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DACTINOMYCIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Dactinomycin, an antineoplastic agent, is the principal component of a mixture of actinomycin antibiotics produced by Streptomyces parvulus.

Specific Substances

    1) Actinomycin C(1)
    2) Actinomycin D
    3) Actinomycin 11 Cosmegen
    4) Actinomycin 7
    5) Actinomycin A IV
    6) Actinomycin C1
    7) Actinomycin I
    8) Actinomycin I1
    9) Actinomycin I(sub 1)
    10) Actinomycin IV
    11) Actinomycin X 1
    12) ACTO-D
    13) ACT
    14) ACT D
    15) AD
    16) Dactinomycin D
    17) Dactinomicina
    18) HBF 386
    19) Meractinomycin
    20) Meractinomycin
    21) Oncostatin K
    22) NCI-C04682
    23) NSC-3053
    1.2.1) MOLECULAR FORMULA
    1) C62H86N12O16

Available Forms Sources

    A) FORMS
    1) Dactinomycin is available as a sterile lyophilized powder for injection after reconstitution. Each vial contains 0.5 mg of dactinomycin and 20 mg of mannitol (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) SOURCES
    1) Dactinomycin, an antineoplastic agent, is the principal component of a mixture of actinomycin antibiotics produced by Streptomyces parvulus (Budavari, 1996).
    C) USES
    1) Dactinomycin is used in combination with other agents to treat Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma, and metastatic nonseminomatous testicular cancer. It is also used as a single agent or in combination with other agents to treat gestational trophoblastic neoplasia (Prod Info Cosmegen(R) intravenous injection, 2012).
    2) Dactinomycin is also indicated for palliative or adjunctive therapy, as a regional perfusion of locally recurrent solid malignancies (Prod Info Cosmegen(R) intravenous injection, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Dactinomycin is used in combination with other agents to treat Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma, and metastatic nonseminomatous testicular cancer. It is also used as a single agent or in combination with other agents to treat gestational trophoblastic neoplasia. Dactinomycin is also indicated for palliative or adjunctive therapy, as a regional perfusion of locally recurrent solid malignancies.
    B) PHARMACOLOGY: Dactinomycin is classified as an antibiotic but is not used as an antimicrobial agent. It is considered to be cell cycle–phase nonspecific. Its antineoplastic action may involve binding to DNA by intercalation between base pairs and inhibition of DNA-dependent RNA synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The dose-limiting toxicity of dactinomycin is myelosuppression. It may be apparent 1 to 7 days after dactinomycin therapy and may initially manifest as thrombocytopenia. Platelet and white cell nadir counts will generally occur within 14 to 21 days following chemotherapy, with recovery in 21 to 25 days. Anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia have been reported in patients receiving dactinomycin. Other adverse effects include alopecia, skin eruptions, erythema, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, dermatitis, hyperpigmentation, hypocalcemia, severe nausea and vomiting, anorexia, abdominal pain, diarrhea, mucositis, gastrointestinal ulceration, elevated liver enzymes, ascites, hepatomegaly, hepatitis, hepatic failure, hepatic veno-occlusive diseases, myalgia, malaise, fatigue, lethargy, pneumonitis, sepsis, (including neutropenic sepsis) with fatal outcome. Dactinomycin is extremely corrosive. Extravasation during intravenous administration may result in severe damage to soft tissues.
    E) WITH POISONING/EXPOSURE
    1) Dactinomycin overdose information is limited. The following effects may occur following an overdose: Nausea, vomiting, diarrhea, mucositis, stomatitis, gastrointestinal ulceration, severe skin disorders (eg, skin exfoliation, exanthema, desquamation and epidermolysis), seizures, choreoathetosis of extremities, muscle weakness, hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, severe hematopoietic depression (eg, anemia, and thrombocytopenia), veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome. A 10-fold overdose in an 18-month-old child resulted in hypotension, pancytopenia, acute renal failure, pancreatitis, and severe mucositis.
    2) INADVERTENT INTRATHECAL EXPOSURE: Hypotonia, hyperreflexia, respiratory failure, lower extremity paraplegia, paraparesis of the upper extremities, bladder sphincter impairment, and respiratory insufficiency developed in a child following the inadvertent intrathecal administration of dactinomycin. Despite aggressive supportive care, persistent paraplegia developed.
    0.2.20) REPRODUCTIVE
