Cosmegen

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Cosmegen

Classes

Actinomycines

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
Doses of 1.35 mg/m2/dose or greater: High
Doses of 10 mcg/kg/dose: Moderate
Administer routine antiemetic prophylaxis prior to treatment.
Extravasation Risk
Vesicant
Administer drug through a central venous line.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous Administration

Monitor patients for signs or symptoms of extravasation; stop the injection or infusion immediately if extravasation occurs.
Reconstitution:
Add 1.1 mL of preservative-free sterile water for injection to the 500-mcg lyophilized, single-dose vial for a final vial concentration of 500 mcg/mL.
The reconstituted vial solution should be clear and gold-colored.
Discard any unused portion of the vial.
Storage: store reconstituted vials or the diluted solution at room temperature (20 to 25 degrees C; 68 to 77 degrees F) for up to 4 hours from vial reconstitution (includes infusion time).[63445] [61766]
Intravenous (IV) Injection:
Withdraw the appropriate amount of dactinomycin and directly inject it into the tubing of a running IV infusion of 5% dextrose injection or 0.9% sodium chloride injection.
If dactinomycin is injected directly into a vein, use a two-needle technique; use one sterile needle to remove the calculated dose from the vial and another sterile needle for direct injection into the vein.[63445]
IV Infusion:
Withdraw the appropriate amount of dactinomycin and dilute it in 5% dextrose injection or 0.9% sodium chloride injection for a final concentration greater than 10 mcg/mL.
Administer as an IV infusion over 10 to 15 minutes.
Do not use an in-line filter with a cellulose ester membrane.[61766]

Adverse Reactions
Severe

pancytopenia / Delayed / Incidence not known
agranulocytosis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
sinusoidal obstruction syndrome (SOS) / Delayed / Incidence not known
hepatic failure / Delayed / Incidence not known
disseminated intravascular coagulation (DIC) / Delayed / Incidence not known
veno-occlusive disease (VOD) / Delayed / Incidence not known
peptic ulcer / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
tissue necrosis / Early / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
new primary malignancy / Delayed / Incidence not known
leukemia / Delayed / Incidence not known
pneumothorax / Early / Incidence not known
tumor lysis syndrome (TLS) / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
visual impairment / Early / Incidence not known

Moderate

neutropenia / Delayed / Incidence not known
thrombocytopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
leukopenia / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
ascites / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hepatomegaly / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
proctitis / Delayed / Incidence not known
esophagitis / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
oral ulceration / Delayed / Incidence not known
stomatitis / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
erythema / Early / Incidence not known
edema / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known
radiation recall reaction / Delayed / Incidence not known
hypocalcemia / Delayed / Incidence not known
pneumonitis / Delayed / Incidence not known
growth inhibition / Delayed / Incidence not known
bleeding / Early / Incidence not known
phlebitis / Rapid / Incidence not known
peripheral neuropathy / Delayed / Incidence not known

Mild

weight gain / Delayed / Incidence not known
abdominal pain / Early / Incidence not known
nausea / Early / Incidence not known
anorexia / Delayed / Incidence not known
vomiting / Early / Incidence not known
cheilitis / Delayed / Incidence not known
diarrhea / Early / Incidence not known
pharyngitis / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
injection site reaction / Rapid / Incidence not known
rash / Early / Incidence not known
acne vulgaris / Delayed / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
lethargy / Early / Incidence not known
malaise / Early / Incidence not known
fatigue / Early / Incidence not known
fever / Early / Incidence not known
myalgia / Early / Incidence not known
infection / Delayed / Incidence not known

Boxed Warning
New primary malignancy

New primary malignancy has been reported (e.g., leukemia) following treatment with radiation and chemotherapy, including dactinomycin. Patients receiving multimodal therapy require long-term and careful observation. DNA damage and cytogenetic effects have been demonstrated in the animal studies.

