Composition, form of production and packaging
Lyophilizate for the preparation of a solution for infusions in the form of a porous mass from yellow to orange-red, hygroscopic, sensitive to light.
1 amp.
dactinomycin 500 mcg
Excipients: mannitol (mannitol) 20.0 mg.
500 Ојg - ampoules (5) - packings of cellular contour (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Antitumor antibiotic from the group of actinomycins (it is the main component in the mixture of actinomycins produced by Streptomyces parvullus). Dactinomycin binds to the residue of guanine in DNA, intercalating between pairs of bases of guanine and cytosine, inhibiting the synthesis of DNA, RNA and proteins.
High concentrations of the drug are found in the bone marrow and tumor cells, maxillary glands, liver and kidneys, penetrates the placenta. Minimally output through the liver.
PHARMACOKINETICS
Dactinomycin is practically not metabolized, accumulates in nuclear cells. It penetrates insignificantly through the BBB (<10%). Much associated with tissue proteins.
C max in plasma is achieved 2-5 minutes after administration. T 1/2 - 36 hours. It is excreted from the body by the intestine - 50%, by the kidneys - by 10%.
If the liver function T 1/2 can increase.
INDICATIONS
- Wilms tumor;
- rhabdomyosarcoma;
Ewing's sarcoma;
non-seminiferous malignant testicular tumors;
- trophoblastic tumors;
- Locally recurrent or locally advanced solid tumors.
DOSING MODE
The dosage regimen is set individually depending on the tolerability of the drug, the size and location of the tumor, as well as the use of other types of treatment. At simultaneous or previous radiotherapy or chemotherapy, it may be necessary to reduce the commonly used doses of the drug given below.
The dose rate for a 2-week course for adults and children should not exceed 15 mcg / kg or 400-600 mcg / m 2 body surface per day, subject to IV administration for 5 days.
When calculating the required dose per kg of body weight for patients with obesity or edema , the surface area of ​​the body should be taken into account so that the result correlates with dosages for patients with normal body weight.
Wilms tumor. Assign 45 Ојg / kg dactipomycin IV in combination with other chemotherapeutic agents in various treatment regimens.
Rhabdomyosarcoma. The recommended dosing regimen is 15 mcg / kg per day for 5 days in combination with other chemotherapeutic agents in various treatment regimens.
Ewing's sarcoma. Assign 1.25 mg / m2 body surface IV in combination with other chemotherapeutic agents in various treatment regimens.
Neseminomnye malignant tumors of the testicle. 1000 mcg / m 2 IV on the first day of treatment in combination with cyclophosphamide, bleomycin, vinblastine and cisplatin.
Histological trophoblastic tumors. 12 mcg / kg / day for 5 days as a monotherapy. 500 mcg IV in the 1st and 2nd days, as a component of the combined regimen with etoposide, methotrexate, calcium folinate, vincristine, cyclophosphamide and cisplatin.
Regional perfusion with locally recurring or locally advanced solid tumors . 50 Ојg / kg (0.05 mg) of body weight when the tumor is localized in the region of the lower extremities or pelvic region. 35 Ојg / kg (0.035 mg) of body weight when the tumor is localized in the region of the upper limbs.
Usually, when prescribing a dose, elderly patients should be cautious and prescribe the lowest doses first, bearing in mind that this group of patients is more likely to have reduced liver, kidney or heart function, as well as taking into account possible co-morbidities or other medications.
Dactinomycin does not undergo significant elimination through the kidneys, therefore, if the kidney function is impaired, correction of the dose of the drug is not required.
Cooking method
The contents of the ampoule are dissolved in 1 ml of sterile water for injection. After dilution, dactinomycin is a clear solution from a golden to yellow color. The resulting solution of dactinomycin will contain approximately 500 Ојg (0.5 mg) in 1 ml. Immediately after dilution, the solution of dactinomycin can be added to infusion solutions of 5% dextrose or 0.9% sodium chloride solution, either directly or through the tube during intravenous infusion.
Although diluted dactinomycin is a chemically stable solution, the preparation does not contain preservatives, accidental ingestion of microorganisms into solution may occur. Any unused portion of the solution should be discarded. The use of water containing preservatives (benzyl alcohol or parabenzene) to dissolve dactinomycin for injection can lead to the formation of a precipitate.
There are reports of partial removal of dactinomycin from solutions for intravenous administration via cellulose ester membrane filters used in some IVI filters.
Since dactinomycin has a pronounced irritant effect on soft tissue, precautions should be taken when working with similar materials.
