Dactinomycin (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Omutninskaya Scientific Experimental-Industrial Base, JSC (Russia)

ATC Code

L01DA01 (Dactinomycin)

Active Substance

Dactinomycin (Rec.INN WHO registered)

Dosage Form

Dactinomycin

Lyophilizate for the preparation of solution for infusion 500 mcg: amp. 5 pcs.

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for infusion in the form of a porous mass from yellow to orange-red in color, hygroscopic, sensitive to light.

Excipients: mannitol (mannite) 20.0 mg.

500 mcg – ampoules (5) – contour cell packaging (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic antibiotic

Pharmacotherapeutic Group

Antineoplastic agent, antibiotic

Pharmacological Action

An antineoplastic antibiotic from the actinomycin group (it is the main component in the mixture of actinomycins produced by Streptomyces parvullus). Dactinomycin binds to the guanine residue in DNA, intercalating between guanine and cytosine base pairs, inhibiting the synthesis of DNA, RNA, and proteins.

High concentrations of the drug are found in the bone marrow and tumor cells, salivary glands, liver, and kidneys; it penetrates the placenta. It is minimally excreted through the liver.

Pharmacokinetics

Dactinomycin is practically not metabolized and accumulates in nuclear cells. It penetrates the blood-brain barrier to a minimal extent (< 10%). It is largely bound to tissue proteins.

C_max in plasma is reached within 2-5 minutes after administration. T_1/2 is 36 hours. It is eliminated from the body via the intestines – 50%, and by the kidneys – 10%.

In case of impaired liver function, T_1/2 may increase.

Indications

• Wilms’ tumor;
• Rhabdomyosarcoma;
• Ewing’s sarcoma;
• Nonseminomatous malignant testicular tumors;
• Trophoblastic tumors;
• Locally recurrent or locally advanced solid tumors.

ICD codes

Dosage Regimen

The dosage regimen is established individually depending on the drug tolerance, 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, it may be necessary to reduce the usually used doses of the drug listed below.

The dose intensity for a 2-week course for adults and children should not exceed 15 mcg/kg or 400-600 mcg/m² of body surface area per day, provided it is administered intravenously 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 taken into account so that the result corresponds to the dosages for patients with normal body weight.

Wilms’ tumor. 45 mcg/kg of dactinomycin is prescribed intravenously in combination with other chemotherapeutic agents in various treatment regimens.

Rhabdomyosarcoma. The recommended dosage regimen is 15 mcg/kg per day intravenously for 5 days in combination with other chemotherapeutic agents in various treatment regimens.

Ewing’s sarcoma. 1.25 mg/m² of body surface area is prescribed intravenously in combination with other chemotherapeutic agents in various treatment regimens.

Nonseminomatous malignant testicular tumors. 1000 mcg/m² intravenously on the first day of treatment in combination with cyclophosphamide, bleomycin, vinblastine, and cisplatin.

Gestational trophoblastic tumors. 12 mcg/kg per day intravenously for 5 days as monotherapy. 500 mcg intravenously on days 1 and 2, as a component of a combined regimen with etoposide, methotrexate, calcium folinate, vincristine, cyclophosphamide, and cisplatin.

Regional perfusion for locally recurrent or locally advanced solid tumors. 50 mcg/kg (0.05 mg) of body weight for tumors located in the lower extremities or pelvic area. 35 mcg/kg (0.035 mg) of body weight for tumors located in the upper extremities.

Usually, when prescribing the drug dose for elderly patients, caution should be exercised and the lowest doses should be prescribed first, bearing in mind that this group of patients more often has reduced liver, kidney, or heart function, and also taking into account the presence of possible concomitant diseases or treatment with other drugs.

Dactinomycin does not undergo significant elimination through the kidneys, therefore, in case of impaired renal function, dose adjustment of the drug is not required.

Preparation method

The contents of the ampoule are dissolved in 1 ml of sterile water for injections. After reconstitution, Dactinomycin is a clear, golden to yellow solution. The resulting dactinomycin solution will contain approximately 500 mcg (0.5 mg) in 1 ml. Immediately after reconstitution, the dactinomycin solution can be added to infusion solutions of 5% dextrose or 0.9% sodium chloride solution either directly or through a tube during intravenous infusion.

Although reconstituted Dactinomycin is a chemically stable solution, the drug does not contain preservatives, and accidental contamination of the solution with microorganisms may occur. Any unused portion of the solution should be discarded. The use of water containing preservatives (benzyl alcohol or parabens) for dissolving dactinomycin for injection may lead to the formation of a precipitate.