Extravasation

Extravasation resulting in severe soft tissue damage has been reported with intravenous dactinomycin use; surgery and skin grafting may be necessary in severe cases. Extravasation may occur with or without a burning or stinging sensation and even if there is good blood return on needle aspiration. Immediately discontinue the injection or infusion if any signs or symptoms of extravasation occur; restart dactinomycin administration in another vein. Apply intermittent ice to the site for 15 minutes 4-times daily for 3 days if extravasation is suspected. If severe extravasation occurs, observe the patient closely and consult a plastic surgeon.[63445] [61766]

Accidental exposure, ocular exposure, requires an experienced clinician

Dactinomycin is highly toxic and its administration requires an experienced clinician knowledgeable in the use of chemotherapy agents. Dactinomycin demonstrates toxic properties such as corrosivity, carcinogenicity, mutagenicity, and teratogenicity; exercise usual cautions for handling, preparing, and administering cytotoxic drugs. Use care to avoid accidental exposure to dactinomycin such as inhaling dust vapors, contact with skin or mucous membranes, or ocular exposure. If accidental exposure occurs, seek medical attention immediately. For ocular exposure, rinse the eyes immediately and thoroughly for at least 15 minutes with water, normal saline, or balanced salt ophthalmic irrigation solution; promptly obtain an ophthalmologic consultation. For accidental skin contact, irrigate the affected area immediately with large amounts of water for at least 15 minutes; remove contaminated clothing and shoes.[63445]

Pregnancy

Dactinomycin is classified as FDA pregnancy risk category D. Due to its potential for teratogenesis, dactinomycin should be avoided during pregnancy.[63445] Dactinomycin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during and after treatment with dactinomycin. Advise pregnant women of the potential risk to the fetus. Embryotoxicity and fetal malformations were observed in pregnant rats, rabbits, and hamsters following dactinomycin administered during organogenesis at doses that were as low as 0.2-times the clinical dose of 1,250 mcg/m2.[61766]

Common Brand Names

Cosmegen

Dea Class

Rx

Description

A cytotoxic antitumor antibiotic
Used in Wilms tumor, rhabdomyosarcoma, Ewing sarcoma, testicular cancer, gestational trophoblastic neoplasia, and certain locally recurrent or locoregional solid malignancies
Fatal sinusoidal obstruction syndrome has been reported

Dosage And Indications
For the treatment of gestational trophoblastic disease. For the treatment of nonmetastatic or low-risk metastatic gestational trophoblastic disease, as a single-agent. Intravenous dosage Female Adults and Post-Menarchal Adolescents and Children

12 mcg/kg IV daily for 5 days.

For high-risk gestational trophoblastic disease in combination with methotrexate, leucovorin, etoposide, cyclophosphamide, and vincristine (EMA-CO regimen). Intravenous dosage Female Adults and Post-Menarchal Adolescents and Children

500 mcg IV daily on days 1 and 2 repeated every 2 weeks for up to 8 weeks in combination with multi-agent chemotherapy.[61766] Dactinomycin has been evaluated in combination with methotrexate, leucovorin, etoposide, cyclophosphamide, and vincristine (EMA-CO regimen) in clinical studies; cure rates have ranged from 70% to 90% in women with high-risk gestational trophoblastic disease. Results are typically better in women who receive EMA-CO as primary therapy and in women without metastatic disease. Growth-factor support should be considered to maintain dose-intensity and prevent hematological toxicity. Complete response is typically defined as three consecutive weekly human chorionic gonadotropin (hCG) levels that are undetectable or less than the upper limit of normal. In studies, treatment was continued for 2 to 3 additional courses after complete hCG response.[33966] [33967]

For high-risk gestational trophoblastic disease in combination with methotrexate, leucovorin, etoposide, and cisplatin (EMA-EP regimen). Intravenous dosage Female Adults and Post-Menarchal Adolescents and Children

500 mcg IV daily on days 1 and 2 repeated every 2 weeks for up to 8 weeks in combination with multi-agent chemotherapy. Dactinomycin has been evaluated in combination with methotrexate, leucovorin, etoposide, and cisplatin (EMA-EP regimen) in a clinical study. Studies in patients with chemotherapy-refractory, high-risk gestational trophoblastic disease have shown response rates of more than 90% with salvage treatment with EMA-EP. Growth-factor support should be considered to maintain dose-intensity and prevent hematological toxicity.

