Dactinomycin (Systemic)

VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): Cosmegen.

Another commonly used name is
actinomycin-D .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Ewing's sarcoma (treatment) or
Carcinoma, testicular (treatment) or
Rhabdomyosarcoma (treatment) or
Wilm's Tumor (treatment)—Dactinomycin is indicated, as part of a combination chemotherapy and/or multi-modality treatment regimen, for the treatment of Ewing's sarcoma, metastatic, nonseminomatous testicular cancer, childhood rhabdomyosarcoma (up to 21 years of age), and Wilm's tumor.^{16}

Tumors, trophoblastic, gestational (treatment)— Dactinomycin is indicated as a single agent or in combination with other chemotherapeutic agents for treatment of gestational trophoblastic tumors ^{01}.^{16}

Note: Dactinomycin is indicated, as a component of regional perfusion, for the palliative and/or adjunctive treatment of locally recurrent or logoregional solid malignancies (e.g., sarcomas, carcinomas, and adenocarcinomas).^{16}


[Sarcoma, Kaposi's (treatment)]¹ or
[Osteosarcoma (treatment)]¹—Dactinomycin is indicated in combination with other chemotherapeutic agents for treatment of Kaposi's sarcoma and osteosarcoma.

Unaccepted
Although dactinomycin has antibacterial activity, its toxic effects preclude its use in the treatment of infectious diseases ^{01}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    1255.43

Mechanism of action/Effect:

Dactinomycin is classified as an antibiotic but is not used as an antimicrobial agent. Dactinomycin 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.


Other actions/effects:

Has some bacteriostatic activity on gram-positive and on gram-negative bacteria and on some fungi ^{01}. Also has some immunosuppressant activity.

Distribution:

Does not cross the blood-brain barrier ^{01}.

Protein binding:

Extensive tissue binding.

Biotransformation:

Minimal ^{01}.

Half-life:

36 hours ^{01}.

Elimination:
    Biliary/fecal—50% unchanged.
    Renal—10% unchanged.
    About 30% of a dose is recoverable in urine and feces in 1 week ^{01}.


Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.

Dactinomycin is carcinogenic in mice and rats as determined by the International Agency on Research on Cancer. Repeated subcutaneous or intraperitoneal injections produced local sarcomas in mice and rats ^{01}{16}. Intraperitoneal injections of 0.05 mg per kg of body weight (mg/kg) two to five times per week for 18 weeks in male F344 rats resulted in mesenchymal tumors, the first tumor appearing at 23 weeks ^{01}.

Dactinomycin has been shown to be mutagenic in both in vitro and in vivo tests (human fibroblasts and leukocytes, HELA cells) and causes DNA damage and cytogenetic effects in mice and rats ^{01}.

Pregnancy/Reproduction
Fertility—
Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.

Adequate fertility studies have not been reported, although current reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.
^{16}
Pregnancy—
Dactinomycin crosses the placenta. Adequate and well-controlled studies in humans have not been done.

First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.

Other hazards to the fetus include adverse reactions seen in adults.

In general, use of a contraceptive is recommended during cytotoxic drug therapy.

Some studies in rats, rabbits, and hamsters have shown that dactinomycin causes malformations and embryotoxicity when given intravenously in doses of 50 to 100 mcg (0.05 to 0.1 mg) per kg of body weight (corresponding to 0.5 to 2 times the maximum recommended human dose on a body surface area basis).^{16}

FDA Pregnancy Category D
^{16}
Breast-feeding

It is not known whether dactinomycin is distributed into breast milk ^{01}. However, breast-feeding is not recommended while dactinomycin is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity).

Pediatrics

Because of the increased risk of toxicity in infants, dactinomycin should be used only in infants older than 6 to 12 months of age, unless potential benefit outweighs risk ^{{01} {12}}.


Geriatrics


No information is available on the relationship of age to the effects of dactinomycin in geriatric patients.


