VA Class:AN200
Dactinomycin is an antineoplastic antibiotic obtained as the principal component of the mixture of actinomycins produced by Streptomyces parvullus.
Dactinomycin is used in combination regimens as an adjunct to surgery with or without radiation therapy in children with Wilms' tumor.100, 101, 103 Various regimens have been used (e.g., dactinomycin and vincristine; dactinomycin, vincristine, and doxorubicin)100, 101, 103 ; however, the best combination or sequential therapy to achieve maximum response and duration of survival has not been established and comparative efficacy is continually being evaluated.100, 103 Dactinomycin generally should not be administered concomitantly with radiation therapy in the treatment of Wilms' tumor (see Cautions: Combined Dactinomycin-Radiation Effects).100, 103 The treatment plan varies according to the stage of disease, histology of the tumor, age of the patient, and tumor size, and dactinomycin-containing therapy should be directly supervised by clinicians who are experienced in the treatment of Wilms' tumor and familiar with recent advances in therapy.100, 103
Dactinomycin is used in combination regimens as an adjunct to surgery with or without radiation therapy for the treatment of rhabdomyosarcoma in children.100, 101, 104 Various regimens have been used (e.g., dactinomycin and vincristine; dactinomycin, vincristine, and cyclophosphamide; dactinomycin, vincristine, and ifosfamide with mesna);100, 101, 104 however, the best combination or sequential therapy to achieve maximum response and duration of survival has not been established and comparative efficacy is continually being evaluated.100, 103 The treatment plan varies according to the extent of disease, the site of primary disease, and the stage and histology of the tumor, and dactinomycin-containing therapy should be directly supervised by clinicians who are experienced in the treatment of rhabdomyosarcoma and familiar with recent advances in therapy.100, 104
Although dactinomycin has been used in combination chemotherapy for the treatment of Ewing's sarcoma100 , other regimens currently are preferred for these neoplasms.101, 105 Standard chemotherapy for the treatment of localized Ewing's sarcoma in the US currently consists of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide.101, 105 Because data from randomized clinical trials have demonstrated improvement in event-free survival with increased dose intensity of doxorubicin during the early months of therapy, dactinomycin is no longer being used in intergroup protocols for the treatment of Ewing's sarcoma.105
Dactinomycin is used alone or with other antineoplastic agents, with or without surgery, in the treatment of trophoblastic tumors (choriocarcinoma and chorioadenoma destruens) in women.100, 101, 106 Dactinomycin used alone is as effective as methotrexate alone in the initial treatment of patients with nonmetastatic choriocarcinoma or patients with metastatic tumors associated with a good prognosis (duration of disease prior to chemotherapy of only a few months, low concentrations of serum or urinary human chorionic gonadotropin, and no metastases to the brain and/or liver); about 90-100% of patients are cured with either agent.106 Although the incidence of toxicity appears to be similar with either agent, most clinicians consider methotrexate the drug of choice for initial therapy in these patients.106 Dactinomycin alone is generally reserved for use in patients whose tumors develop resistance or do not respond to methotrexate or in patients with impaired hepatic or renal function who may have increased risk of toxicity with methotrexate.106
In the treatment of metastatic gestational trophoblastic tumors that are refractory to single-drug therapy, dactinomycin may be used in combination with methotrexate and cyclophosphamide (the MAC regimen).101, 106 In patients who have metastatic gestational trophoblastic tumors associated with a poor prognosis, dactinomycin commonly is used as a component of the EMA-CO regimen, consisting of etoposide, methotrexate, dactinomycin, cyclophosphamide, and vincristine.101, 106
In patients being treated for gestational trophoblastic tumor, it is important to monitor serum β-HCG concentration, which is a sensitive marker of the presence or absence of disease before, during, and after treatment.100, 106
Dactinomycin has been used in the treatment of advanced nonseminomatous testicular carcinoma, principally as a component of the VAB-6 regimen (vinblastine, dactinomycin, bleomycin, cyclophosphamide, and cisplatin).100, 107 Combination therapy for induction of remissions is superior to single-drug therapy. Most clinicians recommend combination chemotherapy containing bleomycin, cisplatin, and etoposide for these tumors.101, 107 However, the best combination or sequential therapy in the treatment of advanced nonseminomatous testicular tumors has not been established, and comparative efficacy is continually being evaluated.107
Dactinomycin has been administered alone or with other antineoplastic agents by regional isolation perfusion as an adjunct to surgery or as palliative therapy alone in the treatment of various sarcomas, carcinomas, and adenocarcinomas.100 Some tumors considered resistant to systemic chemotherapy and radiation therapy may respond when dactinomycin is administered by this route. In some patients, tumor regression and relief of pain may occur, and administration of the drug by regional perfusion may be more effective palliative therapy than is systemic administration.
