Consumer medicine information

Cosmegen

Dactinomycin (actinomycin D)

BRAND INFORMATION

Brand name

Cosmegen

Active ingredient

Dactinomycin (actinomycin D)

Schedule

What is in this leaflet

This leaflet answers some common questions about COSMEGEN. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking COSMEGEN against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What COSMEGEN is used for

COSMEGEN is used alone, or in combination with other chemotherapy or radiotherapy, to treat certain types of cancers, including:

Wilms’ tumour, a type of kidney cancer
Rhabdomyosarcoma, a cancer of the muscle
Nonseminomatous testicular carcinoma, a cancer of the testis
Choriocarcinoma, a cancer of the uterus
Ewing’s sarcoma, a type of bone cancer
Sarcoma botryoides, a cancer of the female reproductive tract.

COSMEGEN may also be used to treat the symptoms of certain cancers, or to treat tumours that are not responding to radiotherapy. It may also be used in people who are having a tumour surgically removed.

COSMEGEN belongs to a group of medicines called antineoplastics. It works by interfering with the growth of cancer cells, which are eventually killed.

Your doctor may have prescribed COSMEGEN for another reason. Ask your doctor if you have any questions about why COSMEGEN has been prescribed for you.

COSMEGEN is not addictive.

Before you are given COSMEGEN

When you must not be given COSMEGEN

Do not use COSMEGEN if you have an allergy to COSMEGEN or any of the ingredients listed at the end of this leaflet.

Do not use COSMEGEN if you have recently had or are currently infected with chicken pox or herpes zoster (shingles).

If you are not sure whether you should start receiving COSMEGEN, talk to your doctor.

Do not use COSMEGEN if you are breast-feeding or intend to breast-feed. COSMEGEN is not recommended for use while breast-feeding. It is not known whether it passes into breast milk.

Before you are given COSMEGEN

Tell your doctor if:

you are pregnant

Like most medicines, COSMEGEN is generally not recommended during pregnancy. However, if there is a need to consider using COSMEGEN during pregnancy, your doctor will discuss the possible risks and benefits to you and your unborn baby.

you are currently receiving radiotherapy
you have Wilms’ tumour and you are either currently receiving radiotherapy or you have had radiotherapy in the last two months
your child is to receive COSMEGEN and is less than 12 months of age

COSMEGEN is not recommended in infants less than 6 to 12 months of age as there is a higher risk of toxic effects.

you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you are given COSMEGEN.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines and COSMEGEN may interfere with each other. This includes:

other chemotherapy
live virus vaccines

These medicines may be affected by COSMEGEN, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while being given COSMEGEN.

How COSMEGEN is given

COSMEGEN is given as a slow injection into a vein. It may also be given by the isolation-perfusion technique.

COSMEGEN must only be given by a doctor or nurse.

Your doctor will decide what dose and how long you will receive COSMEGEN. This depends on several factors, such as your weight, the size and location of your cancer, whether you are receiving or have received other chemotherapy or radiotherapy, and how you tolerate COSMEGEN. It is usually given in short courses.

If you are being given COSMEGEN intravenously, a second course may be given after at least 3 weeks has passed since your last dose of COSMEGEN, and provided you have no signs of toxicity.

Side effects

Tell your doctor, nurse, or pharmacist as soon as possible if you do not feel well while you are being given COSMEGEN.

COSMEGEN helps most people, but it may have unwanted side-effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

nausea, vomiting
loss of appetite (anorexia)
difficulty in swallowing, or discomfort when swallowing
stomach pain
constipation
tiredness, drowsiness, lack of energy, generally feeling unwell
aching muscles, muscle tenderness or weakness, not caused by exercise
cracked, dry lips
hair loss
acne
slowing down of growth
fertility problems
decreased or blurry vision

These side effects usually vary in severity.

Nausea and vomiting usually occur during the first few hours after being given COSMEGEN. Many of the other side effects do not occur until 2 to 4 days after a course of COSMEGEN has stopped and may not be at their worst until after one or two weeks.

