Dactinomycin

Dactinomycin is the main component of the mixture of actinomycins made by Streptomyces parvullus. Actinomycins inhibit bacteria and some fungi, but their toxicity rules out use against infections. Their cytotoxic effect, shown in animals carrying implanted tumours of various types, is the basis for their use in cancer treatment.

Mechanism of Action

• DNA binding: dactinomycin binds strongly but reversibly to DNA.
• Blocked RNA synthesis: by preventing elongation by RNA polymerase, it interferes with RNA synthesis and so with protein synthesis. This is believed to produce its cytotoxic effect.
• No antibiotic use: although it inhibits Gram-positive and Gram-negative bacteria, its toxicity is too great for it to be used as an antibiotic.

Pharmacokinetics

• Absorption: it is given intravenously. It is poorly absorbed from the gastrointestinal tract and must not be taken by mouth.
• Distribution: after single or repeated intravenous doses it distributes rapidly and binds widely to body tissues. It concentrates in nucleated cells and does not cross the blood–brain barrier to a significant extent (the SmPC gives under 10%). About 5% is bound to plasma proteins.
• Metabolism: it is metabolised only very slightly, according to a study with radiolabelled dactinomycin in patients with malignant melanoma.
• Elimination: plasma levels fall quickly over the first 2 hours and then slowly, with a half-life of about 36 hours. About 30% of the dose is excreted in urine and faeces within one week.
• Special populations: the SmPC gives no pharmacokinetic data for renal or hepatic impairment; kidney, liver and bone marrow function are checked often during treatment.

The French SmPC of Cosmegen lists these indications; other national SmPCs of dactinomycin may differ.

• Wilms tumour (nephroblastoma).
• Rhabdomyosarcoma.
• Testicular carcinoma.
• Ewing sarcoma.
• Gestational trophoblastic tumour.

Dactinomycin is given alone or within combination chemotherapy, depending on the tumour (see Administration and Dosage).

• During or shortly after an infection such as chickenpox (varicella) or shingles (herpes zoster), because of the risk of severe, potentially fatal generalised disease.
• In combination with yellow fever vaccine.

Toxic reactions to dactinomycin are frequent and can be severe, which often limits the dose that can be given. Apart from nausea and vomiting, effects usually appear only two to four days after a course ends and can peak after one to two weeks. Deaths have been reported, but the effects are usually reversible once treatment stops. The SmPC lists reactions by organ class and gives no frequency categories.

• Blood and lymphatic system: anaemia, reticulocytopenia, leucopenia, neutropenia, febrile neutropenia, agranulocytosis, thrombocytopenia, bone marrow aplasia, pancytopenia, disseminated intravascular coagulation.
• Infections: sepsis (including neutropenic sepsis, sometimes fatal), infection, pharyngitis.
• Second cancers: second primary cancers, including solid tumours and blood cancers such as acute leukaemia, after dactinomycin with radiotherapy and/or cytotoxic chemotherapy.
• Metabolism and nutrition: anorexia, hypocalcaemia, tumour lysis syndrome.
• Gastrointestinal: nausea, vomiting, abdominal pain, diarrhoea, gastrointestinal ulceration, cheilitis, dysphagia, constipation, oesophagitis, proctitis, ulcerative stomatitis, ascites. Antiemetics can relieve nausea and vomiting in the first hours.
• Liver: hepatotoxicity, abnormal liver tests, hepatomegaly, hepatitis, hepatic failure (sometimes fatal), hepatic encephalopathy, hepatic veno-occlusive disease (sometimes fatal), pleural effusion as a complication of liver disorders.
• Skin: alopecia, rash, skin toxicity and dermatitis, acne, erythema multiforme, flare of erythema or increased pigmentation in previously irradiated skin (radiation recall). Toxic epidermal necrolysis and Stevens-Johnson syndrome have been seen after marketing.
• Respiratory: pneumonia, pulmonary fibrosis, pneumothorax.
• Nervous system and eye: peripheral neuropathy (reported when combined with vincristine, cisplatin and/or cyclophosphamide); optic neuropathy.
• Vascular: haemorrhage, thrombophlebitis.
• Immune system: hypersensitivity.
• Musculoskeletal and general: myalgia, growth retardation, malaise, fatigue, fever.
• Injection site: extravasation, which can cause severe soft-tissue damage; epidermolysis, erythema and oedema, sometimes severe, with local perfusion of limbs.