There are reports of partial removal of dactinomycin from intravenous solutions by cellulose ester membrane filters used in some intravenous filters.

Since Dactinomycin has a pronounced irritating effect on soft tissues, precautions should be taken when handling such materials.

Dactinomycin is highly toxic, so both the lyophilisate and the solution require careful handling. Inhalation of dust or vapors, as well as contact with skin or mucous membranes, especially the eyes, should be avoided. In case of accidental contact with the eye mucosa, the eyes should be immediately rinsed abundantly with water and an ophthalmologist should be consulted as soon as possible. In case of accidental contact with the skin, the affected area should be immediately rinsed abundantly with water for at least 15 minutes. If the drug is administered intravenously by bolus, without infusion, a “two-needle” technique should be used. Reconstitute and draw up the calculated dose of the drug from the vial using one sterile needle. Use another sterile needle directly for intravenous administration.

Regional perfusion for locally recurrent or locally advanced solid tumors.

The advantage of the method is the minimal entry of the drug into other parts of the body through the systemic bloodstream and the prolonged effect on the tumor. The dose of the drug can be significantly higher than the dose used for the systemic route of administration, while the risk of toxic effects is usually lower.

• 50 mcg/kg (0.05 mg) of body weight for tumors located in the lower extremities and pelvic area.
• 35 mcg/kg (0.035 mg) of body weight for tumors located in the upper extremities. Lower doses are recommended for obese patients and for patients who have previously undergone chemotherapy or radiation therapy.

Adverse Reactions

Toxic effects (except for nausea and vomiting) are usually not detected earlier than two to four days after the end of the therapy course and may not reach maximum severity during the first one to two weeks. There are reports of fatal cases. However, side effects are usually reversible after discontinuation of treatment.

Allergic reactions: alopecia, skin rash, acne, recurrence of erythema or increased pigmentation of areas of the skin previously exposed to radiation.

Local reactions when the drug 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, arising from regional perfusion of a limb.

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, fatal hepatic failure, toxic liver damage, including ascites, hepatomegaly, hepatitis, and impaired liver function tests. Nausea and vomiting, occurring early within the first few hours after drug administration, can be controlled by taking antiemetic drugs.

From the hematopoietic organs: anemia, up to the development of aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. Platelet and leukocyte counts should be performed daily to detect severe suppression of hematopoiesis. If the count of both cell types decreases, the drug should be discontinued until bone marrow function recovers. This usually takes about three weeks.

From the blood vessels: 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 irritating effect on soft tissues. With extravasation during careless intravenous administration, severe soft tissue damage can develop. In at least one case, this led to the development of contracture of the upper extremities. Stevens-Johnson syndrome, toxic epidermal necrolysis, sepsis, including neutropenic sepsis, there are reports of multiple disorders of the kidneys, liver, and bone marrow in patients with malignant neoplasms receiving treatment with dactinomycin (frequent examination of liver, kidney, and bone marrow function is recommended).

If any of the side effects listed in the instructions worsen, or you notice any other side effects not listed in the instructions, inform your doctor.

Contraindications

• Hypersensitivity to dactinomycin or any other component of the drug;
• Severe suppression of bone marrow function;
• Severe hepatic insufficiency;
• Pregnancy and breastfeeding period;
• Chickenpox;
• Herpes zoster;
• Childhood (under 6 months).

With caution particular caution should be exercised when prescribing dactinomycin during two-month radiation therapy for right-sided Wilms’ tumor, as there have been reports of hepatomegaly and increased AST levels; age over 65 years (increased risk of myelosuppression), condition after chemotherapy or radiation therapy.

Use in Pregnancy and Lactation

No adequate and controlled clinical studies have been conducted in pregnant women. The use of the drug is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

In case of impaired liver function, T_1/2 may increase. It is contraindicated in severe hepatic insufficiency.

Use in Renal Impairment

Dactinomycin does not undergo significant elimination through the kidneys, therefore, in case of impaired renal function, dose adjustment of the drug is not required.

Geriatric Use

Particular caution should be exercised when prescribing dactinomycin at the age over 65 years.

Special Precautions

Dactinomycin should be used only under the close supervision of a physician experienced in the use of antineoplastic chemotherapeutic drugs. Nausea and vomiting that occur within the first few hours after drug administration can be alleviated with antiemetic drugs.