Tell your doctor or nurse immediately if you notice any of the following:

local reactions at the injection site, including skin burning, redness or swelling
a burning sensation in the chest (heartburn)
swelling of the lungs causing coughing, difficulty breathing and wheezing
bruising or bleeding more easily than normal
signs of anaemia, such as headaches, being short of breath when exercising, dizziness and looking pale
frequent infections such as fever, severe chills, sore throat or mouth ulcers
skin reactions, including blisters or increased pigmentation of skin that has previously been exposed to radiotherapy
widespread peeling or sloughing off of skin
sore back passage, sometimes with bleeding and discharge
diarrhoea
signs of liver problems, including yellowing of the skin and eyes, stomach swelling, and dark coloured urine, ascites, difficulty breathing with thoracic pain, confusion with musty or sweet breath odour and seizures
signs of an allergic reaction, including rash, swelling of the face, tongue, lips, mouth or throat which may cause difficulty in swallowing or breathing
tumor lysis syndrome. Symptoms include irregular heartbeat, tingling, muscle spasm and decreased urine flow
sharp, stabbing pains
severe bleeding or phlebitis caused by disseminated intravascular coagulation

These may be serious side effects of COSMEGEN. You may need urgent medical attention.

Your doctor may ask you to have blood tests every day to monitor your blood cells and your kidney and liver function.

Growth retardation has been reported rarely with COSMEGEN.

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using COSMEGEN

Storage

COSMEGEN will be stored in the pharmacy or on the ward.

It is kept in a cool, dry place where it is protected from light and where the temperature stays below 25°C.

Product description

What it looks like

COSMEGEN comes as a yellow powder in a glass vial.

Ingredients

Active ingredient:

500 microgram of Dactinomycin (actinomycin D) per vial

Inactive ingredients:

mannitol

Supplier

COSMEGEN is supplied by:

Australia

Recordati Rare Diseases Australia, Pty Ltd.
Suite 1802, Level 18, 233
Castlereagh Street,
Sydney, NSW, 2000
Australia
Phone: +61 (0) 408 061 403
[email protected]

New Zealand

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks, Mangere
Mt. Wellington, New Zealand
Email: [email protected]

This leaflet was updated in June 2023

Australian Registration Number:
AUST R 10463

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Cosmegen

Active ingredient

Dactinomycin (actinomycin D)

Schedule

1 Name of Medicine

Dactinomycin (actinomycin D).

2 Qualitative and Quantitative Composition

Cosmegen contains 500 micrograms (0.5 milligram) of dactinomycin and 20.0 milligrams of mannitol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cosmegen is a sterile, yellow lyophilised powder for injection by the intravenous route or by regional perfusion after reconstitution.

4 Clinical Particulars

4.1 Therapeutic Indications

Wilms' tumour.

The neoplasm responding most frequently to Cosmegen is Wilms' tumour. With low doses of both dactinomycin and radiotherapy, temporary objective improvement may be as good as and may last longer than with higher doses of each given alone. In the National Wilms' Tumour study, combination therapy with dactinomycin and vincristine together with surgery and radiotherapy, was shown to have significantly improved the prognosis of patients in groups II and III. Dactinomycin and vincristine were given for a total of seven cycles, so that maintenance therapy continued for approximately 15 months.
Postoperative radiotherapy in group I patients and optimal combination chemotherapy for those in group IV are unsettled issues. About 70 percent of lung metastases have disappeared with an appropriate combination of radiation, dactinomycin and vincristine.

Rhabdomyosarcoma.

Temporary regression of the tumour and beneficial subjective results have occurred with dactinomycin in rhabdomyosarcoma which, like most soft tissue sarcomas, is comparatively radio-resistant.
Several groups have reported successful use of cyclophosphamide, vincristine, dactinomycin and doxorubicin hydrochloride in various combinations. Effective combinations have included vincristine and dactinomycin; vincristine, dactinomycin and cyclophosphamide (VAC therapy) and all four drugs in sequence. At present, the most effective treatment for children with inoperable or metastatic rhabdomyosarcoma has been VAC chemotherapy. Two-thirds of these children were doing well without evidence of disease at a median time of three years after diagnosis.
The sequential use of dactinomycin and methotrexate, along with meticulous monitoring of human chorionic gonadotrophin levels until normal, has resulted in survival in the majority of women with metastatic choriocarcinoma. Sequential therapy is used if there is: stability in gonadotrophin titres following two successive courses of an agent; rising gonadotrophin titres during treatment.