• Yellow fever vaccine (contraindicated): risk of fatal generalised vaccine disease.
• Live attenuated vaccines (not recommended): risk of generalised, possibly fatal vaccine disease, greater in patients already immunocompromised by their illness. An inactivated vaccine should be used where one exists (for example against poliomyelitis).
• Phenytoin and fosphenytoin (not recommended): the cytotoxic can reduce absorption of phenytoin, with a risk of convulsions; phenytoin can also raise the hepatic metabolism of the cytotoxic, increasing its toxicity or reducing its efficacy.
• Vitamin K antagonists (precaution): the thrombotic and haemorrhagic risk is higher in tumour disease, and an interaction with chemotherapy is possible. The INR is checked more often.
• Ciclosporin, everolimus, sirolimus, tacrolimus (to be taken into account): excessive immunosuppression with a risk of lymphoproliferative syndrome.
• Radiotherapy: increases gastrointestinal and bone marrow toxicity and can recall skin reactions in irradiated areas (see Special Instructions).

Dactinomycin is for intravenous use only and must not be taken by mouth. Preparation and administration are directly supervised by a physician familiar with current oncology practice. It is used for short courses only: toxic reactions are frequent, their severity varies and depends only partly on the dose. Doses are expressed in micrograms (mcg) and are calculated carefully before each administration. The doses below apply to adults and to children over 6 months; children under 6 months need dose adaptations.

Dose Limits

• In a 2-week cycle, the dose for an adult or a child must not exceed 15 mcg/kg per day or 400–600 mcg/m² of body surface area, given as a daily intravenous injection over 5 days.
• In obese and oedematous patients, calculate the dose from body surface area, trying to tie it to lean body mass.
• The usual doses may need to be reduced when chemotherapy or radiotherapy is given at the same time or has been given before, and lower doses are advised in obese patients.

Doses by Indication (Adults)

Regimens vary with the combination used.

• Wilms tumour: regimens of 45 mcg/kg intravenously, in various combinations and programmes with other chemotherapy agents.
• Rhabdomyosarcoma: 15 mcg/kg intravenously each day for 5 days, in combination regimens.
• Ewing sarcoma: regimens of 1.25 mg/m² intravenously, in combination regimens.
• Testicular carcinoma: 1,000 mcg/m² intravenously on day 1, with cyclophosphamide, bleomycin, vinblastine and cisplatin.
• Gestational trophoblastic tumour: either 12 mcg/kg intravenously each day for 5 days as monotherapy, or 500 mcg intravenously on days 1 and 2 with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.

Children

• 15 mcg (0.015 mg) per kg of body weight intravenously each day for 5 days.
• Alternatives are a total of 2,500 mcg/m² intravenously over one week, or 1,500 mcg/m² intravenously on a single day, not exceeding 2 mg. The administration is repeated according to the clinical context and treatment regimen.

Repeat Courses

A second course may be given to an adult or a child after an interval of at least three weeks, provided all signs of toxicity have resolved.

Preparation and Administration

• The powder is dissolved in 1.1 mL of sterile water for injections without preservative, using the usual aseptic precautions. The clear, golden solution contains about 500 mcg (0.5 mg) per mL. It is inspected before use and not used if particles or discolouration are present.
• Diluents containing preservatives (benzyl alcohol or parabens) form a precipitate and must not be used.
• The solution can be added to 5% glucose or sodium chloride infusions, directly or into the tubing of a running infusion. If it is injected straight into a vein without an infusion, the double-needle technique is used: the dose is drawn up with one sterile needle and injected with a second.
• Some filters with a cellulose ester membrane partly retain dactinomycin.
• Any unused amount is discarded.
• Cytotoxic solutions are prepared by specialised, trained staff in a dedicated area with protective equipment; excreta and vomit are handled with care, and pregnant women should avoid handling cytotoxic medicines.