Dactinomycin is highly toxic, so both the lyophilizate and the solution require careful handling. Avoid inhalation of dust or vapors, as well as contact with skin or mucous membranes, especially the eyes. In case of accidental contact with the mucous membrane of the eyes, immediately flush eyes with water and consult an ophthalmologist as soon as possible. In case of accidental skin contact, the affected area should be washed immediately with plenty of water for at least 15 minutes. If the drug is injected into the vein struino, without infusion. should be applied "two-needle" technique. Dilute and dial the calculated dose of the drug from the vial with a single sterile needle. Use another sterile needle directly for insertion into the vein.
Regional perfusion with locally recurring or locally advanced solid tumors.
The advantage of the method is the minimal ingestion of the drug to other parts of the body through systemic blood flow and a prolonged effect on the tumor. The dose of the drug can be significantly higher than the dose used in the systemic route of administration, with the danger of toxic effects usually being less.
- 50 mcg / kg (0.05 mg) of body weight when the tumor is localized in the region of the lower extremities and pelvic region.
- 35 mcg / kg (0.035 mg) of body weight when the tumor is localized in the region of the upper limbs. It is recommended that smaller doses are used for obese patients and for patients who have previously undergone chemotherapy or radiotherapy.
SIDE EFFECT
Toxic effects (with the exception of nausea and vomiting) usually do not appear earlier than two to four days after discontinuation of therapy, and may not reach maximum severity within the first one to two weeks. There are reports of deaths. However, side effects are usually reversible after discontinuation of treatment.
Allergic reactions : alopecia, skin rash, acne, relapse of erythema, or increased pigmentation of skin areas previously exposed to radiation.
Local reactions: when the product gets under the skin - redness, pain, inflammation of subcutaneous fat, necrosis of surrounding tissues. There are reports of epidermolysis, erythema and edema, sometimes quite pronounced, due to regional perfusion of the limb.
From the central nervous system: fatigue, malaise, fever, lethargy.
From the skin: erythema multiforme
On the part of the digestive system: anorexia, nausea, vomiting, abdominal pain, diarrhea, ulcerative lesions of the gastrointestinal tract, liver failure with a lethal outcome, toxic liver damage, including ascites, hepatomegaly, hepatitis and violations of liver function. Nausea and vomiting that occur early in the first few hours after prescribing can be stopped by taking anti-emetic medications.
From the hemopoiesis : anemia, up to the development of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. The platelets and white blood cells must be counted daily to detect severe hematopoietic suppression. With a decrease in the number of both types of cells, the drug should be stopped before the restoration of bone marrow function. Usually it takes about three weeks.
From the side of the vessels: a primary thrombosis of the hepatic veins, obliterating endophlebitis of the hepatic veins.
Other: cheilitis, dysphagia, esophagitis, ulcerative stomatitis, pharyngitis, muscle pain, proctitis, growth retardation and infectious diseases, hypocalcemia, pneumonitis.
Dactinomycin has a pronounced irritant effect on soft tissues. During extravasation during an inadvertent intravenous injection of the drug, severe soft tissue damage can develop. At least in one case this led to the development of contracture of the upper limbs. Stevens-Johnson syndrome, toxic epidermal necrolysis, sepsis, including neutropenic, there are reports of multiple violations from the kidneys, liver and bone marrow in patients with malignant tumors receiving treatment with dactinomycin (frequent examination of the liver, kidney and bone marrow is recommended) .
If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, tell your doctor about it
CONTRAINDICATIONS
- hypersensitivity to dactinomycin or any other component of the drug;
- marked suppression of bone marrow function;
severe hepatic impairment;
- Pregnancy and the period of breastfeeding;
- chickenpox;
- Shingles;
- Children's age (up to 6 months).
With caution: special care should be taken when prescribing dactinomycin during a two-month radiotherapy for a right-sided Wilms tumor, as there have been reports of hepatomegaly and an increase in the ACT level; age over 65 years (increased risk of myelosuppression), condition after chemotherapy or radiation therapy.
PREGNANCY AND LACTATION
Pregnant women did not undergo adequate and controlled clinical trials. The use of the drug is contraindicated in pregnancy and during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Dactinomycin does not undergo significant elimination through the kidneys, therefore, if the kidney function is impaired, correction of the dose of the drug is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
If the liver function T 1/2 can increase. In severe hepatic failure is contraindicated.
APPLICATION IN ELDERLY PATIENTS
Particular care should be taken when appointing dactinomycin at the age of 65 years
SPECIAL INSTRUCTIONS
Dactinomycin should only be used under close supervision of a physician with experience in the use of antitumor chemotherapeutic drugs. Nausea and vomiting that occur within the first few hours after taking the drug can be alleviated with antiemetic drugs.
Against the background of therapy with dactinomycin it is necessary to regularly determine the number of platelets and leukocytes in the blood in order to identify oppression of the hematopoietic function, as well as to regularly examine the function of the kidneys and liver.