Severe toxicity preventing adequate therapy.

In patients with non-metastatic choriocarcinoma, dactinomycin or methotrexate or both, have been used successfully, with or without surgery.
Dactinomycin has been beneficial as a single agent in the treatment of metastatic nonseminomatous testicular carcinoma when used in cycles of 500 microgram/day for five consecutive days, every 6-8 weeks for periods of four months or longer.

Other neoplasms.

Dactinomycin has been given intravenously or by regional perfusion, either alone or with other antineoplastic compounds or X-ray therapy, in the palliative treatment of Ewing's sarcoma and sarcoma botryoides. For non-metastatic Ewing's sarcoma, promising results were obtained when dactinomycin (45 microgram/m²) and cyclophosphamide (1200 milligram/m²) were given sequentially and with radiotherapy, over an 18 month period. Those with metastatic disease remain the subject of continued investigation with a more aggressive chemotherapeutic regimen employed initially.
Temporary objective improvement and relief of pain and discomfort have followed the use of dactinomycin usually in conjunction with radiotherapy for sarcoma botryoides. This palliative effect ranges from transitory inhibition of tumour growth to a considerable but temporary regression in tumour size.

Cosmegen and radiation therapy.

Much evidence suggests that dactinomycin potentiates the effects of X-ray therapy. The converse also appears likely; i.e. dactinomycin may be more effective when radiation therapy is also given.
With combined dactinomycin - radiation therapy, the normal skin, as well as the buccal and pharyngeal mucosa, showed early erythema. A smaller than usual X-ray dose when given 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 rather than two to three months. Erythema from previous X-ray therapy may be reactivated by dactinomycin alone, even when irradiation occurred 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 irradiation treatment area includes 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.
Because of this potentiating effect, dactinomycin may be tried in radio-sensitive tumours not responding to doses of X-ray therapy that can be tolerated. Objective improvement in tumour size and activity may be observed when lower, better tolerated doses of both types of therapy are employed.

Cosmegen and perfusion technique.

Dactinomycin alone or with other antineoplastic agents has also been given by the isolation-perfusion technique, either as palliative treatment or as an adjunct to resection of a tumour. Some tumours considered resistant to chemotherapy and radiation therapy may respond when the drug is given by the perfusion technique. Neoplasms in which dactinomycin has been tried by this technique include various types of sarcoma, carcinoma, and adenocarcinoma.
In some instances tumours regressed, pain was relieved for variable periods, and surgery made possible. On other occasions, however, the outcome has been less favourable. Nevertheless, in selected cases, the drug by perfusion may provide more effective palliation than when given systemically.
Dactinomycin by the isolation-perfusion technique offers certain advantages, provided leakage of the drug through the general circulation into other areas of the body is minimal. By this technique the drug is in continuous contact with the tumour for the duration of treatment.
The dose may be increased well over that used by the systemic route, usually without adding to the danger of toxic effects. If the agent is confined to an isolated part, it should not interfere with the patient's defence mechanism. Systemic absorption of toxic products from neoplastic tissue can be minimised by removing the perfusate when the procedure is finished.

4.2 Dose and Method of Administration

Dosage.

Not for oral administration.
Toxic reactions due to dactinomycin are frequent and may be severe (see Section 4.8 Adverse Effects (Undesirable Effects)), thus limiting in many instances the amount that may be given. However, the severity of toxicity varies markedly and is only partly dependent on the dose employed. The drug must be given in short courses.
Careful calculation of the dosage should be performed prior to administration of each dose.

Intravenous use.

The dosage of dactinomycin varies depending on the tolerance of the patient, the size and location of the neoplasm, and the use of other forms of therapy. It may be necessary to decrease the usual dosages suggested below when other chemotherapy or X-ray therapy is used concomitantly or has been used previously.
The dosage of Cosmegen is calculated in microgram (mcg). The dosage for adults or children should not exceed 15 micrograms/kg or 400-600 micrograms/square metre of body surface daily intravenously for five days. The usual adult dosage is 500 micrograms (0.5 milligram) daily intravenously for a maximum of five days. Calculation of the dosage for obese or oedematous patients should be on the basis of surface area in an effort to relate dosage to lean body mass.

Adults.