    A) Dactinomycin is classified as FDA pregnancy category D. There was no evidence of congenital anomalies or embryotoxicity in one large study and a case report. However, structural congenital cardiac defects were reported in 2 of 20 children whose mothers had been given dactinomycin in childhood or adolescence for treatment of pediatric cancer. Malformations and embryotoxicity have been reported in animal studies.
    0.2.21) CARCINOGENICITY
    A) Secondary primary tumors, including leukemia, have been reported at an increased incidence following radiation and antineoplastic therapy, such as dactinomycin.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor renal function and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    E) Monitor serial CBC with differential and platelet count. Platelet and granulocyte nadirs generally occur 14 to 21 days after therapeutic doses.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) in patients who develop severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. Early onset thrombocytopenia (within 1 to 4 days of administration) without granulocytopenia appears to be immune related and is often resistant to platelet transfusion. It has been treated with prednisone. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Severe nausea and vomiting may respond to a combination of agents from different drug classes. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) INTRATHECAL INJECTION
    1) There are few reports of therapy for intrathecal dactinomycin overdose. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 18 to 24 hours). Albumin 5% or fresh frozen plasma (25 mL FFP/liter NS or LR) have been used for perfusion. Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; dactinomycin is only available parenterally.
    E) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with persistent seizures, respiratory distress, or severe allergic reactions.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors if patients develop severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Early onset thrombocytopenia (within 1 to 4 days of administration) without granulocytopenia appears to be immune related and is often resistant to platelet transfusion. It has been treated with prednisone 2 mg/kg/day. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. For example: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    K) STOMATITIS
    1) Treat mild mucositis with bland oral rinses with 0.9% saline, sodium bicarbonate, and water. For moderate cases with pain, consider adding a topical anesthetic (eg, lidocaine, benzocaine, dyclonine, diphenhydramine, or doxepin). Treat moderate to severe mucositis with topical anesthetics and systemic analgesics. Patients with mucositis and moderate xerostomia may receive sialagogues (eg, sugarless candy/mints, pilocarpine/cevimeline, or bethanechol) and topical fluorides to stimulate salivary gland function. Consider prophylactic antiviral and antifungal agents to prevent infections. Topical oral antimicrobial mouthwashes, rinses, pastilles, or lozenges may be used to decrease the risk of infection. In patients with a dactinomycin overdose, administer palifermin 60 mcg/kg/day IV bolus injection starting 24 hours after the overdose for 3 consecutive days.
    L) EXTRAVASATION INJURY
    1) If suspected, immediately terminate infusion. Intermittent application of ice for 15 minutes 4 times daily for 3 days may be beneficial. Surgery consult if severe injury has occurred.
    M) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    N) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of dactinomycin. Some toxic effects of overdose may be delayed (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking dactinomycin may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    O) PHARMACOKINETICS
    1) Metabolism: Minimally metabolized. Excretion: Approximately 30% of a dactinomycin dose was recovered in urine and feces in one week. Elimination half-life: Approximately 36 hours.
    P) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose has not been established; however, a 10-fold overdose (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day) in an 18-month-old child resulted in hypotension, pancytopenia, acute renal failure, pancreatitis, and severe mucositis. Electrolyte abnormalities, severe mucositis and diarrhea, pancytopenia, generalized edema, and dermatitis were reported after a patient received a second 2.5 mg dose of dactinomycin 24 hours after receiving a 2.5 mg dose as part of a normal chemotherapeutic regimen. INTRATHECAL administration of 350 mcg dactinomycin to a 5-year-old caused paraplegia despite aggressive treatment.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN: Dactinomycin for any indication should NOT exceed 15 mcg/kg/day or 400 to 600 mcg/m(2)/day IV for 5 days per 2-week cycle. CHILDREN LESS THAN 6 MONTHS OF AGE: Dactinomycin should NOT be used in this patient population due to an increased frequency of toxic effects.