Dental

The bone marrow depressant effects of dactinomycin may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Dactinomycin commonly causes ulcerative stomatitis and pharyngitis associated with considerable discomfort. Sores often occur under the tongue.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Allopurinol or
Colchicine or
» Probenecid or
» Sulfinpyrazone    (dactinomycin may raise the concentration of blood uric acid; dosage adjustment of antigout agents may be necessary to control hyperuricemia and gout; allopurinol may be preferred because of risk of uric acid nephropathy with uricosuric antigout agents)


Blood dyscrasia–causing medications (see Appendix II )    (leukopenic and/or thrombocytopenic effects of dactinomycin may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of dactinomycin, if necessary, should be based on blood counts)


» Bone marrow depressants, other (see Appendix II ) or
» Radiation therapy^{01}    (concurrent use with dactinomycin may potentiate the effects of these medications and radiation therapy, including gastrointestinal toxicity, bone marrow depression, and erythema and tanning of the skin; lower doses of each are recommended. Dactinomycin alone may reactivate erythema from previous radiation therapy)


Doxorubicin    (concurrent or sequential ^{13} use may result in increased cardiotoxicity; it is recommended that the total dose of doxorubicin not exceed 450 mg per square meter of body surface area)


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by dactinomycin therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by dactinomycin therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the dactinomycin therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bioassay procedures for determinations of antibacterial drug concentrations    (may be interfered with ^{01})

With physiology/laboratory test values
Hepatic enzymes    (serum values may rarely be increased)


Uric acid concentrations in blood and urine    (may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression
» Chickenpox, existing or recent^{01} (including recent exposure) or
» Herpes zoster^{01}    (risk of severe generalized disease)


Gout, history of or
Urate renal stones, history of    (risk of hyperuricemia)


» Hepatic function impairment    (some clinicians recommend reduction of dosage by one third or one half in patients with hyperbilirubinemia)


» Infection
Sensitivity to dactinomycin
» Caution should be used also in patients who have had previous cytotoxic drug therapy or radiation therapy.

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; (» = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin concentrations, serum and
Lactate dehydrogenase (LDH) values, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


» Checking patient's mouth for ulceration    (recommended before administration of each dose)


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (determinations recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)


Uric acid concentrations, serum    (recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)




Side/Adverse Effects

Note: Many “side effects” of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
Most side effects appear 2 to 4 days after a course is completed and may not be maximal for 1 to 2 weeks. However, most adverse reactions usually stop with the discontinuation of therapy.^{16}
Combination therapy with radiation may be associated with more frequent and severe side effects of the radiation, including gastric distress ^{01} and inflammation of mucous membranes at the irradiated site. Severe reactions may occur if high dosages are used. Hepatotoxicity (hepatomegaly, increased serum aspartate aminotransferase [AST (SGOT)], ascites) has occurred when dactinomycin was used within the first 2 months after radiation therapy for right-sided Wilms' tumor ^{{01} {05} {06}}.
Complications associated with use of isolation-perfusion administration are mainly related to how much medication reaches the systemic circulation and may include myelosuppression, absorption of toxic products from massive neoplastic tissue destruction, increased risk of infection, impaired wound healing, and superficial gastric mucosal ulceration ^{01}. Other potential side/adverse effects include edema of the extremity involved, soft tissue damage in the exposed area, and venous thrombosis ^{01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia, possibly progressing to aplastic anemia ^{01} (unusual tiredness or weakness)
    
esophagitis (difficulty in swallowing; heartburn)
    
gastrointestinal ulceration ^{01} or proctitis (black, tarry stools; continuing diarrhea; continuing stomach pain)
    
leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)— usually asymptomatic
    
thrombocytopenia (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)— usually asymptomatic
    
ulcerative stomatitis ^{01} (sores in mouth and on lips)

Note: Bone marrow depression occurs approximately 7 to 10 days after a course of therapy, with the nadir reached at about 3 weeks and recovery within about 3 weeks after nadir. It may be severe and progress to pancytopenia, reticulocytopenia and agranulocytosis, which are potentially fatal.^{16}
With ulcerative stomatitis, sores often occur under the tongue.