Dactinomycin is used in alternative regimens for the treatment of ovarian germ cell tumors†.101, 102 Dactinomycin has also been used in the management of acute organ rejection in patients with kidney or heart transplants†.
Reconstitution and Administration
Dactinomycin is usually administered IV.100 The drug is extremely irritating to tissues and, therefore, should not be given IM or subcutaneously.100 Care should be taken to avoid extravasation of the drug. 100 (See Cautions: Local Effects.) Dactinomycin may also be administered by regional isolation perfusion.100 Dactinomycin is not administered orally.100
Dactinomycin is highly toxic, and both the powder and solution must be handled and administered with care.100 Exposure to dactinomycin should be avoided during pregnancy.100 Because of the toxic properties of the drug, including corrosivity, carcinogenicity, mutagenicity, and teratogenicity, special handling procedures should be reviewed prior to handling the drug and should be followed carefully.100 Appropriate protective equipment should be worn when handling dactinomycin.100 (For additional information on proper procedures for handling antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].) Inhalation of dust or vapors and contact with the skin or mucous membranes, especially those of the eyes, must be avoided.100 In case of accidental eye contact, copious irrigation for at least 15 minutes with water, 0.9% sodium chloride, or a balanced salt ophthalmic irrigating solution should be performed immediately, and prompt ophthalmologic consultation should be obtained.100 If contact with the skin occurs, the affected area must be irrigated immediately with copious amounts of water for at least 15 minutes.100 Contaminated clothing and shoes should be removed; the clothing should be destroyed, and shoes should be cleaned thoroughly before reuse.100 Medical attention should be sought immediately.100
The powder for injection is reconstituted by adding 1.1 mL of sterile water for injection without preservatives (see Chemistry and Stability: Stability) to the vial labeled as containing 500 mcg of the drug.100 The resultant solution contains approximately 500 mcg of dactinomycin per mL.100 For IV administration, the desired dose of the reconstituted solution may then be injected over a few minutes directly into any suitable vein or preferably into the tubing or sidearm of a freely flowing IV infusion to reduce the risk of severe local reactions due to extravasation of the drug.100 Following injection of dactinomycin, some clinicians recommend flushing the vein with the running IV infusion for 2-5 minutes and/or injecting 5-10 mL of IV solution into the sidearm to flush any remaining drug from the tubing. If dactinomycin is administered by direct IV injection, the dose of the reconstituted solution should be withdrawn from the vial with one sterile needle and another sterile needle should be used for direct injection into the vein.100 Reconstituted solutions of the drug may also be added to IV infusions of 5% dextrose or 0.9% sodium chloride injection.100 An in-line cellulose ester membrane filter should not be used during administration of dactinomycin solutions. (See Chemistry and Stability: Stability.)
Dactinomycin for injection and reconstituted solutions of dactinomycin should be inspected visually for particulate matter and discoloration whenever solution and container permit.
