Daktinomycin - instructions for use, doses, side effects, contraindications

Active substanceDactinomycinDactinomycin

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Aknomid®

solution in / in d / perfusion

Adikom, Open Company Russia

Dactinomycin

lyophilizate in / in d / perfusion

OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC Russia

Cosmogen®

lyophilizate for injections

Orphan Europe France

Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration and perfusion

Composition:

1 ampoule contains:

active substance: dactinomycin - 0.5 mg;

auxiliary substance: mannitol (mannitol) - 20.0 mg.

Description:

The porous mass is from yellow to orange in red. It is hygroscopic. Sensitive to the action of light.

Pharmacotherapeutic group:Antitumor agent, antibiotic

ATX: & nbsp

L.01.D.A.01 Dactinomycin

L.01.D.A Actinomycins

Pharmacodynamics:Antitumor antibiotic from the group of actinomycins (it is the main component in the mixture of actinomycins produced 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 blood-brain barrier (<10%). Much associated with tissue proteins. The maximum concentration in plasma is reached in 2-5 minutes after administration. Half-life is 36 hours. It is excreted from the body by the intestine - 50%, by the kidneys - 10%. If the liver function is impaired, the elimination half-life may increase.

Indications:

Wilms tumor; Rhabdomyosarcoma; Ewing's sarcoma; Neseminomnye malignant testicular tumors; Trophoblastic tumors; Locally recurrent or locally advanced solid tumors.

Contraindications:Hypersensitivity to dactinomycin or any other component of the drug, severe inhibition of bone marrow function, severe hepatic insufficiency, pregnancy and the period of breastfeeding, chicken pox, shingles, children's age (up to 6 months).

Carefully:Particular care should be taken when administering dactinomycin during a two-month radiotherapy for a right-sided Wilms tumor, as there have been reports of hepatomegaly and an increase in the level ACT; 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.

Dosing and Administration:

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. With simultaneous or previously conducted radiation or chemotherapy, there may be a need 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 μg / kg or 400-600 μg / m² body surface per day, subject to intravenous administration for 5 days. When calculating the required dose per kg of body weight for patients with obesity or edema, the body surface area should be considered, so that the result is consistent with the dosages for patients with normal body weight.

Wilms tumor.Assign 45 μg / kg dactinomycin intravenously in combination with other chemotherapeutic agents in various treatment regimens. Rhabdomyosarcoma. The recommended dosing regimen is 15 mcg / kg per day intravenously for 5 days in combination with other chemotherapeutic agents in various treatment regimens.

Ewing's sarcoma. Assign 1.25 mg / m² surface of the body intravenously in combination with other chemotherapeutic agents in various treatment regimens.

Neseminomnye malignant tumors of the testicle. 1000 μg / m² intravenously on the first day of treatment in combination with cyclophosphamide, bleomycin, vinblastine and cisplatin.

Histological trophoblastic tumors. 12 mcg / kg / day intravenously for 5 days as a monotherapy. 500 μg intravenously on days 1 and 2, 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 μg / kg (0.05 mg) of body weight when the tumor is localized in the region of the lower extremities or pelvic region. 35 μg / 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 decreased liver, kidney or heart function, as well as taking into account possible co-morbidities or treatment with other drugs. Dactinomycin is not subject to significant elimination through the kidneys, therefore, if the kidney function is not corrected, dose adjustment is not required.

Cooking method

The contents of the ampoule are dissolved in 1 ml of sterile water for injection. After breeding dactinomycin is a solution transparent from golden to yellow. The resulting solution of dactinomycin will contain approximately 500 μg (0.5 mg) in 1 ml. Immediately after dilution, a 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 divorced dactinomycin and is a chemically stable solution, the preparation does not contain preservatives, accidental ingress of microorganisms into solution can 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 intravenous filters.