Clinical Effects

Summary Of Exposure

    A) USES: Dactinomycin is used in combination with other agents to treat Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma, and metastatic nonseminomatous testicular cancer. It is also used as a single agent or in combination with other agents to treat gestational trophoblastic neoplasia. Dactinomycin is also indicated for palliative or adjunctive therapy, as a regional perfusion of locally recurrent solid malignancies.
    B) PHARMACOLOGY: Dactinomycin is classified as an antibiotic but is not used as an antimicrobial agent. It is considered to be cell cycle–phase nonspecific. Its antineoplastic action may involve binding to DNA by intercalation between base pairs and inhibition of DNA-dependent RNA synthesis.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The dose-limiting toxicity of dactinomycin is myelosuppression. It may be apparent 1 to 7 days after dactinomycin therapy and may initially manifest as thrombocytopenia. Platelet and white cell nadir counts will generally occur within 14 to 21 days following chemotherapy, with recovery in 21 to 25 days. Anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia have been reported in patients receiving dactinomycin. Other adverse effects include alopecia, skin eruptions, erythema, Stevens Johnson Syndrome, Toxic Epidermal Necrolysis, dermatitis, hyperpigmentation, hypocalcemia, severe nausea and vomiting, anorexia, abdominal pain, diarrhea, mucositis, gastrointestinal ulceration, elevated liver enzymes, ascites, hepatomegaly, hepatitis, hepatic failure, hepatic veno-occlusive diseases, myalgia, malaise, fatigue, lethargy, pneumonitis, sepsis, (including neutropenic sepsis) with fatal outcome. Dactinomycin is extremely corrosive. Extravasation during intravenous administration may result in severe damage to soft tissues.
    E) WITH POISONING/EXPOSURE
    1) Dactinomycin overdose information is limited. The following effects may occur following an overdose: Nausea, vomiting, diarrhea, mucositis, stomatitis, gastrointestinal ulceration, severe skin disorders (eg, skin exfoliation, exanthema, desquamation and epidermolysis), seizures, choreoathetosis of extremities, muscle weakness, hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, severe hematopoietic depression (eg, anemia, and thrombocytopenia), veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome. A 10-fold overdose in an 18-month-old child resulted in hypotension, pancytopenia, acute renal failure, pancreatitis, and severe mucositis.
    2) INADVERTENT INTRATHECAL EXPOSURE: Hypotonia, hyperreflexia, respiratory failure, lower extremity paraplegia, paraparesis of the upper extremities, bladder sphincter impairment, and respiratory insufficiency developed in a child following the inadvertent intrathecal administration of dactinomycin. Despite aggressive supportive care, persistent paraplegia developed.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-month-old child developed hypotension refractory to dopamine and norepinephrine therapy 11 days after receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day). Hypotension resolved after administration of hydrocortisone (40 mg/m(2)/day), amid concerns of hypoadrenalism (Brogan et al, 1999).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) Pneumonitis has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) CASE REPORT: A 7-year-old girl with Ewing's sarcoma received 3 courses of VACA chemotherapy (vincristine, dactinomycin, cyclophosphamide, and adriamycin) and radiotherapy, and subsequently developed pneumonitis, consisting of dyspnea, cyanosis, and crepitation at the base of the right lung, after initiating the fourth course of VACA chemotherapy. The patient gradually improved with administration of methylprednisolone; however, her condition deteriorated with reduction of the methylprednisolone dose. An open lung biopsy showed obliteration of the alveolar spaces and thickening of the alveolar walls by fibrosis. The patient's condition continued to deteriorate and she subsequently died, 3 weeks later, of pulmonary failure. It is believed that dactinomycin, given post-radiotherapy, was the causative agent since both cyclophosphamide and vincristine had been previously given after radiotherapy without occurrence of any pulmonary reaction (Cohen et al, 1991).
    B) ATELECTASIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A newborn infant developed apnea and died four days after beginning dactinomycin therapy, 15 mcg/kg/day, for treatment of a Wilms' tumor. An autopsy revealed atelectasis of the lungs. Neutropenia was not present and there was no evidence of aspiration. It is speculated that dactinomycin therapy may have been a contributing factor in the infant's death (Lascari, 1972).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) NEUROLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Malaise, fatigue, and lethargy have been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Inadvertent intrathecal administration of 350 mcg dactinomycin instead of 12 mg of methotrexate occurred in a 5-year-old child with stage I T-cell lymphoblastic lymphoma. She developed hypotonia, hyperreflexia, respiratory failure, lower extremity paraplegia, paraparesis of the upper extremities, bladder sphincter impairment, and respiratory insufficiency. Despite aggressive supportive care (sedation, cerebrospinal fluid (CSF) exchange, CSF perfusion, intrathecal corticosteroids and ascorbic acid, intravenous sodium thiosulfate) and eventual hospital discharge, paraplegia of the lower extremities, paresis of the upper extremities, and bladder sphincter impairment continued to persist. It is believed that the patient's neurotoxicity was due to the necrotizing effects of dactinomycin (Kavan et al, 2001).
