Dactinomycin

Registered South African indications:

• Nephroblastoma, childhood rhabdomyosarcoma, Ewing’s sarcoma, and metastatic nonseminomatous testicular cancer
  - As part of a combination chemotherapy and/or multi-modality treatment regimen
• Gestational trophoblastic neoplasia
  - As a single agent, or as part of a combination chemotherapy regimen
• Locally recurrent or locoregionally metastatic melanoma
  - As a component of regional perfusion in combination with melphalan

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Use in patients with varicella or herpes zoster. If dactinomycin is given at or about the time of infection with chickenpox or herpes zoster, a severe generalised disease, which may be fatal can occur
• Pregnancy

South African recommendations

Caution in the following patient groups

• Breastfeeding
• Renal impairment
• Hepatic impairment
• Elderly

Handling cautions

• Dactinomycin is HIGHLY TOXIC (e.g. corrosive, carcinogenic, mutagenic and teratogenic, etc), therefore, both the powder and solution must be handled and administered with care
• Since dactinomycin is extremely corrosive to soft tissues, it is intended for intravenous administration only
• Inhalation of dust or vapours and contact with skin or mucous membranes, especially those of the eyes, must be avoided
• Appropriate protective equipment should be worn when handling dactinomycin
• Should accidental eye contact occur, copious irrigation for at least 15 minutes with water, normal saline or a balanced salt ophthalmic irrigating solution should be instituted immediately, followed by prompt ophthalmic consultation
• Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes while removing contaminated clothing and shoes. Medical attention should be sought immediately. Contaminated clothing should be destroyed and shoes cleaned thoroughly before reuse

Administration cautions

• If extravasation occurs during intravenous use, severe damage to soft tissue may occur.
• Dactinomycin, is a toxic medicine, and very careful and frequent observation of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body, most frequently the haematopoietic system resulting in myelosuppression. The possibility of an anaphylactoid reaction should be borne in mind

Additional observations

• It is extremely important to observe the patient daily for toxic side effects when combined therapy is used, since a full course of therapy is occasionally not tolerated
• If stomatitis, diarrhoea or severe haematopoietic depression appear during therapy, these medicines should be discontinued until the patient has recovered

Veno-occlusive disease

• Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months

Dactinomycin and radiation therapy

• An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combination therapy incorporating dactinomycin and radiation
• Moreover, the normal skin, as well as the buccal and pharyngeal mucosa, may show early erythema
• A smaller than usual radiation dose administered in combination 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
• Erythema from previous radiation therapy may be reactivated by dactinomycin alone, even when radiotherapy was administered 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 radiotherapy involves 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
• Particular caution is necessary when administering dactinomycin within two months of irradiation for the treatment of right-sided nephroblastoma, since hepatomegaly and elevated AST levels have been noted
• In general, dactinomycin should not be concomitantly administered with radiotherapy in the treatment of nephroblastoma
• Reports indicate an increased incidence of secondary primary tumours (including leukaemia) following treatment with radiation and antineoplastic agents, such as dactinomycin
• Multi-modal therapy creates the need for careful, long-term observation of cancer survivors

Laboratory tests

• A variety of abnormalities of renal, hepatic and bone-marrow function have been reported in patients with neoplastic disease receiving dactinomycin
• Renal, hepatic and bone-marrow functions should be assessed frequently
• Dactinomycin contains mannitol and may have a laxative effect

Effects on ability to drive and use machines

• Dactinomycin may cause fatigue and lethargy which affect mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision

Forms avail. in SA and covered in this monograph: poi

South African registered indications and dosages

Dactinomycin should be administered only under the supervision of a medical practitioner who is experienced in the use of a cancer

Nephroblastoma
- As part of a combination chemotherapy and/or multi-modality treatment regimen

• IV: 45μg/kg (corresponds to 1200-1800μg/m² or 1.2-1.8mg/m²)

Rhabdomyosarcoma
- As part of a combination chemotherapy and/or multi-modality treatment regimen

• IV: 15μg/kg, dly for 5 days

Ewing’s sarcoma
- As part of a combination chemotherapy and/or multi-modality treatment regimen

• IV: 1.25mg/m²

Metastatic nonseminomatous testicular cancer
- As part of a combination chemotherapy and/or multi-modality treatment regimen