With the development of severe myelosupresin, dactinomycin therapy, especially when used in combination with other antitumor drugs, should be discontinued until bone marrow function is restored. Usually it takes about three weeks.
When introducing dactinomycin, extravasation should be carefully avoided. When the first signs of extravasation (burning or pain at the injection site or other signs) appear, the introduction of dactinomycin should be stopped immediately; the rest of the drug should be injected into another vein. On the extravasation area it is recommended to apply ice for 15 minutes 4 times a day for 3 days. Careful observation is recommended for the patient. In the event of the appearance of blisters, ulcers and / or constant pain, it is necessary to discuss with a plastic surgeon the possibility of excision of a large area of ​​skin followed by a split skin flap transplant.Primary thrombosis of the veins (mainly the liver) can lead to death of the patient, especially children younger than 48 months.
In addition, on the normal skin, as well as on the mucous cheeks and pharynx, early signs of erythema can be detected. The use of less than usual doses of radiotherapy in combination with dactinomycin causes the appearance of erythema and vesiculation, which progress more rapidly, passing through the stages of compaction and desquamation. The healing in this case can occur within four to six weeks instead of two to three months. Erythema as a result of previous radiation therapy may reoccur after exposure to monotherapy with dactinomycin even if the irradiation was performed many months ago, and more likely if the time interval between the two therapies was short. Such a potentiation of the effects of radiation therapy is of particular importance when the irradiation zone includes the mucosa. If irradiation is directed to the nasopharynx, then combined treatment can lead to severe inflammation of the mucous membrane of the oropharynx.
Expressed reactions can occur in the case of simultaneous administration of high doses of dactinomycin and radiotherapy, as well as with increased sensitivity of the patient to such a combination therapy.
Special care should be taken when administering dactinomycin during a two-month radiation therapy for the treatment of a right-sided Wilms tumor, because there is evidence of hepatomegaly and an increase in the ACT level. In most cases, it is not recommended to administer dactinomycin concomitantly with radiotherapy for the treatment of Wilms tumor, unless the benefit to the patient exceeds the possible risk.
There are reports of increased incidence of secondary malignancies, including leukemia, after the application of treatment regimens including dactinomycin, irrespective of the concomitant use of radiotherapy. Women and men during treatment and within 3 months after the end of therapy with dactinomycin should use reliable methods of contraception. When using the drug should be observed all the usual instructions adopted for the use of cytotoxic drugs. If it gets on the skin or mucous membranes, they should be washed immediately and thoroughly with water, physiological solution.
Complications of perfusion techniques are mainly related to the amount of the drug that has entered the systemic circulation, and may include suppression of hematopoiesis, absorption of toxic substances from the site of massive destruction of malignant tissue, increased vulnerability to infections, deterioration of wound healing and superficial ulceration of the gastric mucosa. Other adverse effects may include swelling of the involved limb, soft tissue damage in the perfusion zone and (potentially) venous thrombosis.
Impact on the ability to drive vehicles and other mechanisms
Some side effects of the drug may adversely affect the ability to drive vehicles and carry out potentially dangerous activities that require increased concentration and speed of psychomotor reactions. During therapy with dactinomycin, it is recommended to refrain from engaging in these activities.
OVERDOSE
There is only limited information on cases of overdose in humans. Manifestations of an overdose include nausea, vomiting, diarrhea, stomatitis, gastrointestinal ulcers, severe hematopoietic suppression, acute renal failure, acute skin damage (including peeling, exanthema, desquamation and epidermolysis), primary vein thrombosis, sepsis (including neutropenic) with fatal outcome .
Antidote to the drug is not known. Treatment is symptomatic and supportive. It is recommended that the kidneys, liver and bone marrow function be monitored frequently.
DRUG INTERACTION
During the period of treatment, vaccination with viral vaccines is not recommended (with the introduction of viral vaccines against the background of treatment, it is possible to strengthen the replication of the vaccine virus and increase its side effects, inactivated vaccines - to reduce the production of antiviral antibodies).
With the simultaneous use of dactinomycin with drugs that have a myelotoxic effect, it is possible to intensify the toxic effect. With the simultaneous use of dactinomycin with uricosuric agents, the risk of developing nephropathy is increased.
May enhance the cardiotoxic effect of doxorubicin, weaken the effect of vitamin K.
With the simultaneous use of dactinomycin and radiation therapy, toxic effects on the part of the gastrointestinal tract and hematopoiesis are enhanced.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Shelf life - 2 years. Do not use after the expiration date printed on the package.
In the dark place at a temperature of no higher than 25 В° C. Keep out of the reach of children.