    B) CHOREOATHETOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-month-old child developed choreoathetosis of all extremities and muscle weakness of the right arm after inadvertently receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day). Although the choreoathetosis and right arm weakness had gradually improved at the time of hospital discharge, the patient continued to experience slightly diminished functionality of his right arm 4 years post-overdose (Brogan et al, 1999).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old male experienced a generalized seizure after inadvertently receiving a 2.5-mg dose of dactinomycin 24 hours after receiving a 2.5-mg dose as part of his normal chemotherapeutic regimen. He recovered following intravenous administration of diazepam (Choonara et al, 1988).
    D) LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 5-year-old boy with the diagnosis of Wilms' tumor had symptoms consistent with reversible posterior leukoencephalopathy syndrome (ie, headache, abnormal mental status, seizures, and abnormalities in white/gray matter of the parieto-occipital lobes) following seizure post-induction therapy with vincristine (1.4 mg/m(2)/dose) and intravenous actinomycin-D (5 mcg/kg/dose). He was not hypertensive, but was hyponatremic with a sodium of 128 mEq/L. All other biochemical tests were normal. MRI showed multiple cortical and subcortical lesions and the bilateral posterior temporal, parietal, and frontal lobes. He developed hypertension on the 5th day of treatment. The patient was discharged after 20 days without any neurological sequelae (Ozyurek et al, 2005).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Severe nausea and vomiting can occur within a few hours following dactinomycin therapy (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) INCIDENCE: Nausea and vomiting occurred in 16 of 36 patients and 12 of 42 patients who received dactinomycin 0.45 mg/m(2) days 1 through 5 or IV dactinomycin 1.7 mg/m(2) on day 8, respectively, as part of a chemotherapeutic combination regimen. The combination regimen also included vincristine given intravenously and cyclophosphamide given intravenously or intramuscularly (Carli et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    2) WITH POISONING/EXPOSURE
    a) Diarrhea may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    E) ACUTE MUCOSITIS
    1) WITH POISONING/EXPOSURE
    a) Mucositis may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) CASE REPORT: An 18-month-old child experienced severe mucositis after receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day) (Brogan et al, 1999).
    c) CASE REPORT: Severe mucositis and diarrhea developed in a 17-year-old, with orbitobasal rhabdomyosarcoma, after he inadvertently received a second 2.5-mg dose of dactinomycin 24 hours after receiving a 2.5 mg dose as part of his normal chemotherapeutic regimen. The total dose of dactinomycin received was 0.1 mg/kg (3.3 mg/m(2)). The patient gradually recovered with supportive care (Choonara et al, 1988).
    F) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis has been reported in several patients following therapeutic administration of dactinomycin and may be dose-limiting (Prod Info Cosmegen(R) intravenous injection, 2012; Carli et al, 1988; Blumenreich et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Stomatitis may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    G) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-month-old child developed pancreatitis after inadvertently receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day) (Brogan et al, 1999).
    H) ULCER
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal ulceration has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    2) WITH POISONING/EXPOSURE
    a) Gastrointestinal ulceration may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INJURY OF LIVER
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzymes, ascites, hepatomegaly, hepatitis, hepatic failure, and hepatic veno-occlusive diseases have been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) Severe hepatic toxicity, consisting of lethargy, vomiting, ascites, and elevated transaminase levels, occurred in several children who were treated with a chemotherapeutic regimen that included single high-dose IV dactinomycin (60 mcg/kg) and vincristine (2 mg/m(2)). None of the patients received radiation therapy. Reducing the dose of dactinomycin from 60 mcg/kg to 45 mcg/kg appeared to decrease the incidence of hepatotoxicity. One study reported the occurrence of hepatic toxicity in 5 of 35 patients (14.3%) who received 60 mcg/kg of dactinomycin as compared with 4 of 108 patients (3.7%) who received 45 mcg/kg of dactinomycin (Green et al, 1990; Green et al, 1988).
    B) VENO-OCCLUSIVE DISEASE OF THE LIVER
    1) WITH THERAPEUTIC USE
    a) Three children presented with abdominal pain within days after receiving combination chemotherapy, consisting of dactinomycin and vincristine, for treatment of Wilms' tumor. None of the patients received any radiotherapy. Ultrasonography revealed hepatomegaly and thickening of the gallbladder walls and laboratory analyses showed elevated transaminase levels, decreased hemoglobin levels (ranging from 6.8 g/dL to 7.7 g/dL) and thrombocytopenia (platelet counts ranging from 19,000/mm(3) to 26,000/mm(3)), all of which was consistent with a diagnosis of hepatic veno-occlusive disease. All three patients recovered following supportive care and discontinuation of dactinomycin therapy (Schiavetti et al, 1996).
    b) Hepatic veno-occlusive disease (VOD) was reported in 6 male patients aged 6 to 48 months (median, 19 months) who received dactinomycin (n=6), vincristine (n=6), and doxorubicin (n=2); 3 patients died and 3 recovered. Within 7 to 10 days after the second (n=5) or third (n=1) course of dactinomycin therapy, severe VOD presented with intravascular coagulopathy with median platelet count of 12 x 10(9)/L, median international normalized ratio (INR) of 3.8, median fibrinogen 1.6 mg/dL, and fibrin degradation products of 80 mcg/L or greater. Thrombocytopenia without neutropenia was evident before the clinical onset of VOD in 4 of 4 patients with available serial platelet counts (D'Antiga et al, 2001).