• IV: 1000μg/m², on day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin

Gestational trophoblastic neoplasia
- As a single agent

• IV: 12μg/kg, dly for 5 days as a single agent

- Or as part of a combination chemotherapy regimen

• IV: 500μg on days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin

Locally recurrent or locoregionally metastatic melanoma
- As a component of regional perfusion in combination with melphalan

For a lower extremity or pelvis

• IV: 50μg/kg bodyweight

For an upper extremity

• IV: 35μg/kg bodyweight

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Dose intensity

The dose of dactinomycin is calculated in micrograms. The dose intensity per two-week cycle should not exceed 15μg/kg per day or 400-600 μg/square meter of body surface daily, intravenously, for 5 days. Calculation of the dose for obese or oedematous patients should be on the basis of surface area in an effort to relate dosage to lean body mass

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For the indication of locally recurrent or locoregionally metastatic melanoma, it may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed

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Toxic reactions due to dactinomycin are frequent and may be severe, thus limiting the dose that may be administered in many cases. However, the severity of toxicity varies markedly and is only partly dependent on the dose administered

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Dose of dactinomycin will vary with the tolerance of the patient, the size and location of the neoplasm, and the concurrent use of other forms of therapy. It may be necessary to reduce the usual dose suggested when additional chemotherapy or radiation therapy is used concurrently or has been used previously

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A wide variety of single agent and combination chemotherapy regimens with dactinomycin may be used. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of medical practitioner's familiar with current oncologic practices and new advances in therapy

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Method of administration

Reconstituted dactinomycin is for intravenous administration. For instructions on reconstitution of the medicine before administration, see additional prescribing points

Although reconstituted dactinomycin is chemically stable, the product does not contain a preservative and accidental microbial contamination might result. Any unused portion of the solution should be discarded. Partial removal of dactinomycin from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported. If dactinomycin is to be injected directly into the vein without the use of an infusion, the ‘two-needle’ technique should be used. The calculated dose should be reconstituted and withdrawn from the vial with one sterile needle; direct injection into the vein should then be performed with another sterile needle

Paed. forms avail. in SA and covered in this monograph: poi

South African registered indications and dosages

Dactinomycin should be administered only under the supervision of a medical practitioner who is experienced in the use of a cancer

Nephroblastoma, childhood rhabdomyosarcoma, Ewing’s sarcoma, and metastatic nonseminomatous testicular cancer
- As part of a combination chemotherapy and/or multi-modality treatment regimen
Gestational trophoblastic neoplasia
- As a single agent, or as part of a combination chemotherapy regimen
Locally recurrent or locoregionally metastatic melanoma
- As a component of regional perfusion in combination with melphalan

• See adult dosages

Pregnancy 

South African recommendations

• Contraindicated
• Dactinomycin has been shown to be teratogenic in animals and should not be given to pregnant women
• Teratogenicity: Dactinomycin has been shown to cause malformations and embryotoxicity in the rat, rabbit and hamster when given in doses of 50-100μg/kg intravenously (three to seven times the maximum recommended human dose)

Breastfeeding

South African recommendations

• Caution; not recommended
• Dactinomycin should not be administered to mothers who are breastfeeding

Fertility

South African recommendations

• Adequate fertility studies have not been reported, although, an increased incidence of infertility following treatment with other antineoplastic agents has been reported

South African recommendations

• Caution; no information available
  A variety of abnormalities of renal function have been reported in patients with neoplastic disease receiving dactinomycin

South African recommendations

• Caution; no information available
  A variety of abnormalities of hepatic function have been reported in patients with neoplastic disease receiving dactinomycin

South African recommendations

• Caution; no dose adjustment recommended
  The general considerations also apply to elderly patients. Administration of dactinomycin to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients

Infections and Infestations

Frequency unknown

• Sepsis (including neutropenic sepsis) with fatal outcome
• Infection
• Pharyngitis

Blood and Lymphatic System Disorders

Frequency unknown

• Anaemia (even to the point of aplastic anaemia)
• Agranulocytosis
• Disseminated intravascular coagulation (DIC)
• Leukopenia
• Thrombocytopenia
• Pancytopenia
• Reticulocytopenia
• Neutropenia
• Febrile neutropenia