Dosage of dactinomycin should be calculated carefully before administration of each dose.100 Dosage of dactinomycin must be based on the clinical and hematologic response and tolerance of the patient and whether other chemotherapy or radiation therapy has been or is also being used in order to obtain optimum therapeutic results with minimum adverse effects. Dosage should be based on body surface area in obese or edematous patients .100 If radiation therapy or other chemotherapy is used concomitantly with or prior to dactinomycin, the dosage of dactinomycin may need to be reduced.100 Clinicians should consult published protocols for the dosage of dactinomycin and other chemotherapeutic agents and the method and sequence of administration. Dosing and administration of dactinomycin should be performed under the direct supervision of clinicians familiar with current oncologic practices and new advances in therapy.100
Dactinomycin IV dosage for each 2-week course of therapy in adults or children should not exceed 15 mcg/kg daily or 400-600 mcg/m2 daily for 5 days.100
For the treatment of Wilms' tumor, dactinomycin 15 mcg/kg IV daily for 5 days has been administered in various combinations and schedules with other chemotherapeutic agents.100
For the treatment of rhabdomyosarcoma, dactinomycin 15 mcg/kg IV daily for 5 days has been administered in various combinations and schedules with other chemotherapeutic agents.100
Although dactinomycin is labeled for use in combination chemotherapy for the treatment of Ewing's sarcoma100 , other regimens currently are preferred for these neoplasms.101, 105 (See Uses: Ewing's Sarcoma.) When used for the treatment of Ewing's sarcoma, dactinomycin 15 mcg/kg IV daily for 5 days has been administered in various combinations and schedules with other chemotherapeutic agents.100
When used as monotherapy for the treatment of gestational trophoblastic neoplasia, a dactinomycin dosage of 12 mcg/kg IV daily for 5 days has been administered.100 As part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide, and cisplatin (i.e., EMA-CO regimen with cisplatin added for salvage therapy), dactinomycin 500 mcg IV on days 1 and 2 has been administered.100, 110
For the treatment of metastatic nonseminomatous testicular cancer, a dactinomycin dosage of 1000 mcg/m2 IV on day one has been administered as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.100
For administration of dactinomycin by regional isolation perfusion, the dosage and techniques used are varied, and specialized references should be consulted.100 The usual perfusion doses of dactinomycin are 50 mcg/kg for the pelvis or a lower extremity and 35 mcg/kg for an upper extremity.100 The dose of dactinomycin may need to be reduced in patients who are obese or who have received prior chemotherapy or radiation therapy.100
Hematologic toxicity is one of the major and dose-limiting adverse effects of dactinomycin and is manifested primarily by leukopenia and thrombocytopenia. Anemia, pancytopenia, reticulopenia, agranulocytosis, and aplastic anemia may also occur. Myelosuppression, which is often first manifested by a decrease in the platelet count, usually occurs 1-7 days after completion of a course of therapy with dactinomycin. Leukocyte and platelet nadirs generally occur 14-21 days following completion of a course of therapy, and leukocyte and platelet counts usually return to normal levels within 21-25 days. The patient's hematologic status must be carefully monitored. If severe myelosuppression develops in patients receiving dactinomycin, particularly when used in combination with other antineoplastic agents, therapy must be discontinued until these adverse effects have resolved.100 (See Cautions: Precautions and Contraindications.)