    1) Thrombocytopenia disappeared within 7 days of onset of VOD in the 3 patients who recovered, but thrombocytopenia and elevated fibrin degradation products persisted (n=2) or fluctuated (n=1) until death in the other 3 patients. Encephalopathy, hepatomegaly, ascites, and reversed portal flow were present at clinical onset. Treatment was supportive and consisted of fluid and sodium restriction, preservation of intravascular volume and oncotic pressure, maintenance of platelets and hemoglobin, maintenance of INR with N-acetylcysteine and vitamin K, broad spectrum antibiotics and antifungals, spironolactone, and octreotide (D'Antiga et al, 2001).
    2) Hepatopathy-thrombocytopenia syndrome (HTS) occurred in 6 of 355 (1.7%) of children receiving combination chemotherapy containing dactinomycin for Wilms' tumor. Clinical presentation included hepatomegaly with elevated liver function tests (transaminase levels greater than 1000 international units/liter in 4 of the 6 children) in combination with severe thrombocytopenia (platelet count 20 x 10(9)/L or less). Onset of the syndrome was less than 10 weeks after initiation of dactinomycin therapy. This syndrome resolved with supportive treatment and lasted an average of 12 days (Raine et al, 1991). It is believed that the development of hepatic veno-occlusive disease is the most likely cause of HTS in these 6 patients.
    c) RISK FACTORS: According to a study conducted to determine the risk factors for hepatopathy, including hepatic veno-occlusive disease and hepatopathy-thrombocytopenia syndrome, following administration of vincristine, dactinomycin, and cyclophosphamide for treatment of childhood rhabdomyosarcoma, age appears to be the most prevalent risk factor. Eighteen of 339 children enrolled in the study, developed hepatopathy. The risk of hepatopathy, for patients under 3 years of age (n=89), was 15%, and included two deaths. The risk of hepatopathy, for patients 3 years of age or older (n=239), was 4%, and included two deaths. The initial protocol dose of dactinomycin was 0.025 mg/kg for children less than 12 months of age, 0.05 mg/kg for children 1 to 3 years of age, and 1.5 mg/m(2) for children greater than 3 years of age. The protocol was eventually amended to 0.025 mg/kg for children less than 12 months of age and 0.045 mg/kg for children 12 months of age or older. The higher dose of dactinomycin appeared to be directly related to the incidence of hepatopathy in these children (Arndt et al, 2004).
    d) One study found that VOD occurs in patients with "low-stage" rhabdomyosarcoma treated with vincristine and actinomycin D. The authors reported four cases of VOD. All patients recovered with no evidence of permanent hepatic damage. Resumption of chemotherapy, particularly actinomycin D, was well-tolerated (Sulis et al, 2004).
    2) WITH POISONING/EXPOSURE
    a) Veno-occlusive disease may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    C) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) Sixty days after initiation of dactinomycin 15 mcg/kg/day (two 5-day courses plus irradiation), centrilobular congestion with liver necrosis developed in a 5-year-old girl with Wilms' tumor. Liver function returned to normal 100 days after therapy initiation (Jayabose et al, 1976).
    D) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Hepatitis has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) Dactinomycin, 180 mcg/day plus irradiation, produced hepatitis with thrombocytopenia in a 5-year-old boy after 4 days. Liver function gradually improved over 12 weeks and the platelet count returned to normal after 18 months (Harris et al, 1974).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Acute renal failure may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) CASE REPORT: An 18-month-old child developed acute anuric renal failure 9 days after receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day). Continuous venovenous hemofiltration was performed and the patient gradually recovered 13 days after onset of symptoms (Brogan et al, 1999).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) The dose-limiting toxicity of dactinomycin is bone marrow suppression. It may be apparent 1 to 7 days after dactinomycin therapy and may initially manifest as thrombocytopenia. Platelet and white cell nadir counts will generally occur within 14 to 21 days following chemotherapy, with recovery in 21 to 25 days (Sweetman, 2004; Blumenreich et al, 1985). Anemia, aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia have been reported in patients receiving dactinomycin. Recovery may take up to 3 weeks (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) Dactinomycin may trigger an immune mechanism with the formation of platelet antibodies, thus leading to thrombocytopenia. Treatment with prednisone appeared to improve platelet counts in several patients (Khatua et al, 2004; Shannon et al, 2003; Hara et al, 1986; Hodder et al, 1985).
    2) WITH POISONING/EXPOSURE
    a) Severe hematopoietic depression and sepsis (including neutropenic sepsis) with fatal outcome may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) CASE REPORT: An 18-month-old child developed pancytopenia after receiving a 10-fold overdose of dactinomycin for 3 days (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day). The patient gradually recovered following supportive care (Brogan et al, 1999).
    c) CASE REPORT: Severe anemia, neutropenia, and thrombocytopenia occurred in a 17-year-old who inadvertently received a second 2.5-mg dose of dactinomycin 24 hours after receiving a 2.5 mg dose as part of his normal chemotherapeutic regimen. The total dose of dactinomycin received was 0.1 mg/kg (3.3 mg/m(2)). His neutrophil and platelet nadir counts were 0.03 x 10(9)/L on day 14 and 15 x 10(9)/L on day 6, respectively. The patient's platelet count did not exceed 100 x 10(9)/L until 6 weeks after receiving the second dose of dactinomycin (Choonara et al, 1988).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia has been reported with dactinomycin therapy (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Dactinomycin therapy has been associated with skin eruptions, erythema, and increased pigmentation of previously irradiated skin (Prod Info Cosmegen(R) intravenous injection, 2012; Coppes et al, 1997) and has been reported to potentiate dermatologic adverse effects of ionizing radiation (Blatt et al, 1981). Epidermolysis and erythema have been reported with regional limb perfusion (Prod Info Cosmegen(R) intravenous injection, 2012).
