Cosmegen (Page 2 of 3)

5.7 Renal Toxicity

Abnormalities of renal function can occur with COSMEGEN. Monitor creatinine and electrolytes frequently during COSMEGEN therapy.

5.8 Hepatotoxicity

Hepatotoxicity can occur with COSMEGEN. Monitor AST, ALT, alkaline phosphatase, and bilirubin prior to and during COSMEGEN therapy.

5.9 Potentiation of Radiation Toxicity and Radiation Recall

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.

5.10 Embryo-Fetal Toxicity

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 ( 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, COSMEGEN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)] . In animal reproduction studies, administration of dactinomycin to pregnant animals during the period of organogenesis was teratogenic, resulting in malformations at doses lower than the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus [see Use in Special Populations ( 8.3)] .

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Dactinomycin was teratogenic in animals. Administration of dactinomycin to pregnant rats, rabbits, and hamsters during the period of organogenesis, increased the incidence of fetal malformations and caused embryotoxicity at doses (based on body surface area) as low as 0.2 times the clinical dose of 1250 mcg/m 2.

8.2 Lactation

Risk Summary

There are no data on the presence of dactinomycin or its metabolites in human milk or their effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from 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.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

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

Contraception

COSMEGEN 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 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 ( 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 COSMEGEN have not been established in pediatric patients undergoing regional perfusion for locally recurrent or locoregional solid malignancies.

8.5 Geriatric Use

Clinical studies of COSMEGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

11 DESCRIPTION

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

COSMEGEN chemical structure
(click image for full-size original)

COSMEGEN (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.

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