As dactinomycin has a pronounced irritant effect on soft tissue, care should be taken when working with similar materials. Dactinomycin highly toxic, so both the lyophilizate and the solution require careful handling. Avoid inhalation of dust or fumes, as well as contact with skin or mucous membranes, especially the eye. 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, two-needle technique should be used.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 disseminated 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 μg / kg (0.05 mg) of body weight when the tumor is localized in the region of the lower extremities and pelvic region.

- 35 μg / 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 effects:

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: if the product gets under the skin, redness, pain, inflammation of the subcutaneous fat, necrosis of surrounding tissues. There are reports of epidermolysis, erythema and edema, sometimes quite pronounced, due to regional limb perfusion.

From the central nervous system: fatigue, malaise, fever, lethargy.

From the skin: erythema multiforme

From the digestive system: anorexia, nausea, vomiting, abdominal pain, diarrhea, ulcerative lesions of the gastrointestinal tract, hepatic insufficiency with lethal outcome, toxic liver damage, including ascites, hepatomegaly, hepatitis and impaired liver function. Nausea and vomiting that occur early in the first few hours after the drug is administered can be stopped by taking anti-emetic medications.

On the part of the organs of hematopoiesis: anemia, up to the development of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutrons, 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 vessels: primary thrombosis of hepatic veins, obliterating eidophlebitis of hepatic veins.

Other: Hailit, 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 the careless intravenous administration 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 of the kidneys, liver and bone marrow in patients with cancer receiving treatment daktipomitsinom (recommended frequent inspection of the liver, kidney and bone marrow).

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.

Overdose:

There is only limited information on cases of overdose in humans. Manifestations overdose include nausea, vomiting, diarrhea, stomatitis, gastrointestinal ulcers, pronounced inhibition of hematopoiesis, acute renal failure, acute dermal (including peeling, exanthema, desquamation and epidermolysis), primary vein thrombosis, sepsis (including neutropenic) fatalities .

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.

Interaction:

During the period of treatment is not recommended vaccination viral vaccines (when administered during treatment with live virus vaccines may increase replication of the vaccine virus and the strengthening of its side effects,inactivated vaccines - decreased 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.

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 myelosuppression, therapy with dactinomycin, 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 smaller than usual doses of radiotherapy in combination with dactinomycin causes the appearance of erythema and vesicles, 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 resulting from previous radiation therapy may reappear under the influence of monotherapy with dactinomycin even when the irradiation was performed many months ago, and with greater probability, 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 prescribing dactinomycin during a two-month radiotherapy for the treatment of a right-sided tumor of Wilms,because there is evidence of hepatomegaly and ACT. In most cases it is not recommended to appoint dactinomycin together with radiotherapy for the treatment of Wilms tumor, with the exception of cases where the benefit to the patient exceeds the possible risk.

There are reports of increased incidence of secondary malignant neoplasms, including leukemia, after the application of treatment regimens including dactinomycin, irrespective of the simultaneous appointment 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.

The complications of perfusion techniques are mainly associated with the amount of the drug that has entered the systemic circulation, and may include suppression of hematopoiesis, the 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.

Effect on the ability to drive transp. cf. and fur:

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.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration and perfusion 0.5 mg.

Packaging:

Lyophilizate for the preparation of a solution for intravenous administration and perfusion 0.5 mg in ampoules. For 5 ampoules or one ampoule in the contour acheikova packing, 1 contour pack with instructions for use in a cardboard bundle.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.Keep out of the reach of children.

Destruction of unused dactinomycin
Unused prepared solution and open empty ampoules: Trisodium phosphate 5% for 30 minutes destroys dactinomycin. Closed ampoules: burn at high temperature.

Shelf life:

Shelf life 2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002917

Date of registration:17.03.2015 / 23.11.2016

Expiration Date:17.03.2020

The owner of the registration certificate:OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC Russia

Manufacturer: & nbsp

OMUTNINSK SCIENTIFIC EXPERIMENTAL-INDUSTRIAL BASE, OJSC Russia

Information update date: & nbsp17.03.2017

Illustrated instructions

Instructions

Dactinomycin (Dactinomycin)