Incidence rare
    
Anaphylaxis ^{01} (wheezing)
    
cellulitis or phlebitis (pain at injection site)
    
hepatotoxicity, including ascites, hepatomegaly, hepatitis, and hepatic function test abnormalities ^{{01} {05} {06}} (yellow eyes or skin)
    
hyperuricemia or uric acid nephropathy (joint pain; lower back or side pain; swelling of feet or lower legs)

Note: Hepatotoxicity is usually reversible, but fatalities have been reported ^{{05} {06}}.
Hyperuricemia or uric acid nephropathy occurs most commonly during initial treatment of patients with leukemia or lymphoma, as a result of rapid cell breakdown which leads to elevated serum uric acid concentrations.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Darkening of skin —if patient has received previous radiation therapy ^{01}
    
fatigue (unusual tiredness or weakness)^{16}
    
fever ^{16}
    
infection ^{16}
    
lethargy ( unusual drowsiness, dullness, tiredness, weakness; feeling of sluggishness)^{16}
    
malaise ( general feeling of discomfort or illness ; unusual tiredness or weakness)^{16}
    
nausea and vomiting
    
redness of skin ^{01}
    
skin rash or acne ^{01}

Note: Nausea and vomiting occur during the first few hours after administration ^{01}, and may last 4 to 20 hours.




Those not indicating need for medical attention
Incidence more frequent
    
Loss of hair ^{01}

Note: Loss of hair usually begins 7 to 10 days after administration and may involve scalp and eyebrows.




Those indicating the need for medical attention if they occur after medication is discontinued
    
Bone marrow depression (black, tarry stools; blood in urine or stools; cough or hoarseness; fever or chills; lower back or side pain; painful or difficult urination; pinpoint red spots on skin ; unusual bleeding or bruising)
    
gastrointestinal ulceration (black, tarry stools ; diarrhea; stomach pain)
    
hepatotoxicity (yellow eyes or skin)
    
stomatitis (sores in mouth and on lips)




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Dactinomycin (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to dactinomycin

Pregnancy—Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected





Breast-feeding—Not recommended because of risk of serious side effects





Use in children—Not recommended in infants less than 6 to 12 months of age

Other medications, especially probenecid, sulfinpyrazone, other bone marrow depressants, live virus vaccines, or previous cytotoxic drug or radiation therapy
Other medical problems, especially chickenpox, hepatic function impairment, herpes zoster, or infection

Proper use of this medication
Caution in taking combination therapy; taking each medication at the right time

Frequency of nausea and vomiting; importance of continuing medication despite stomach upset

» Proper dosing

Precautions while using this medication
» Importance of close monitoring by physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during periods of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur
» Possibility of local tissue injury and scarring if infiltration of intravenous solution occurs; telling physician or nurse right away about redness, pain, or swelling at injection site


Side/adverse effects
May cause adverse effects such as blood problems and cancer; importance of discussing possible effects with physician

Signs of potential side effects, especially anemia, esophagitis, gastrointestinal ulceration, proctitis, leukopenia, thrombocytopenia, ulcerative stomatitis, anaphylaxis, cellulitis, phlebitis, hepatotoxicity, hyperuricemia, and uric acid nephropathy

Physician or nurse can help in dealing with side effects

Possibility of hair loss; normal hair growth should return after treatment has ended


General Dosing Information
It is recommended that dactinomycin be administered only under supervision of a physician experienced in cancer chemotherapy ^{01}.

A variety of dosage schedules and regimens of dactinomycin, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature as well as the manufacturer's literature in choosing a specific dosage.

Dosage must be adjusted to meet the individual requirements of each patient, based on size and location of the neoplasm, clinical response, and appearance or severity of toxicity.

A lower dosage of dactinomycin (based on body surface area) and daily observation for toxicity is recommended for obese patients, especially if they are receiving dactinomycin by regional isolation perfusion; calculation of dosage on the basis of body surface area (i.e., to relate dosage to lean body mass) is recommended ^{01}. A lower dosage is also recommended for those who are receiving or have received within 3 to 6 weeks other antineoplastic chemotherapy or radiation therapy.

Intravenous fluid therapy and administration of allopurinol for 4 to 5 days may be necessary during a period of severe oral toxicity (i.e., if the patient cannot drink) to prevent hyperuricemia and hyperuricuria resulting from tumor regression.

It is recommended that dactinomycin be given no later than the first 5 to 7 days of radiation therapy because of the risk of severe vesiculation.

Dactinomycin must be given in short intermittent courses to avoid serious toxicity, which may not appear until 2 to 4 days after the last dose and may not be maximal for 1 to 2 weeks.