    b) CASE REPORT: A 4-year-old child with Wilms' tumor developed maculopapular exanthematous skin lesions on the torso and axillary regions and on the lower extremities after receiving chemotherapy containing dactinomycin. The patient also had palmar/plantar erythema and desquamation but no itching or any other complaint. Skin biopsy revealed perivascular infiltration with lymphocytes and melanin-containing histocytes. Treatment was continued and, despite prophylactic antihistamines and corticosteroids, the child had a warm pruritic rash on the knees and elbows with scales on the palms and soles. Gradually, all skin lesions disappeared over the course of 2 months, and chemotherapy was continued without incident. The authors suggest that this patient had prior epidermal damage as evidenced by the presence of pigment-ladened macrophages, and do not consider this an allergic reaction (Van Gool et al, 1998).
    c) CASE REPORT: A case report describes a 23-year-old woman with a 4-month history of choriocarcinoma who was treated with 9 cycles of methotrexate, which she had completed 8 weeks prior to evaluation. The patient was seen with severe mucositis and acute onset of axillary and inguinal lesions. She started treatment with dactinomycin 3 weeks prior to evaluation and, during the second cycle, she developed asymptomatic dark brown patches on her axillae, neck, inguinal region, and umbilicus. Pathologic evaluation revealed non-specific post-inflammatory pigmentary abnormalities and mild hyperkeratosis. The patient remained asymptomatic and a follow-up visit, 10 days later, showed only post-inflammatory change. The patient subsequently tolerated a third cycle of dactinomycin with no recurrence of the rash (Waller et al, 2006). In the literature, 4 cases like this have been described, though mostly in children. For the most part, this rash is self-limited and occurrence of these lesions do not necessarily warrant discontinuation of dactinomycin.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 17-year-old developed generalized edema of all extremities and trunk and intense erythema which progressively developed into a purpuric rash associated with severe thrombocytopenia, after inadvertently receiving two 2.5-mg doses of dactinomycin given 24 hours apart. The total dactinomycin dose received was 0.1 mg/kg (3.3 mg/m(2)). He also developed superficial peeling and several bullae of the left arm. The patient gradually recovered without sequelae (Choonara et al, 1988).
    C) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) During postmarketing experience, Stevens Johnson Syndrome (SJS) was observed in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    D) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) During postmarketing experience, Toxic Epidermal Necrolysis (TEN) was observed in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    E) DERMATITIS
    1) WITH THERAPEUTIC USE
    a) A maculopapular rash, involving the axillae, groin, and central venous line exit site, occurred in two children approximately one week after receiving dactinomycin therapy, 0.015 mg/kg/day for 5 days. One of the two patients also developed diffuse facial hyperpigmentation. Skin biopsies of both patients revealed interface dermatitis with syringometaplasia. Neither patient had received any radiation treatment prior to presentation of the rash. Both patients gradually recovered following discontinuation of dactinomycin therapy (Kanwar et al, 1995).
    F) EXTRAVASATION INJURY
    1) WITH THERAPEUTIC USE
    a) Dactinomycin is extremely corrosive, and extravasation during IV administration can result in cellulitis and damage to soft tissues. In one case, extravasation led to contracture of the arms (Prod Info Cosmegen(R) intravenous injection, 2012).
    G) RADIATION DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Dactinomycin can potentiate the radiation effect. Erythema from previous radiation therapy may be reactivated by dactinomycin alone, especially with brief intervals between dactinomycin and radiotherapy, but even with an interval of several months between therapies. When dactinomycin and radiotherapy are administered concurrently, a smaller than usual radiation dose causes erythema and vesiculation, which progresses more rapidly through the stages of tanning and desquamation. Healing may occur in 4 to 6 weeks rather than 2 to 3 months. If high doses of both dactinomycin and radiation therapy are used, or if the patient is particularly sensitive to the combined therapy, severe reactions may occur (Prod Info Cosmegen(R) intravenous injection, 2012).
    H) ACNE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 8-year-old girl developed severe acne of the forehead within 10 days of beginning dactinomycin therapy. Serum androgen levels, taken 1 week after the acne appeared, were elevated (androstenedione 171 nanograms (ng)/dL, DHEA 354 ng/dL). Following discontinuation of dactinomycin therapy, the patient's acne gradually disappeared and her serum androgen levels normalized (Blatt & Lee, 1993).
    I) LICHENOID DERMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 20-month-old boy, with a history of renal tumor concerning for Wilms' tumor, received neoadjuvant chemotherapy with a first course of dactinomycin (0.015 mg/kg/day for 3 days) and vincristine (1.5 mg/m(2)/day for 1 day) and a second course of vincristine alone 1 week later. Twelve days post-administration of dactinomycin and vincristine, the child presented to the hospital febrile (39 degrees C) with a rapid onset of a pruritic skin rash initially erupting on his face and extending to his trunk, extremities, palms, and soles. There were no blisters, conjunctival or genital involvement, but there was cheilitis. A skin biopsy revealed lichenoid, intra-epidermal necrosis, and inflammatory lymphocytic infiltrate at the dermo-epidermal junction. A diagnosis of lichenoid eruption secondary to dactinomycin was made. The patient's rash resolved 4 weeks post-presentation following application of topical steroids and oral administration of dexchlorpheniramine; however, he did have residual hyperpigmentation (Ridola et al, 2006).
