose of COSMEGEN, as part of a multi-agent combination chemotherapy regimen, is 1250 mcg/m2 intravenously once every 3 weeks for 51 weeks.
The recommended dose of COSEMGEN, as part of a cisplatin-based, multi-agent combination chemotherapy regimen, is 1000 mcg/m2 intravenously once every 3 weeks for 12 weeks.
The recommended dose of COSEMEGEN for nonmetastatic and low-risk metastatic disease is 12 mcg/kg intravenously daily for five days as a single agent.
The recommended dose of COSEMEGEN, 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.
The recommended dose of COSMEGEN, in combination with melphalan, is 50 mcg/kg once for lower extremity or pelvis.
The recommended dose of COSMEGEN, 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.
For injection: 500 mcg as a sterile, amorphous yellow to orange, lyophilized powder in a singledose vial.
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 25°C (68 to 77°F); excursions permitted between 15 to 30°C (59 to 86°F) [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].
COSMEGEN is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
REFERENCES
“OSHA Hazardous Drugs.” OSHA. https://www.osha.gov/SLTC/hazardousdrugs/index.html
Manufactured by: Baxter Oncology GmbH, 33790 Halle/Westfalen, Germany. Revised: Aug 2018
The following serious adverse reactions are described elsewhere in the labeling:
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
No Information Provided
Included as part of the "PRECAUTIONS" Section
The risk of developing secondary malignancies, including leukemia, is increased following treatment with COSMEGEN.
Severe and fatal hepatic veno-occlusive disease (VOD) can occur with COSMEGEN. Risk factors for the development of VOD include age younger than 4 years or concomitant radiotherapy. After treatment with COSMEGEN, 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 COSMEGEN. Resume, reduce dose or permanently discontinue based on severity of reaction and disease being treated.
Extravasation of COSMEGEN 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]. Observe closely and consult plastic surgery if necessary based on severity of reaction.
Severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia and anemia, can occur with COSMEGEN. 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 COSMEGEN if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction and disease being treated.
The safety with live viral vaccines following COSMEGEN has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.
Severe mucocutaneous reactions, such as Steven-Johnson syndrome and Toxic Epidermal Necrolysis (TEN), can occur with COSMEGEN. Permanently discontinue COSMEGEN in patients who experience a severe mucocutaneous reaction.
Abnormalities of renal function can occur with COSMEGEN. Monitor creatinine and electrolytes frequently during COSMEGEN therapy.
Hepatotoxicity can occur with COSMEGEN. Monitor AST, ALT, alkaline phosphatase, and bilirubin prior to and during COSMEGEN therapy.
COSMEGEN can increase radiation-induced gastrointestinal toxicity, myelosuppression, or erythema and vesiculation of the skin or buccal and pharyngeal mucosa. Reduce the dose of COSMEGEN by 50% during concomitant radiation.
Radiation recall, affecting previously treated radiation fields, can occur in patients who receive COSMEGEN after prior radiation therapy. Although the risk can occur with distant radiation exposure, the risk appears highest when COSMEGEN is administered within two months of prior radiation.
Based on findings from animal studies and its mechanism of action, COSMEGEN 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 COSMEGEN 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 COSMEGEN and for 3 months after the final dose [see Use In Specific Populations].
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.
Based on findings from animal studies and its mechanism of action, COSMEGEN can cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. 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 Females And Males Of Reproductive Potential].
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.
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.
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 COSMEGEN, advise women not to breastfeed during treatment with COSMEGEN and, based on limited published data regarding the dactinomycin half-life, for 14 days after the final dose.
Verify the pregnancy status of females of reproductive potential prior to initiating COSMEGEN [see Pregnancy].
COSMEGEN can cause fetal harm when administered to a pregnant woman [see Pregnancy].
Females
Advise females of reproductive potential to use effective contraception during treatment with COSMEGEN 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 COSMEGEN and for 3 months after the final dose [see Nonclinical Toxicology].
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 COSMEGEN have not been established in pediatric patients undergoing regional perfusion for locally recurrent or locoregional solid malignancies.
Clinical studies of COSMEGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
No Information Provided
None.
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.
Dactinomycin exposure-response relationships and the time course of pharmacodynamics response are unknown.
The distribution and excretion of radiolabeled dactinomycin (3H actinomycin D) were assessed in three adult patients with malignant melanoma.
3H actinomycin D is concentrated in nucleated cells and does not penetrate the blood-brain barrier.
Excretion
Following administration of radiolabeled dactinomycin, approximately 30% was recovered in urine and feces in one week.
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.
Published in vitro studies report that dactinomycin may be a substrate of the P-glycoprotein and OATP1B3 transporter systems.
Advise patients of the increased risk of secondary malignancies [see WARNINGS AND PRECAUTIONS].
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].
Advise patients to contact their healthcare provider for any signs or symptoms of myelosuppression or infection [see WARNINGS AND PRECAUTIONS].
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].
Advise patients of the need for periodic laboratory testing to monitor for renal toxicity and hepatotoxicity [see WARNINGS AND PRECAUTIONS].
Advise patients of the risk of increased radiation-induced gastrointestinal, myelosuppression and skin toxicity [see WARNINGS AND PRECAUTIONS].
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, Use In Specific Populations].
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].
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].
Advise females not to breastfeed during treatment with COSMEGEN and for 14 days after the final dose [see Use In Specific Populations].