Reconstituted solutions of dactinomycin may be injected slowly into the tubing of a running intravenous infusion or diluted for administration by intravenous infusion ^{01} over 10 to 15 minutes in 5% dextrose injection or 0.9% sodium chloride injection.

Prescribers should consult the medical literature in choosing a dosage and technique for isolation-perfusion administration.

Care should be taken to avoid contact of dactinomycin, which is very corrosive, with soft tissues. In at least one case, extravasation has led to contracture of the arms ^{01}. If the medication is given directly into the vein rather than by infusion, one sterile needle should be used for reconstituting and withdrawing the dose from the vial and another for administration.

If extravasation of dactinomycin occurs during intravenous administration, the injection or infusion should be stopped immediately and the remaining dose given via another vein, care being taken to avoid soft tissue contact.

Systemic absorption of toxic products from neoplastic tissue destruction during administration of dactinomycin by isolation-perfusion can be minimized by removing the perfusate after the procedure ^{01}.

If marked leukopenia (particularly granulocytopenia), thrombocytopenia, diarrhea, or stomatitis occurs, dactinomycin therapy should be withdrawn immediately. When leukocyte and platelet counts return to satisfactory levels and the patient has recovered, therapy may be reinstituted. This often takes up to three weeks. ^{01}{16}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of dactinomycin. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Safety considerations for handling this medication
This drug is highly toxic and both powder and solution should be handled and administered with care. Inhalation of dust or vapors and contact with the skin or mucous membranes, especially those of the eyes should be avoided. Due to the toxic properties (corrosivity, carcinogenic, mutagenicity, teratogenicity) special handling procedures should be reviewed prior to handling and should be followed diligently.^{16}

There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include:    • Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.
   • Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).
   • Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.
A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.


Combination chemotherapy
Dactinomycin may be used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, dactinomycin is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses):    —methotrexate, dactinomycin, cyclophosphamide (MAC) ^{{03} {09}}.
   —etoposide, methotrexate, dactinomycin, leucovorin, vincristine, cyclophosphamide (EMA-CO) ^{{03} {09}}.
   —vinblastine, dactinomycin, bleomycin, cisplatin, cyclophosphamide (VAB-6) ^{{02} {04}}.
   —vincristine and dactinomycin ^{08}.
   —vincristine, dactinomycin, and cyclophosphamide (VAC) ^{10}.
   —doxorubicin, vincristine, dactinomycin, and cyclophosphamide ^{07}.
   —doxorubicin, vinblastine, bleomycin, dacarbazine, vincristine, and dactinomycin ^{14}.
   —high-dose methotrexate, leucovorin, doxorubicin, bleomycin, cyclophosphamide, cisplatin, and dactinomycin ^{11}.
For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

DACTINOMYCIN FOR INJECTION USP

Note: Dosing is calculated in micrograms (mcg).^{16}


Usual adult dose
Ewing's Sarcoma or
Wilm's Tumor or
Rhabdomyosarcoma
Intravenous, 15 mcg (0.015 mg) per kilogram (kg) a day forfive days , administered in various combinations and schedules with other chemotherapeutic agents. ^{01}{16}.

Carcinoma, testicular
Intravenously, 1000 mcg (1.0 mg) per square meter of body surface area (m²) on day 1, as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.^{16}

Tumors, trophoblastic, gestational
Intravenous, 12 mcg (0.012 mg) per kg daily for five days, as a single agent.

Intravenous, 500 mcg (0.5 mg) on days 1 and 2, as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide, and cisplatin.^{16}


Note: For regional perfusion in locally recurrent and locoregional solid malignancies, dosages and schedules vary. Consult published literature for details. General dosing guidelines are suggested: 50 mcg (0.05 mg) per kg of body weight for lower extremity or pelvis and 35 mcg (0.035 mg) per kg of body weight for upper extremity. Lower dosages may be necessary in obese patients, or when previous chemotherapy or radiation therapy has been employed.^{16}

[Sarcoma, Kaposi's ]¹ or
[Osteosarcoma]¹
Consult medical literature and manufacturer's literature for specific dosage.


Note: Dosage should be based on body surface area in obese or edematous patients ^{01}.