    J) HYPERPIGMENTATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case report describes a 23-year-old woman with a 4-month history of choriocarcinoma who was treated with 9 cycles of methotrexate, which she had completed 8 weeks prior to evaluation. The patient was seen with severe mucositis and acute onset of axillary and inguinal lesions. She started treatment with dactinomycin 3 weeks prior to evaluation and, during the second cycle, she developed asymptomatic dark brown patches on her axillae, neck, inguinal region, and umbilicus. Pathologic evaluation revealed non-specific post-inflammatory pigmentary abnormalities and mild hyperkeratosis. The patient remained asymptomatic and a follow-up visit, 10 days later, showed only post-inflammatory change. The patient subsequently tolerated a third cycle of dactinomycin with no recurrence of the rash (Waller et al, 2006). In the literature, 4 cases like this have been described, though mostly in children. For the most part, this rash is self-limited and occurrence of these lesions do not necessarily warrant discontinuation of dactinomycin.
    K) DISORDER OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Severe skin disorders, including skin exfoliation, exanthema, desquamation and epidermolysis may occur following an overdose (Prod Info Cosmegen(R) intravenous injection, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia has been reported in patients receiving dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Dactinomycin is classified as FDA pregnancy category D. There was no evidence of congenital anomalies or embryotoxicity in one large study and a case report. However, structural congenital cardiac defects were reported in 2 of 20 children whose mothers had been given dactinomycin in childhood or adolescence for treatment of pediatric cancer. Malformations and embryotoxicity have been reported in animal studies.
    3.20.2) TERATOGENICITY
    A) CARDIAC DEFECTS
    1) Structural congenital cardiac defects were reported in 2 of 20 children whose mothers had been given dactinomycin in childhood or adolescence for treatment of pediatric cancer (Green et al, 1991).
    B) LACK OF EFFECT
    1) A larger study was conducted to determine the possible occurrence of birth defects following dactinomycin therapy. None of the 52 children, born to 36 cancer survivors who had received dactinomycin therapy during childhood or adolescence (11 men and 25 women), developed a major birth defect as compared to 74 of 2146 offspring of unexposed cancer survivors who had a major malformation, including 17 children who developed congenital heart disease (Byrne & Nicholson, 1992).
    2) CASE REPORT: A 16-year-old woman became pregnant after long-term treatment with dactinomycin and irradiation for choriocarcinoma. She delivered a healthy infant without complications (O'Neill et al, 1976).
    3) There have been no reports of congenital malformations caused by maternal use. Normal pregnancies have been reported after dactinomycin was used as part of combination chemotherapy (Bakri et al, 1991; Sivanesaratnam & Sen, 1988; Rustin & Booth M Dent, 1984).
    4) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by most practitioners as the most critical for abnormal fetal development (Glantz, 1994).
    C) ANIMAL STUDIES
    1) RATS, RABBITS, HAMSTERS: Malformations and embryotoxicity have been reported in rats, rabbits, and hamsters following administration of dactinomycin at doses of 50 to 100 mcg/kg (approximately 0.5 to 2 times the maximum recommended daily human dose on a body surface area basis) (Prod Info Cosmegen(R) intravenous injection, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Dactinomycin was classified by the manufacturer as FDA pregnancy category D (Prod Info Cosmegen(R) intravenous injection, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info Cosmegen(R) intravenous injection, 2012).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) Adequate fertility studies have not been reported. However, current reports suggest an increased incidence of infertility following treatment with other antineoplastic agents (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) ANIMAL STUDIES
    1) MALE: Dactinomycin (actinomycin D) induced abnormal sperm morphology in mice at high doses and in hamsters at 16 mcg/kg (RTECS, 1996). Testicular lesions were seen in dogs receiving single doses (07).
    2) FEMALE: Dactinomycin (actinomycin D) does not appear to affect fertility in women (Cohen, 1971; Pastorfide & Goldstein, 1973; Rosenshein, 1979; Walden & Bagshawe, 1979; Schwartz & Vidone, 1981; Rustin, 1984; Curtin & Adcock, 1986).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS50-76-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Actinomycin D
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.2) SUMMARY/HUMAN
    A) Secondary primary tumors, including leukemia, have been reported at an increased incidence following radiation and antineoplastic therapy, such as dactinomycin.
    3.21.3) HUMAN STUDIES
    A) SECONDARY PRIMARY TUMORS
    1) An increased incidence of secondary primary tumors, including leukemia, have been reported following radiation and antineoplastic therapy, such as dactinomycin (Prod Info Cosmegen(R) intravenous injection, 2012).
    3.21.4) ANIMAL STUDIES
    A) NEOPLASMS
    1) MICE, RATS: Dactinomycin is a positive carcinogen in animals, according to the International Agency on Research on Cancer. Local sarcomas were reported in mice and rats following repeated subcutaneous or intraperitoneal administration. Mesenchymal tumors occurred in male rats following intraperitoneal administration of dactinomycin at doses of 50 mcg/kg 2 to 5 times per week for 18 weeks. The first tumor appeared 23 weeks after beginning dactinomycin administration (Prod Info Cosmegen(R) intravenous injection, 2012).