For the treatment of metastatic nonseminomatous testicular cancer, as part of a multiphase combination chemotherapy regimen. Intravenous dosage Male Adults, Adolescents, and Children

1,000 mcg/m2 IV once every 3 weeks for 12 weeks in combination with cisplatin-based, multi-agent chemotherapy. Dactinomycin has been evaluated in combination with cyclophosphamide, bleomycin, vinblastine, and cisplatin (VAB-6 regimen).

For the treatment of Wilms' tumor, as part of a multiphase combination chemotherapy regimen. Intravenous dosage Adults, Adolescents, Children, and Infants

45 mcg/kg IV once every 3 to 6 weeks for up to 26 weeks in combination with multi-agent chemotherapy.[61766] An alternative regimen is dactinomycin 15 mcg/kg IV daily for 5 days in combination with other chemotherapy agents.

For the treatment of malignant melanoma. For the treatment of malignant melanoma as a single-agent or in combination with other chemotherapy†. Intravenous dosage Adults

1.2 mg/m2 IV on day 1 every 3 weeks has been given in combination with a single-dose of dacarbazine 800 mg/m2 IV on day 1 of the first course. In a small study of 18 patients, the ORR was 22% with this combination.Single-agent dacarbazine alone has produced response rates of 20%. In another study, dactinomycin in combination with bleomycin, dacarbazine, and vindesine produced an ORR of 33%.

Intra-arterial dosage (isolated limb perfusion) Adults

50 mcg/kg for the legs or 35 mcg/kg for the arms in combination with hyperthermia has been utilized.

For the treatment of rhabdomyosarcoma. For the treatment of rhabdomyocarcoma, as part of a multiphase combination chemotherapy regimen. Intravenous dosage Adults, Adolescents, Children, and Infants

15 mcg/kg IV once daily for 5 days every 3 to 9 weeks for up to 112 weeks in combination with multi-agent chemotherapy. An alternative regimen is dactinomycin 15 mcg/kg IV daily for 5 days in combination with other chemotherapy agents.[63445]

For the first-line treatment of rhabdomyosarcoma, in combination with vincristine, ifosfamide, and doxorubicin. Intravenous dosage Adolescents and Children

Ifosfamide 6,000 mg/m2 continuous IV infusion (CIV) over 48 hours on days 1, 29, and 50 in combination with mesna 6,000 mg/m2/day CIV over 48 hours on days 1, 29, and 50, doxorubicin 40 mg/m2/day IV on days 29 and 30, dactinomycin 0.5 mg/m2/day IV on days 1 through 3 and 50 through 52, and vincristine 1.5 mg/m2 IV on days 1, 8, 15, and 22. The duration of therapy was dependent on stage at diagnosis (stage I: 16 weeks; II: 26 weeks; III: 40 weeks; IV: 48 weeks).

For the treatment of osteogenic sarcoma†. Intravenous dosage Adults, Adolescents, and Children

0.6 mg/m2/day IV on days 1 and 2 or on days 1, 2, and 3 in combination with bleomycin and cyclophospamide (BCD regimen) has been incorporated into multiple treatment protocols. In the POG-8651 protocol, 106 patients (younger than 30 years old) with previously untreated nonmetastatic high-grade osteogenic sarcoma were randomized to receive 3 days of BCD each cycle as part of a multiagent chemotherapy regimen in sequence with doxorubicin and cisplatin, and high-dose methotrexate, either before or after surgical resection. Event-free survival (EFS), the primary endpoint, was not significantly different between the treatment arms, and reached 69% at 5 years in the post-operative group. In a comparison of the Memorial Sloan-Kettering Cancer Center T-10 and T-12 protocols, 73 patients (ages 4.6 to 36.4 years) with previously untreated, high-grade osteogenic sarcoma received BCD on days 1 and 2 of each cycle as part of a multiagent chemotherapy regimen in sequence with doxorubicin and cisplatin, high-dose methotrexate, and surgical resection. The 5-year EFS was 78% and 73% in the T-12 and T-10 protocols, respectively. The use of BCD alone has also been studied in 8 patients (ages 9.1 to 16.4 years) with previously treated metastatic osteogenic sarcoma. Patients received 1 to 5 courses of BCD. No tumor regression could be measured for any of the patients, and progressive tumor enlargement was demonstrated in 2 patients. Use in patients older than 40 years of age has not been adequately assessed.