The other major and dose-limiting adverse effects of dactinomycin are GI and oral mucosal toxicities. Nausea and vomiting usually occur within a few hours after administration of the drug and can last up to 24 hours. Antiemetics may be effective in preventing or treating nausea and vomiting. Anorexia, abdominal pain, diarrhea, proctitis, and GI ulceration may also occur. Stomatitis, cheilitis, glossitis, dysphagia, and oral ulceration occur often in patients receiving dactinomycin; esophagitis and pharyngitis may also occur. If stomatitis or diarrhea develops in patients receiving dactinomycin, particularly when used in combination with other antineoplastic agents, therapy must be discontinued until these symptoms have subsided.100
Combined Dactinomycin-Radiation Effects
Dactinomycin appears to potentiate the effects of radiation therapy. In patients treated with radiation therapy and dactinomycin, erythema occurs early in normal skin and buccal and pharyngeal mucosa.100 Erythema at the site of irradiation may be followed rapidly by hyperpigmentation and/or edema, desquamation, vesiculation, and rarely necrosis. Radiation myelitis has also been associated with the drug. Dactinomycin may reactivate these effects in previously irradiated tissues, especially if the interval between radiation therapy and administration of the drug is brief; however, these effects may recur even if dactinomycin is administered months after radiation therapy.100 Reactivation of radiation enteritis by dactinomycin has also been reported. If radiation therapy encompasses regions containing mucous membranes, severe reactions may occur if high doses of both dactinomycin and radiation are used or if the patient is especially sensitive to such combination therapy.100 Severe oropharyngeal mucositis has occurred in patients receiving dactinomycin and radiation therapy directed to the nasopharynx.100 Dactinomycin should be administered with particular caution in the first 2 months after radiation therapy in patients treated for right-sided Wilms' tumor, because hepatomegaly, elevated serum AST (SGOT) concentrations, and ascites have reportedly occurred in some of these patients. Dactinomycin generally should not be administered concomitantly with radiation therapy in the treatment of Wilms' tumor unless the benefit outweighs the risk.100 Increased incidence of GI toxicity and myelosuppression has also been reported with concurrent administration of dactinomycin and radiation therapy.
Adverse dermatologic effects of dactinomycin include alopecia, pruritic maculopapular rash, and various other skin reactions including folliculitis, acne, and acneiform eruptions. Alopecia, which is reversible after discontinuation of therapy, usually begins 7-10 days after administration of the drug and may involve the scalp and eyebrows.
Pain and erythema may occur at the injection site. Extravasation of dactinomycin can produce severe local tissue damage, necrosis, cellulitis, phlebitis, and inflammation and, in at least one patient, has led to contracture of the arms.100 Epidermolysis, erythema, and edema, sometimes severe, have been reported with regional limb perfusion.100 Extravasation is usually accompanied by immediate pain. However, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle.100 If any signs or symptoms of extravasation occur, the injection or infusion should be terminated immediately and restarted in another vein.100 If extravasation is suspected, intermittent application of ice to the affected area for 15 minutes 4 times daily for 3 days may be helpful.100 The benefit of locally administered drugs has not been clearly established.100 Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation are recommended.100 The occurrence of blistering, ulceration, and/or persistent pain indicate the need for wide excision surgery followed by split-thickness skin grafting.100
Hepatic failure and hepatic veno-occlusive disease, sometimes fatal, have been reported in patients receiving dactinomycin.100 Hepatic veno-occlusive disease may be associated with intravascular clotting disorder and multiorgan failure.100 Veno-occlusive disease (mainly hepatic) may be fatal, particularly in children younger than 4 years of age.100 Other hepatotoxicity, including abnormal results of liver function tests, ascites, hepatomegaly, and hepatitis, has been reported in patients receiving dactinomycin.100
Other reported adverse effects of IV dactinomycin include anaphylactoid reactions, malaise, fatigue, lethargy, growth retardation, fever, infection, myalgia, pneumonitis, and hypocalcemia.100 Dactinomycin has also been associated with exacerbation of congestive heart failure in one patient with doxorubicin-induced cardiomyopathy.
Adverse effects of dactinomycin administered by regional isolation perfusion include edema of the extremity involved, damage to soft tissues of the perfused region, and, if the drug is absorbed systemically, myelosuppression, increased susceptibility to infection, and impaired wound healing.100 Other complications such as absorption of toxic products accompanying extensive tumor destruction, superficial ulceration of the gastric mucosa, and venous thrombosis may also occur.100
Precautions and Contraindications
Dactinomycin is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity. The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents who are familiar with current practice and advances in therapy involving dactinomycin.100 Exposure to dactinomycin should be avoided during pregnancy.100
Dactinomycin typically causes myelosuppression; live virus vaccines should not be administered during dactinomycin therapy.100
Patients who receive myelosuppressive drugs experience an increased frequency of infections as well as possible hemorrhagic complications. Because these complications are potentially fatal, the patient should be instructed to notify the clinician if fever, sore throat, or unusual bleeding or bruising occurs. Platelet and leukocyte counts should be determined frequently during treatment with dactinomycin to detect severe myelosuppression.100 If the platelet or leukocyte count markedly decreases or severe myelosuppression occurs, therapy should be discontinued to allow bone marrow recovery, which often takes up to 3 weeks.100 Treatment of severe hematologic toxicity may consist of supportive therapy, anti-infectives for complicating infections, and blood product transfusions. Dactinomycin should be used with extreme caution in patients with impaired bone marrow function.