Usual adult prescribing limits
15 mcg (0.015 mg) per kg of body weight per day or 400 to 600 mcg (0.4 to 0.6 mg) per square meter of body surface area per day for five days (per two week cycle)^{01}{16}.

Usual pediatric dose
Children up to 6 to 12 months of age: Dosage has not been established.^{16}

Children 12 months of age and older: See Usual adult dose.^{16}

Note: For regional perfusion in locally recurrent and locoregional solid malignancies, dosages and schedules vary. Consult published literature for details. Children up to 12 months of age: Dosage has not been established. Children 12 months of age and older: See Usual adult dose .^{16}

[Osteosarcoma ]¹
Consult medical literature and manufacturer's literature for specific dosage.


Note: Because of the increased risk of toxicity in infants, dactinomycin should be used only in infants older than 6 to 12 months of age.


Usual pediatric prescribing limits
See Usual adult prescribing limits^{16}

Strength(s) usually available
U.S.—


500 mcg (0.5 mg) (Rx) [Cosmegen (mannitol 20 mg)]

Canada—


500 mcg (0.5 mg) (Rx) [Cosmegen (mannitol 20 mg)]

Packaging and storage:
Store at 25 °C (77 °F) excursions permitted between 15 and 30 °C (59 and 86 °F) ^{01}. Protect from light, humidity, and excessive heat ^{01}{16}.

Preparation of dosage form:
Dactinomycin for Injection USP is reconstituted for use by adding 1.1 mL of sterile water for injection (without preservative) to the vial, producing a clear, gold-colored solution containing 500 mcg (0.5 mg) of dactinomycin per mL ^{01}. Use of sodium chloride injection or water for injection containing preservatives (benzyl alcohol, parabens) for reconstitution results in precipitation ^{01}.

Reconstituted solutions of dactinomycin may be diluted in 5% dextrose injection or 0.9% sodium chloride injection for administration by intravenous infusion ^{01}.

Stability:
Discard any unused portion of reconstituted dactinomycin solutions ^{01}.

Note: This drug is highly toxic and both powder and solution must be handled and administered with care. Great care should be taken to prevent inhalation of dust, vapors and particles of Dactinomycin for Injection USP and exposure of skin to it. If accidental eye contact occurs, immediate irrigation with copious amounts of water, followed by an ophthalmologic consultation, is recommended ^{01}{16}; if accidental skin contact occurs, irrigation with water for at least 15 minutes is recommended ^{01}.
Use of some intravenous in-line filters containing cellulose ester membrane filters has been reported to partially remove dactinomycin from intravenous solution ^{01}.

Developed: 07/11/1994
Revised: 08/22/2001

References

Note: References used in the development and subsequent revision of this monograph have not been incorporated into the database and therefore are not listed below.

1. Cosmegen package insert (Merck—US), Rev 12/88; 2/93; 2/97.
   

2. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Co; 1997. p. 1411.
   

3. National Cancer Institute. Gestational trophoblastic tumors. Available from: URL: http://cancernet.nci.nih.gov
   

4. National Cancer Institute. Testicular cancer. Available from: URL: http://cancernet.nci.nih.gov
   

5. D'Angio GJ. Unexpected toxicity encountered in the National Wilms' Tumor Study [letter]. Cancer Treat Rep 1987 Oct; 71: p. 993.
   

6. White L, Tobias V, O'Gorman HDW. Actinomycin D-induced hepatoxocity. Pediatr Hematol Oncol 1989; 6(1): 53-7.
   

7. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Co; 1997. p. 2109.
   

8. National Cancer Institute. Wilms' tumor. Available from: URL: http://cancernet.nci.nih.gov
   

9. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Co; 1997. p. 1501.
   

10. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Co; 1997. p. 2109.
    

11. Reviewers' consensus on monograph revision of 6/90.
    

12. Panel comment, 6/90.
    

13. Panel comment, 6/90.
    

14. Reviewers' consensus on monograph revision of 6/90.
    

15. Devita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 5th ed. Philadelphia: JB Lippincott Co; 1997. p. 1044-8.
    

16. Product Information: Cosmegen®, dactinomycin. Merck & Co., West Point, PA (PI Issued 7/2000) PI reviewed 7/2001.