DACTINOMYCIN
DESCRIPTION:
(ACTINOMYCIN D)
WARNING
Dactinomycin is extremely corrosive to soft
tissue. If extravasation occurs during
intravenous use, severe damage to soft
tissues will occur. In at least one
instance, this has led to contracture of
the arms.
DOSAGE
The dosage of DACMOZEN* (Dactinomycin for
Injection) is calculated in micrograms
(mcg). The usual adult dosage is 500
micrograms (0.5 mg) daily intravenously for
a maximum of five days. The dosage for
adults or children should not exceed 15
mcg/kg or 400-600 mcg/square meter of body
surface daily intravenously for five days.
Calculation of the dosage for obese or
edematous patients should be on the basis
of surface area in an effort to relate
dosage to lean body mass.
Dactinomycin is one of the actinomycins, a group of antibiotics produced by
various species of Streptomyces. Dactinomycin is the principal component of the
mixture of actinomycins produced by Streptomyces Parvullus. Unlike other species
of Streptomyces, this organism yields an essentially pure substance that
contains only traces of similar compounds differing in the amino acid content of
the peptide side chains. The empirical formula is C62H86N12O16.
DACMOZEN is a sterile, yellow lyophilized powder for injection by the
intravenous route or by regional perfusion after reconstitution. Each vial
contains 0.5 mg (500 mcg) of dactinomycin and 20.0 mg of mannitol.
ACTIONS/CLINICAL PHARMACOLOGY:
Action
Generally, the actinomycins exert an inhibitory effect on gram-positive and
gram-negative bacteria and on some fungi. However, the toxic properties of the
actinomycins (including dactinomycin) in relation to antibacterial activity are
such as to preclude their use as antibiotics in the treatment of infectious
diseases.
Because the actinomycins are cytotoxic, they have an antineoplastic effect which
has been demonstrated in experimental animals with various types of tumor
implant. This cytotoxic action is the basis for their use in the palliative
treatment of certain types of cancer.
Pharmacokinetics And Metabolism
Results of a study in patients with malignant melanoma indicate that
dactinomycin (3H actinomycin D) is minimally metabolized, is concentrated in
nucleated cells, and does not penetrate the blood=brain barrier. Approximately
30% of the dose was recovered in urine and feces in one week. The terminal
plasma half-life for radioactivity was approximately 36 hours.
INDICATIONS AND USAGE:
Wilms' Tumor
The neoplasm responding most frequently to DACMOZEN is Wilms' tumor. With low
doses of both dactinomycin and radiotherapy, temporary objective improvement may
be as good as and may last longer than with higher doses of each given alone. In
the National Wilms' Tumor study, combination therapy with dactinomycin and
vincristine together with surgery and radiotherapy, was shown to have
significantly improved the prognosis of patients in groups II and III.
Dactinomycin and vincristine were given for a total of seven cycles, so that
maintenance therapy continued for approximately 15 months.
Postoperative radiotherapy in group I patients and optimal combination
chemotherapy for those in group IV are unsettled issues. About 70 percent of
lung metastases have disappeared with an appropriate combination of radiation,
dactinomycin and vincristine.
Rhabdomyosarcoma
Temporary regression of the tumor and beneficial subjective results have
occurred with dactinomycin in rhabdomyosarcoma which, like most soft tissue
sarcomas, is comparatively radio- resistant.
Several groups have reported successful use of cyclophosphamide, vincristine,
dactinomycin and doxorubicin hydrochloride in various combinations. Effective
combinations have included vincristine and dactinomycin; vincristine,
dactinomycin and cyclophosphamide (VAC therapy) and all four drugs in sequence.
At present, the most effective treatment for children with inoperable or
metastatic rhabdomyosarcoma has been VAC chemotherapy. Two- thirds of these
children were doing well without evidence of disease at a median time of three
years after diagnosis.
Carcinoma Of Testis And Uterus
The sequential use of dactinomycin and methotrexate, along with meticulous
monitoring of human chorionic gonadotropin levels until normal, has resulted in
survival in the majority of women with metastatic choriocarcinoma. Sequential
therapy is used if there is:
1. Stability in gonadotropin titers following two successive courses of an
agent.
2. Rising gonadotropin titers during treatment.
3. Severe toxicity preventing adequate therapy.
In patients with nonmetastatic choriocarcinoma, dactinomycin or methotrexate or
both, have been used successfully, with or without surgery.