In addition to monitoring the patient's hematologic status, the manufacturer recommends frequent determinations of renal and hepatic function in patients receiving the drug.100 For additional information on precautions associated with the use of dactinomycin, see the sections in Cautions on GI and Oral Mucosa, Combined Dactinomycin-Radiation, and Local Effects.
Dactinomycin is contraindicated in patients with hypersensitivity to the drug or to any component of the formulation.100 Dactinomycin is contraindicated in patients at or about the time of infection with chickenpox or herpes zoster; administration of the drug to these patients may result in severe generalized disease and death.100
Adverse effects of dactinomycin occur with an increased incidence in infants, and the manufacturer recommends that the drug be used only in infants older than 6-12 months of age.100 Veno-occlusive disease (mainly hepatic) may be fatal, particularly in children younger than 4 years of age.100
Clinical studies of dactinomycin did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.100 While other clinical experience has not revealed age-related differences in response, analysis of pooled data from all studies of dactinomycin performed by the Eastern Cooperative Oncology Group (ECOG) during a 13-year period suggests that the risk of myelosuppression associated with dactinomycin therapy is greater in geriatric patients.100 Drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.100 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.100
Mutagenicity and Carcinogenicity
Dactinomycin is mutagenic and carcinogenic.100 The drug has been shown to be carcinogenic in animals.100 An increased incidence of secondary malignancies, including leukemia, has been reported in patients treated with radiation therapy and antineoplastic agents, such as dactinomycin.100 Careful, long-term observation for the occurrence of secondary malignancy is necessary in patients receiving combined modality treatment for cancer.100
Pregnancy, Fertility, and Lactation
Dactinomycin can cause fetal toxicity when administered to pregnant women, but potential benefits from use of the drug may be acceptable in certain conditions despite the possible risks to the fetus.108, 109 Dactinomycin has been shown to be teratogenic and embryotoxic in rats, rabbits, and hamsters when given IV at doses approximately 0.5-2 times the maximum recommended human dose.100 Women of child-bearing potential should be advised to avoid becoming pregnant while receiving dactinomycin,100 and the drug should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.100, 108 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.100
Adequate studies to determine the effects of dactinomycin on fertility have not been performed to date;100 however, reports suggest an increased incidence of infertility following treatment with other antineoplastic agents.100
It is not known if dactinomycin is distributed into milk.100 Because of the potential for serious adverse reactions to dactinomycin in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.100
Dactinomycin may interefere with bioassay procedures for the determination of antibacterial drug concentrations.100
Limited information is available on acute overdosage of dactinomycin.100 The drug was lethal to mice and rats when administered at IV doses of 700 and 500 mcg/kg, respectively (approximately 3.8 and 5.4 times the maximum recommended human dose on a body surface area basis, respectively).100 The oral LD50 of dactinomycin is 7.8 mg/kg in mice and 7.2 mg/kg in rats.100
Overdosage of dactinomycin produces symptoms such as nausea, vomiting, diarrhea, mucositis including stomatitis, GI ulceration, skin disorders including exanthema, desquamation and epidermolysis, severe hematopoietic depression, veno-occlusive disease, and acute renal failure.100 Fatalities have occurred in patients receiving overdosage of dactinomycin.100
Specific information for the treatment of overdosage with dactinomycin is not available.100 Treatment of toxicity is mainly symptomatic and supportive.100 Skin and mucous membrane integrity, as well as renal, hepatic, and bone marrow functions, should be checked frequently.100
Dactinomycin is an antineoplastic antibiotic. The drug has bacteriostatic activity, particularly against gram-positive organisms, but its cytotoxicity precludes its use as an anti-infective agent. Although the exact mechanism(s) of action has not been fully elucidated, the drug appears to inhibit DNA-dependent RNA synthesis by forming a complex with DNA by intercalating with guanine residues and impairing the template activity of DNA. Protein and DNA synthesis are also inhibited but less extensively and at higher concentrations of dactinomycin than are needed to inhibit RNA synthesis. Dactinomycin is immunosuppressive and also possesses some hypocalcemic activity similar to plicamycin.