Genotoxicity

    A) Dactinomycin is mutagenic in several in vitro and in vivo test systems, including human fibroblasts and leukocytes and HeLa cells (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) There is also evidence of DNA damage and cytogenic effects in mice and rats (Prod Info Cosmegen(R) intravenous injection, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor renal function and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    E) Monitor serial CBC with differential and platelet count. Platelet and granulocyte nadirs generally occur 14 to 21 days after therapeutic doses.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    4.1.2) SERUM/BLOOD
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serial CBC with differential and platelet count. Platelet and granulocyte nadirs generally occur 14 to 21 days after therapeutic doses.
    C) Monitor renal function and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    4.1.4) OTHER
    A) OTHER
    1) Monitor vital signs and mental status in symptomatic patients.
    2) LAB ASSAY INTERFERENCE: Dactinomycin may interfere with bioassays for determination of antibacterial drug levels (Prod Info Cosmegen(R) intravenous injection, 2012).

Methods

    A) CHROMATOGRAPHY
    1) Liquid chromatography-mass spectrometry has been used to determine the presence of dactinomycin in human plasma. The limit of quantitation was 1 nanograms/mL (Veal et al, 2003).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status in symptomatic patients.
    C) Monitor renal function and liver enzymes in symptomatic patients.
    D) Monitor serum electrolytes in patients with severe vomiting and/or diarrhea.
    E) Monitor serial CBC with differential and platelet count. Platelet and granulocyte nadirs generally occur 14 to 21 days after therapeutic doses.
    F) In patients with neutropenia, monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; dactinomycin is only available parenterally.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose has not been established; however, a 10-fold overdose (0.15 mg/kg/day instead of the prescribed 0.015 mg/kg/day) in an 18-month-old child resulted in hypotension, pancytopenia, acute renal failure, pancreatitis, and severe mucositis. Electrolyte abnormalities, severe mucositis and diarrhea, pancytopenia, generalized edema, and dermatitis were reported after a patient received a second 2.5 mg dose of dactinomycin 24 hours after receiving a 2.5 mg dose as part of a normal chemotherapeutic regimen. INTRATHECAL administration of 350 mcg dactinomycin to a 5-year-old caused paraplegia despite aggressive treatment.
    B) THERAPEUTIC DOSE: ADULTS AND CHILDREN: Dactinomycin for any indication should NOT exceed 15 mcg/kg/day or 400 to 600 mcg/m(2)/day IV for 5 days per 2-week cycle. CHILDREN LESS THAN 6 MONTHS OF AGE: Dactinomycin should NOT be used in this patient population due to an increased frequency of toxic effects.

Therapeutic Dose

    7.2.1) ADULT
    A) Dactinomycin for any indication should NOT exceed 15 mcg/kg/day or 400 to 600 mcg/m(2)/day per 2-week cycle. Dactinomycin dosages may need to be adjusted to accommodate patient tolerance, neoplasm size and location, and administration of other therapy. If additional chemotherapy or radiotherapy is coadministered or if there is a history of past use, it may be necessary to adjust the usual dose (Prod Info Cosmegen(R) intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) Dactinomycin for any indication should NOT exceed 15 mcg/kg/day or 400 to 600 mcg/m(2)/day per 2-week cycle. Dactinomycin dosages may need to be adjusted to accommodate patient tolerance, neoplasm size and location, and administration of other therapy. If additional chemotherapy or radiotherapy is coadministered or if there is a history of use, it may be necessary to adjust the usual dose (Prod Info Cosmegen(R) intravenous injection, 2012).
    B) LESS THAN 6 MONTHS OF AGE: Dactinomycin should NOT be used in this patient population due to an increased frequency of toxic effects (Prod Info Cosmegen(R) intravenous injection, 2012).

Maximum Tolerated Exposure

    A) CASE REPORT: Inadvertent intrathecal administration of 350 mcg dactinomycin instead of 12 mg of methotrexate occurred in a 5-year-old child with stage I T-cell lymphoblastic lymphoma, resulting in hypotonia, hyperreflexia, lower extremity paraplegia, paraparesis of the upper extremities, bladder sphincter impairment, and respiratory insufficiency. Despite aggressive supportive care and eventual hospital discharge, paraplegia of the lower extremities, paresis of the upper extremities, and bladder sphincter impairment continued to persist (Kavan et al, 2001).
    B) CASE REPORT: An 18-month-old child inadvertently received a 10-fold overdose of dactinomycin (0.15 mg/kg/day for 3 days instead of the prescribed 0.015 mg/kg/day). She developed hypotension, pancytopenia, acute renal failure, choreoathetosis and right arm weakness, pancreatitis, and severe mucositis. The child gradually recovered with residual functional impairment of his right arm (Brogan et al, 1999).
    C) CASE REPORT: A 17-year-old, with orbitobasal rhabdomyosarcoma, developed electrolyte abnormalities, severe mucositis and diarrhea, pancytopenia, generalized edema, and dermatitis after receiving a second 2.5-mg dose of dactinomycin 24 hours after receiving a 2.5-mg dose as part of his normal chemotherapeutic regimen. He gradually recovered with supportive care (Choonara et al, 1988).

Workplace Standards

    A) ACGIH TLV Values for CAS50-76-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS50-76-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS50-76-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Actinomycin D
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS50-76-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 500 to 750 mcg/kg (RTECS, 2004)
    B) LD50- (ORAL)MOUSE:
    1) 13 to 20 mg/kg (RTECS, 2004)
    C) LD50- (SUBCUTANEOUS)MOUSE:
    1) 500 mcg/kg (RTECS, 2004)
    D) LD50- (INTRAPERITONEAL)RAT:
    1) 100 mcg/kg (RTECS, 2004)
    E) LD50- (ORAL)RAT:
    1) 7200 mcg/kg (RTECS, 2004)
    F) LD50- (SUBCUTANEOUS)RAT:
    1) 800 mcg/kg (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dactinomycin is an antibiotic obtained from cultures of Streptomyces parvulus. The drug's cytotoxicity precludes its use as a bacteriostatic anti-infective agent. Experimental evidence indicates that dactinomycin acts by forming complexes with DNA and selectively inhibiting the DNA-directed synthesis of RNA. Dactinomycin is thought to inhibit protein synthesis by inhibiting the synthesis of messenger RNA. Dactinomycin inhibits DNA synthesis, but in much higher concentrations than are required to inhibit RNA synthesis (Chabner et al, 1996).

Physicochemical

Physical Characteristics

    A) Dactinomycin is a yellow to orange lyophilized powder (Prod Info COSMEGEN(R) intravenous injection, 2008) that is soluble in water at 10 degrees C, slightly soluble in water at 37 degrees C, freely soluble in alcohol, and very slightly soluble in ether (Sweetman, 2004).

Ph

    A) 5.5 to 7.9 (reconstituted solution) (Trissel, 1983)

Molecular Weight

    A) 1255.4 (Sweetman, 2004)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
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