Dactinomycin has been beneficial as a single agent in the treatment of
metastatic nonseminomatour testicular carcinoma when used in cycles of 500
mcg/day for five consecutive days, every 6-8 weeks for periods of four months or
longer.
Other Neoplasms
Dactinomycin has been given intravenously or by regional perfusion, either alone
or with other antineoplastic compounds or x-ray therapy, in the palliative
treatment of Ewing's sarcoma and sarcoma botryoides. For nonmetastatic Ewing's
sarcoma, promising results were obtained when dactinomycin (45 mcg/M(squared))
and cyclophosphamide (1200 mg/M(squared)) were given sequentially and with
radiotherapy, over an 18 month period. Those with metastatic disease remain the
subject of continued investigation with a more aggressive chemotherapeutic
regimen employed initially.
Temporary objective improvement and relief of pain and discomfort have followed
the use of dactinomycin usually in conjunction with radiotherapy for sarcoma
botryoides. This palliative effect ranges from transitory inhibition of tumor
growth to a considerable but temporary regression in tumor size.
DACMOZEN (Dactinomycin For Injection)
And Radiation Therapy
Much evidence suggests that dactinomycin potentiates the effects of x-ray
therapy. The converse also appears likely; i.e., dactinomycin may be more
effective when radiation therapy also is given.
With combined dactinomycin-radiation therapy, the normal skin, as well as the
buccal and pharyngeal mucosa, show early erythema. A smaller than usual x-ray
dose when given with dactinomycin causes erythema and vesiculation, which
progress more rapidly through the stages of tanning and desquamation. Healing
may occur in four to six weeks rather than two to three months. Erythema from
previous x-ray therapy may be reactivated by dactinomycin alone, even when
irradiation occurred many months earlier, and especially when the interval
between the two forms of therapy is brief. This potentiation of radiation effect
represents a special problem when the irradiation treatment area includes the
mucous membrane. When irradiation is directed toward the nasopharynx, the
combination may produce severe oropharyngeal mucositis. Severe Reactions May
Ensue If High Doses Of Both Dactinomycin And Radiation Therapy Are Used Or If
The Patient Is Particularly Sensitive To Such Combined Therapy.
Because of this potentiating effect, dactinomycin may be tried in radio-
sensitive tumors not responding to doses of x-ray therapy that can be tolerated.
Objective improvement in tumor size and activity may be observed when lower,
better tolerated doses of both types of therapy are employed.
DACMOZEN (Dactinomycin For Injection)
And Perfusion Technic
Dactinomycin alone or with other antineoplastic agents has also been given by
the isolation- perfusion technic, either as palliative treatment or as an
adjunct to resection of a tumor. Some tumors considered resistant to
chemotherapy and radiation therapy may respond when the drug is given by the
perfusion technic. Neoplasms in which dactinomycin has been tried by this
technic include various types of sarcoma, carcinoma, and adenocarcinoma.
In some instances tumors regressed, pain was relieved for variable periods, and
surgery made possible. On other occasions, however, the outcome has been less
favorable. Nevertheless, in selected cases, the drug by perfusion may provide
more effective palliation than when given systemically.
Dactinomycin by the isolation-perfusion technic offers certain advantages,
provided leakage of the drug through the general circulation into other areas of
the body is minimal. By this technic the drug is in continuous contact with the
tumor for the duration of treatment. The dose may be increased well over that
used by the systemic route, usually without adding to the danger of toxic
effects. If the agent is confined to an isolated part, it should not interfere
with the patient's defense mechanism. Systemic absorption of toxic products from
neoplastic tissue can be minimized by removing the perfusate when the procedure
is finished.
CONTRAINDICATIONS:
If dactinomycin is given at or about the time of infection with chicken pox or
herpes zoster, a severe generalized disease, which may result in death, may
occur.
WARNINGS:
WARNING
Dactinomycin is extremely corrosive to soft
tissue. If extravasation occurs during
intravenous use, severe damage to soft
tissues will occur. In at least one
instance, this has led to contracture of
the arms.