For the treatment of Kaposi's sarcoma†. Intravenous dosage Adults and Adolescents

0.42 mg/m2/day IV on days 1 through 5, every 3 or 4 weeks (after recovery from myelosuppression) has been studied. Dactinomycin has been given with or without vincristine 1.4 mg/m2 IV weekly until the end of the second course of dactinomycin, then vincristine was given on days 1 and 5 of each subsequent course. In a small study, 9/10 patients (5 CR, 4 PR) receiving dactinomycin achieved a response, and 13/14 patients (10 CR, 3 PR) receiving dactinomycin/vincristine achieved a response.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not provided by the manufacturer; however, a 50% dactinomycin dosage reduction has been suggested in patients with hepatic impairment (e.g., any level of elevated hepatic enzymes).[53549]

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

How Supplied

Cosmegen/Dactinomycin Intravenous Inj Pwd F/Sol: 500mcg

Maximum Dosage

NOTE: The correct dose of dactinomycin will vary based on specific protocol used. Clinicians should consult the appropriate references to verify the dose.

Adults

15 mcg/kg or 400 to 600 mcg/m2 IV daily for 5 days; 45 mcg/kg or 1,250 mcg/m2 IV as a single dose.

Geriatric

15 mcg/kg or 400 to 600 mcg/m2 IV daily for 5 days; 45 mcg/kg or 1,250 mcg/m2 IV as a single dose.

Adolescents

15 mcg/kg or 400 to 600 mcg/m2 IV daily for 5 days; 45 mcg/kg or 1,250 mcg/m2 IV as a single dose.

Children

15 mcg/kg or 400 to 600 mcg/m2 IV daily for 5 days; 45 mcg/kg or 1,250 mcg/m2 IV as a single dose.

Infants

15 mcg/kg IV daily for 5 days; 45 mcg/kg or 1,250 mcg/m2 IV as a single dose.

Mechanism Of Action

Dactinomycin is a cell cycle-phase nonspecific, antibiotic that is more active in actively proliferating cells. It complexes with DNA by intercalating between DNA residues, causing the helix to uncoil and thereby inhibiting DNA synthesis and DNA-dependent RNA synthesis. Dactinomycin selectively inhibits messenger RNA synthesis.

Pharmacokinetics

Dactinomycin is administered intravenously (IV); additionally, it may be administered via regional perfusion. Radiolabeled dactinomycin did not penetrate the blood-brain barrier in 3 adult patients with malignant melanoma. It is minimally metabolized and is concentrated in nucleated cells. Approximately 30% of radiolabeled dactinomycin was recovered in urine and feces within 1 week. The terminal plasma half-life was about 36 hours.[63445] [61766]
Affected cytochrome P450 isoenzymes or drug transporters: P-gp, OATP1B3Dactinomycin is a substrate of P-glycoprotein and OATP1B3 transporters in vitro.[61766]

Pregnancy And Lactation
Pregnancy

Dactinomycin is classified as FDA pregnancy risk category D. Due to its potential for teratogenesis, dactinomycin should be avoided during pregnancy.[63445] Dactinomycin may cause fetal harm when administered during pregnancy, based on its mechanism of action and data from animal studies. Females of reproductive potential should avoid pregnancy during and after treatment with dactinomycin. Advise pregnant women of the potential risk to the fetus. Embryotoxicity and fetal malformations were observed in pregnant rats, rabbits, and hamsters following dactinomycin administered during organogenesis at doses that were as low as 0.2-times the clinical dose of 1,250 mcg/m2.[61766]

Counsel patients about the reproductive risk and contraception requirements during dactinomycin treatment. Pregnancy testing should be performed prior to starting dactinomycin in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for at least 6 months after dactinomycin therapy. Women who become pregnant while receiving dactinomycin should be apprised of the potential hazard to the fetus. Additionally, male patients with a female partner of reproductive potential should use effective contraception during and for 3 months after dactinomycin therapy due to the risk of male-mediated teratogenicity.[61766]