Dactinomycin is poorly absorbed from the GI tract. The drug is extremely irritating to tissues and, therefore, must be administered IV.
Dactinomycin is rapidly distributed into tissues, with high concentrations in bone marrow and nucleated cells, including granulocytes and lymphocytes. The drug appears to cross the blood-brain barrier poorly, if at all. Dactinomycin apparently crosses the placenta. It is not known if dactinomycin is distributed into milk.
Following IV administration of dactinomycin H 3 in one study, plasma concentrations of radioactivity decreased rapidly within the first hour and then declined slowly with a half-life of about 36 hours.
Dactinomycin appears to be only slightly metabolized; small amounts of monolactones of the drug have been detected in the urine. Dactinomycin is excreted in the urine and bile. Following IV administration of radiolabeled dactinomycin in one study, about 30% of the dose was excreted in the urine and feces in 9 days; the drug was excreted in the urine primarily as unchanged dactinomycin.
Dactinomycin is an antibiotic obtained as the principal component of the mixture of actinomycins produced by Streptomyces parvullus. 100 Dactinomycin occurs as a bright red, somewhat hygroscopic, crystalline powder, is soluble in water at 10°C and slightly soluble in water at 37°C, and is freely soluble in alcohol. The drug is commercially available as a lyophilized dactinomycin-mannitol mixture, which is an amorphous yellow to orange powder and should be protected from light.100 Reconstituted solutions containing 500 mcg of dactinomycin per mL are clear and gold-colored and have a pH of 5.5-7.
Dactinomycin powder for injection should be protected from light and humidity and stored at 25°C; the manufacturer states that brief exposure to temperatures within the range of 15-30°C is acceptable.100
Dactinomycin powder for injection must be reconstituted with sterile water for injection without preservatives because preservatives may cause precipitation.100 The manufacturer states that reconstituted solutions of the drug may be added to IV infusions of 5% dextrose or 0.9% sodium chloride injection.100 The manufacturer states that solutions of the drug should be prepared immediately before use and any portion unused for the injection should be discarded since the solutions do not contain a preservative.100 Cellulose ester membrane filters, such as those used in IV fluid sterilization or administration, have been shown to partially remove dactinomycin.100
Additional Information
For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Only references cited for selected revisions after 1984 are available electronically.
100. Merck & Co., Inc. Cosmegen® for injection (dactinomycin for injection) prescribing information. Whitehouse Station, NJ; 2005 Jun.
101. Anon. Drugs of choice for cancer. Treat Guidel Med Lett . 2003; 1:41-52. [PubMed 15529105]
102. Ovarian germ cell tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.
103. Wilms' tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.
104. Childhood rhabdomyosarcoma. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.
105. Ewing's family of tumors including primitive neuroectodermal tumor (PNET). From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Oct.
106. Gestational trophoblastic tumor. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Jun.
107. Testicular cancer. From: CancerNet/PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Aug.
108. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066]. Fed Regist . 1979; 44:37434-67.
109. Department of Health and Human Services, Food and Drug Administration. Subpart B-Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.
110. Newlands ES, Bagshawe KD, Begent RH et al. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol . 1991; 98:550-7. [PubMed 1651757]