DOSAGE
The dosage of DACMOZEN* (Dactinomycin for
Injection) is calculated in micrograms
(mcg). The usual adult dosage is 500
micrograms (0.5 mg) daily intravenously for
a maximum of five days. The dosage for
adults or children should not exceed 15
mcg/kg or 400-600 mcg/square meter of body
surface daily intravenously for five days.
Calculation of the dosage for obese or
edematous patients should be on the basis
of surface area in an effort to relate
dosage to lean body mass.
PRECAUTIONS:
General
DACMOZEN should be administered only under the supervision of a physician who is
experienced in the use of cancer chemotherapeutic agents.
This drug is highly toxic and both powder and solution must be handled and
administered with care. Inhalation of dust or vapors and contact with skin or
mucous membranes, especially those of the eyes, must be avoided. Should
accidental eye contact occur, copious irrigation with water should be instituted
immediately, followed by prompt ophthalmologic consultation. Should accidental
skin contact occur, the affected part must be irrigated immediately with copious
amounts of water for at least 15 minutes.
As with all antineoplastic agents, dactinomycin is a toxic drug and very careful
and frequent observation of the patient for adverse reactions is necessary.
These reactions may involve any tissue of the body. The possibility of an
anaphylactoid reaction should be borne in mind.
Increased incidence of gastrointestinal toxicity and marrow suppression has been
reported when dactinomycin was given with x-ray therapy.
Particular caution is necessary when administering dactinomycin within two
months of irradiation for the treatment of right-sided Wilms' tumor, since
hepatomegaly and elevated SGOT levels have been noted.
Nausea and vomiting due to dactinomycin make it necessary to give this drug
intermittently. It is extremely important to observe the patient daily for toxic
side effects when multiple chemotherapy is employed, since a full course of
therapy occasionally is not tolerated. If stomatitis, diarrhea, or severe
hemopoietic depression appear during therapy, these drugs should be discontinued
until the patient has recovered.
Recent reports indicate an increased incidence of second primary tumors
following treatment with radiation and anti-neoplastic agents, such as
dactinomycin. Multi-modal therapy creates the need for careful, long-term
observation of cancer survivors.
Laboratory Tests
Many abnormalities of renal, hepatic, and bone marrow function have been
reported in patients with neoplastic disease and receiving dactinomycin. It is
advisable to check renal, hepatic, and bone marrow functions frequently.
Drug/Laboratory Test Interactions
It has been reported that dactinomycin may interfere with bioassay procedures
for the determination of antibacterial drug levels.
Carcinogenesis, Mutagenesis,
Impairment Of Fertility
The International Agency on Research on Cancer has judged that dactinomycin is a
positive carcinogen in animals. Local sarcomas were produced in mice and rats
after repeated subcutaneous or intraperitoneal injection. Mesenchymal tumors
occurred in male F344 rats given intraperitoneal injections of 0.05 mg/kg, 2 to
5 times per week for 18 weeks. The first tumor appeared at 23 weeks.
Dactinomycin has been shown to be mutagenic in a number of test systems In Vitro
and In Vivo including human fibroblasts and leucocytes, and HELA cells. DNA
damage and cytogenetic effects have been demonstrated in the mouse and the rat.
Adequate fertility studies have not been reported.
Pregnancy
Pregnancy Category C. DACMOZEN has been shown to cause malformations and
embryotoxicity in the rat, rabbit and hamster when given in doses of 50-100
mcg/kg intravenously (3-7 times the maximum recommended human dose). There are
no adequate and well-controlled studies in pregnant women. DACMOZEN should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs
are excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from DACMOZEN, a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.
Pediatric Use
The greater frequency of toxic effects of dactinomycin in infants suggest that
this drug should be given to infants only over the age of 6 to 12 months.
ADVERSE REACTIONS:
Toxic effects (excepting nausea and vomiting) usually do not become apparent
until two to four days after a course of therapy is stopped, and may not be
maximal before one to two weeks have elapsed. Deaths have been reported.
However, adverse reactions are usually reversible on discontinuance of therapy.
They include the following:
Miscellaneous: malaise, fatigue, lethargy, fever, myalgia, proctitis,
hypocalcemia.
Oral: cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis.
Gastrointestinal: anorexia, nausea, vomiting, abdominal pain, diarrhea,
gastrointestinal ulceration, liver toxicity including ascites, hepatomegaly,
hepatitis, and liver function test abnormalities. Nausea and vomiting, which
occur early during the first few hours after administration, may be alleviated
by giving antiemetics.