Immune System Disorders

Frequency unknown

• Hypersensitivity

Metabolism and Nutrition Disorders

Frequency unknown

• Anorexia
• Hypocalcaemia
• Tumour lysis syndrome

Nervous System Disorders

Frequency unknown

• Peripheral neuropathy
• Lethargy

Eye Disorders

Frequency unknown

• Optic neuropathy

Vascular Disorders

Frequency unknown

• Haemorrhage
• Thrombophlebitis

Respiratory, Thoracic and Mediastinal Disorders

Frequency unknown

• Pneumonitis

Gastrointestinal Disorders

Frequency unknown

• Nausea
• Vomiting
• Abdominal pain
• Diarrhoea
• Gastro-intestinal ulceration
• Cheilitis
• Dysphagia
• Constipation
• Oesophagitis
• Proctitis
• Ulcerative stomatitis
• Ascites

Hepato-biliary Disorders

Frequency unknown

• Liver toxicity including liver function test abnormalities
• Hepatomegaly
• Hepatitis
• Hepatic failure with reports of death
• Hepatic veno-occlusive disease
• Hepatic encephalopathy
• Pleural effusion as a complication of various hepatic disorders

Skin and Subcutaneous Tissue Disorders

Frequency unknown

• Alopecia
• Rash
• Skin toxicity and dermatitis
• Erythema multiforme
• Acne
• Flare-up of erythema or increased pigmentation of previously irradiated skin
• Toxic Epidermal Necrolysis (TEN)
• Stevens Johnson Syndrome (SJS)
• Epidermolysis
• Erythema
• Oedema

Musculoskeletal, Connective Tissue and Bone Disorders

Frequency unknown

• Myalgia
• Growth retardation

General Disorders and Administrative Site Conditions

Frequency unknown

• Epidermolysis
• Erythema
• Oedema
• Fatigue
• Fever
• Growth retardation
• Lethargy
• Malaise

• No significant interactions

Other interactions

• X-ray therapy
• Bio-assay procedures for the determination of antibacterial medicine levels

• Hepatic function
• Renal function
• Bone-marrow function
• Platelet count
• White blood-cell count

Additional observations

• Adverse reactions
• Signs or symptoms of extravasation
• Toxic effects in infants

Reconstitution and administration

• Reconstitution: Dactinomycin is reconstituted by adding 1.1ml of water for Injections Ph Eur without preservative to the vial. Only Water for Injections Ph Eur (which does not contain preservatives) should be used. Other injection fluids may cause precipitation. Dactinomycin should be inspected for particulate matter and discoloration, whenever possible. The reconstituted solution is clear and gold- coloured
• Injection: For injection, 1.0ml of the reconstituted solution, which will contain 500 micrograms of dactinomycin, is withdrawn into the syringe. Studies conducted on dactinomycin lyophilized powder for injection demonstrate that drug product diluted at concentrations of 10µg/ml or higher in WFI, 0.9% saline and 5% dextrose in glass or PVC infusion containers are stable for up to 10 hours when stored at ambient room temperature. Drug product diluted to concentrations lower than 10µg/ml and stored at ambient room temperature showed significantly lower recoveries. Therefore, only product diluted at concentrations greater than 10µg/ml and stored for not more than 10 hours at ambient room temperature are recommended for administration

Special handling

• Animal studies have shown dactinomycin to be corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic
• Due to the drug’s toxic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of dactinomycin for parenteral administration. Inhalation of dust or vapours and contact with skin or mucous membranes, especially those of the eyes must be avoided
• It is recommended that the preparation of injectable antineoplastic drugs should be performed in a Class II laminar flow biological safety cabinet. Personnel preparing drugs of this class should wear chemical resistant, impervious gloves, safety goggles, outer garments, and shoe covers. Additional body garments should be used based upon the task being performed (e.g. sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin surfaces and inhalation of vapours and dust. Appropriate techniques should be used to remove potentially contaminated clothing
• Several guidelines for proper handling and disposal of antineoplastic medicines have been published and should be considered

Dactinomycin inhibits the proliferation of cells by forming a stable complex with DNA and interfering with DNA-dependent RNA synthesis. 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.

Powder for Injection (0,5 mg per 3 ml vial)

• Cosmegen (Key Oncologics Pty Ltd)