Special Populations

• Children under 6 months: higher risk of toxic effects; the benefit and risk are weighed case by case.
• Elderly: a meta-analysis showed a higher risk of bone marrow hypoplasia than in younger patients.
• Renal or hepatic impairment: the SmPC gives no specific dose adjustment; kidney, liver and bone marrow function are checked often.
• Missed dose: the SmPC gives no rule; doses follow the oncologist’s schedule.

Supervision and Monitoring

Dactinomycin may be given only under the supervision of a physician experienced in anticancer chemotherapy, with daily checks for toxic effects, especially in combination regimens. If stomatitis, diarrhoea or severe bone marrow hypoplasia develops, the medicines are stopped until the patient has fully recovered. Platelet and white cell counts are done often; if they fall markedly, treatment is interrupted so the marrow can recover, which often takes three weeks. Kidney, liver and marrow function are also checked often.

Extravasation

Dactinomycin is extremely corrosive to soft tissue and must be given intravenously. If it leaks outside the vein during injection, severe soft-tissue damage follows. The infusion must be stopped immediately. If extravasation is suspected, ice applied to the site for 15 minutes four times a day for 3 days may help.

Hepatic Veno-occlusive Disease

Cases, mainly hepatic and some fatal, have been reported. Risk factors are age under 4 years and concomitant radiotherapy. After treatment, patients are watched for raised AST and ALT, raised total bilirubin, an enlarged liver, weight gain or ascites.

Radiotherapy

• Combining dactinomycin with radiotherapy increases gastrointestinal and bone marrow toxicity.
• Erythema can appear in a previously irradiated area after dactinomycin alone (radiation recall), even if the irradiation was months earlier. The risk seems highest when dactinomycin is given within two months of radiotherapy.
• This is a particular problem after irradiation of the liver, the lung or the gastrointestinal mucosa. Irradiation of the nasopharynx can lead to severe inflammation of the oropharyngeal mucosa.
• An enlarged liver and/or raised AST were seen when dactinomycin was given within 2 months of irradiation for a right-sided Wilms tumour, so, in this indication, clinical and laboratory liver monitoring is needed when it is given within 2 months of irradiation.
• Severe reactions can occur with high doses of dactinomycin plus radiotherapy in a patient who is particularly sensitive to the combination.

Second Primary Cancers

Dactinomycin with radiotherapy and/or cytotoxic chemotherapy increases the risk of a second primary cancer, including leukaemia, so long-term follow-up is justified.

Severe Skin Reactions

Toxic epidermal necrolysis (Lyell syndrome) and Stevens-Johnson syndrome, which can be life-threatening or fatal, have been reported. If they occur, dactinomycin must be stopped permanently.

Handling

Dactinomycin is highly toxic (corrosive, carcinogenic, mutagenic, teratogenic). Inhaling dust or vapour and contact with skin or mucous membranes, especially the eye, must be avoided. After eye contact, wash immediately and copiously for at least 15 minutes with water, normal saline or balanced salt eye wash, and see an ophthalmologist as soon as possible. After skin contact, wash with plenty of water for at least 15 minutes while removing contaminated clothing and shoes, and seek medical advice immediately.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 7 months after the last dose; men with female partners of childbearing potential, during treatment and for at least 4 months after the last dose.
• Pregnancy: not recommended at any stage, because clinical and animal data are too limited to assess malformation or foetal toxicity. If pregnancy occurs during treatment, the newborn is monitored closely.
• Breastfeeding: not recommended; there are no data on passage into milk and the infant could suffer serious effects.
• Fertility: dactinomycin can cause sterility. Patients should be told about the risk and about options for preserving gametes before starting.

Effect on Driving

Some adverse effects of dactinomycin can impair the ability to drive or use machines in some patients.

Store the vial at a temperature not above 25 °C, tightly closed and protected from moisture, in its original packaging to protect it from light. No refrigeration is required. Keep out of the sight and reach of children.

3 years for the unopened vial stored as above. Any unused reconstituted solution is discarded.

Prescription only (Rx). Dactinomycin is given intravenously under the direct supervision of a physician experienced in anticancer chemotherapy, with daily monitoring for toxic effects, so it is supplied to the hospital or clinic that administers it.