During therapy with dactinomycin, it is necessary to regularly determine the number of platelets and leukocytes in the blood to detect suppression of hematopoietic function, and also to regularly examine kidney and liver function.

If severe myelosuppression develops, dactinomycin therapy, especially in cases where it is used in combination with other antineoplastic drugs, should be discontinued until bone marrow function recovers. This usually takes about three weeks.

When administering dactinomycin, extravasation should be carefully avoided. At the first signs of extravasation (burning or pain at the injection site or other signs), the administration of dactinomycin should be stopped immediately; the remainder of the drug should be administered into another vein. It is recommended to apply ice to the area of extravasation for 15 minutes 4 times a day for 3 days. The patient should be closely monitored. If blisters, ulcers, and/or persistent pain appear, the possibility of excision of an extensive skin area followed by split-thickness skin grafting should be discussed with a plastic surgeon. Primary venous thrombosis (mainly of the liver) can lead to patient death, especially in children under 48 months.

Furthermore, early signs of erythema may be detected on normal skin, as well as on the mucous membrane of the cheeks and pharynx. The use of lower than usual doses of radiation therapy in combination with dactinomycin causes erythema and vesiculation, which progress more rapidly, passing through the stages of induration and desquamation. Healing in this case may occur within four to six weeks instead of two to three months. Erythema resulting from previous radiation therapy may recur under the influence of dactinomycin monotherapy even if the radiation was administered many months ago, and with a greater likelihood if the time interval between the two types of therapy was short. Such potentiation of radiation therapy effects is particularly important when the radiation field includes the mucous membrane. If radiation is directed to the nasopharynx area, combined treatment may lead to severe inflammation of the oropharyngeal mucosa.

Severe reactions may occur in case of simultaneous administration of high doses of dactinomycin and radiation therapy, as well as with increased patient sensitivity to such combined therapy.

Particular caution should be exercised when prescribing dactinomycin during two-month radiation therapy for the treatment of right-sided Wilms’ tumor, as there are data on the development of hepatomegaly and increased AST levels. In most cases, it is not recommended to prescribe Dactinomycin simultaneously with radiation therapy for the treatment of Wilms’ tumor, except in cases where the benefit to the patient outweighs the possible risk.

There are reports indicating an increased incidence of secondary malignant neoplasms, including leukemia, after the use of treatment regimens including Dactinomycin, regardless of the simultaneous administration of radiation therapy. Women and men during treatment and for 3 months after the end of dactinomycin therapy should use reliable methods of contraception. All standard instructions adopted for the use of cytotoxic drugs must be observed when using the drug. If it gets on the skin or mucous membranes, they should be immediately and thoroughly rinsed with water or saline.

Complications of perfusion technique are mainly associated with the amount of the drug entering 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, impaired wound healing, and superficial ulceration of the gastric mucosa. Other undesirable effects may include edema of the involved limb, soft tissue damage in the perfusion area, and (potentially) venous thromboses.

Effect on the ability to drive vehicles and operate machinery

Some side effects of the drug may negatively affect the ability to drive vehicles and perform other potentially hazardous activities that require increased concentration and speed of psychomotor reactions. During dactinomycin therapy, it is recommended to refrain from engaging in these activities.

Overdose

There is only limited information on cases of overdose in humans. Manifestations of overdose include nausea, vomiting, diarrhea, stomatitis, gastrointestinal ulcers, severe suppression of hematopoiesis, acute renal failure, acute skin damage (including peeling, exanthema, desquamation, and epidermolysis), primary venous thrombosis, sepsis (including neutropenic) with fatal outcome.

There is no known antidote for the drug. Treatment is symptomatic and supportive. Frequent monitoring of kidney, liver, and bone marrow function is recommended.

Drug Interactions

Vaccination with viral vaccines is not recommended during treatment (administration of live viral vaccines against the background of treatment may enhance the replication of the vaccine virus and increase its side effects, inactivated vaccines – reduce the production of antiviral antibodies).

With simultaneous use of dactinomycin with drugs that have a myelotoxic effect, an increase in the toxic effect is possible. With simultaneous use of dactinomycin with uricosuric agents, the risk of nephropathy increases.

It may enhance the cardiotoxic effect of doxorubicin and weaken the effect of vitamin K.

When dactinomycin and radiation therapy are used concurrently, the toxic effects on the gastrointestinal tract and hematopoietic organs are enhanced.

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the package.

In a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of the reach of children.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.