Hematologic: anemia, even to the point of aplastic anemia, agranulocytosis,
leukopenia, thrombopenia, pancytopenia, reticulopenia. Platelet and white cell
counts should be done Daily to detect severe hemopoietic depression. If either
count markedly decreases, the drug should be withheld to allow marrow recovery.
This often takes up to three weeks.
Dermatologic: alopecia, skin eruptions, acne, flare-up of erythema or increased
pigmentation of previously irradiated skin.
Soft Tissues. Dactinomycin is extremely corrosive. If extravasation occurs
during intravenous use, severe damage to soft tissues will occur. In at least
one instance, this has led to contracture of the arms.
OVERDOSAGE:
The intravenous LD50 of DACMOZEN in the rat is 460 mcg/kg.
DOSAGE AND ADMINISTRATION:
Toxic reactions due to dactinomycin are frequent and may be severe (see ADVERSE
REACTIONS), thus limiting in many instances the amount that may be given.
However, the severity of toxicity varies markedly and is only partly dependent
on the dose employed. The drug must be given in short courses.
Intravenous Use
The dosage of dactinomycin varies depending on the tolerance of the patient, the
size and location of the neoplasm, and the use of other forms of therapy. It may
be necessary to decrease the usual dosages suggested below when other
chemotherapy or x-ray therapy is used concomitantly or has been used previously.
The dosage for adults or children should not exceed 15 mcg/kg or 400-600
mcg/square meter of body surface daily intravenously for five days. Calculation
of the dosage for obese or edematous patients should be on the basis of surface
area in an effort to relate dosage to lean body mass.
Adults: The usual adult dosage is 500 mcg (0.5 mg) daily intravenously for a
maximum of five days.
Children: In children 15 mcg (0.015 mg) per kilogram of body weight is given
intravenously daily for five days. An alternative schedule is a total dosage of
2500 mcg (2.5 mg) per square meter of body surface given intravenously over a
one week period.
In both adults and children, a second course may be given after at least three
weeks have elapsed, provided all signs of toxicity have disappeared.
Reconstitute DACMOZEN by adding 1.1 ml of STERILE WATER FOR INJECTION (WITHOUT
PRESERVATIVE) using aseptic precautions. The resulting solution of dactinomycin
will contain approximately 500 mcg (0.5 mg) per mL.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
When reconstituted, DACMOZEN is a clear, gold-colored solution.
Once reconstituted, the solution of dactinomycin can be added to infusion
solutions of Dextrose Injection 5 percent or Sodium Chloride Injection either
directly or to the tubing of a running intravenous infusion.
Although reconstituted DACMOZEN is chemically stable, the product does not
contain a preservative and accidental microbial contamination might result. Any
unused portion should be discarded. Use of water containing preservatives
(benzyl alcohol or parabens) to reconstitute DACMOZEN for Injection, results in
the formation of a precipitate.
Partial removal of dactinomycin from intravenous solutions by cellulose ester
membrane filters used in some intravenous in-line filters has been reported.
Since Dactinomycin Is Extremely Corrosive To Soft Tissue, Precautions For
Materials Of This Nature Should Be Observed.
If the drug is given directly into the vein without the use of an infusion, the
"two-needle technic" should be used. Reconstitute and withdraw the calculated
dose from the vial with one sterile needle. Use another sterile needle for
direct injection into the vein.
Discard any unused portion of the dactinomycin solution.
Isolation-Perfusion Technic
The dosage schedules and the technic itself vary from one investigator to
another; the published literature, therefore, should be consulted for details.
In general, the following doses are suggested:
50 mcg (0.05 mg) per kilogram of body weight for lower extremity or pelvis.
35 mcg (0.035 mg) per kilogram of body weight for upper extremity.
It may be advisable to use lower doses in obese patients, or when previous
chemotherapy or radiation therapy has been employed.
Complications of the perfusion technic are related mainly to the amount of drug
that escapes into the systemic circulation and may consist of hemopoietic
depression, absorption of toxic products from massive destruction of neoplastic
tissue, increased susceptibility to infection, impaired wound healing, and
superficial ulceration of the gastric mucosa. Other side effects may include
edema of the extremity involved, damage to soft tissues of the perfused area,
and (potentially) venous thrombosis.
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