The usual adult dosage is 500 micrograms (0.5 milligram) daily intravenously for a maximum of five days.

Children.

In children 15 micrograms (0.015 milligram) per kilogram of body weight is given intravenously daily for five days. An alternative schedule is a total dosage of 2500 micrograms (2.5 milligrams) per square metre of body surface given intravenously over a one week period.
In both adults and children, a second course may be given after at least three weeks have elapsed, provided all signs of toxicity have disappeared.

Method of administration.

Cosmegen may be reconstituted by adding 1.1 millilitre (mL) of sterile water for injection (without preservative) using aseptic precautions. The resulting solution of dactinomycin will contain approximately 500 microgram or 0.5 milligram per mL.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. When reconstituted, Cosmegen is a clear, gold-coloured solution.
Once reconstituted, the solution of dactinomycin can be further diluted with infusion solutions such as 5% glucose or 0.9% sodium chloride, either directly or added to the tubing of a running intravenous infusion. However, only solutions diluted to concentrations of 10 micrograms/mL or higher should be used for administration. This is because diluted solutions below 10 micrograms/mL suffer a loss in potency.
Although reconstituted and further diluted solutions of Cosmegen are physically and chemically stable for up to 10 hours at ambient room temperature, the product does not contain any antimicrobial preservative. Consequently, to reduce microbiological hazard, any reconstituted and/or further diluted solution should be used as soon as practicable. If storage is necessary, hold at 2-8°C (Refrigerate. Do not freeze) for not more than 24 hours. Any unused portion must be discarded.
Do not use water for injections containing a preservative (benzyl alcohol or parabens) to reconstitute Cosmegen powder for injection because this will result in the formation of a precipitate.
Partial removal of dactinomycin from intravenous solutions by cellulose ester membrane filters used in some intravenous in-line filters has been reported.
Since dactinomycin is extremely corrosive to soft tissue, precautions for materials of this nature should be observed.
Cosmegen is highly toxic and both powder and solution must be handled and administered with care. Inhalation of dust or vapours and contact with skin or mucous membranes, especially those of the eyes, must be avoided. Avoid exposure during pregnancy. Should accidental eye contact occur, copious irrigation with water should be instituted immediately, followed by prompt ophthalmologic consultation. Should accidental skin contact occur, the affected part must be irrigated immediately with copious amounts of water for at least 15 minutes (see Special handling below).
If the drug is given directly into the vein without the use of an infusion, the "two-needle technique" should be used. Reconstitute and withdraw the calculated dose from the vial with one sterile needle. Use another sterile needle for direct injection into the vein.

Isolation-perfusion technique.

The dosage schedules and the technique itself vary from one investigator to another; the published literature, therefore, should be consulted for details.
In general, the following doses are suggested:
50 micrograms (0.05 milligram) per kilogram of body weight for lower extremity or pelvis;
35 micrograms (0.035 milligram) per kilogram of body weight for upper extremity.
It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.
Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of haemopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing, and superficial ulceration of the gastric mucosa. Other side effects may include oedema of the extremity involved, damage to soft tissues of the perfused area, and (potentially) venous thrombosis.

Special handling.

Due to the drug's toxic and mutagenic properties, appropriate precautions including the use of appropriate safety equipment are recommended for the preparation of Cosmegen for parenteral administration. The United States National Institute of Health presently recommends that the preparation of injectable antineoplastic drugs would be performed in a Class II laminar flow biological safety cabinet and that personnel preparing drugs of this class should wear surgical gloves and a closed front surgical-type gown with knit cuffs.

Management of extravasation.

Stop the infusion and disconnect the IV administration set but leave the cannula or needle in situ. Attempt to aspirate the extravasated drug via the cannula or needle. Elevate the limb and apply a cold compress for 45 minutes.
There is no generally-accepted antidote for local use, but the following have been used with some success:
sodium thiosulphate 25% (1.6 mL + 3 mL of water for injection);
sodium thiosulphate 10% (4 mL + 6 mL of water for injection);
ascorbic acid injection (50 milligrams/mL) (1 mL).
In severe cases, debridement may become necessary.

4.3 Contraindications

Hypersensitivity to any component of this product.
If dactinomycin is given at or about the time of infection with chickenpox or herpes zoster, a severe generalised disease, which may result in death, may occur.

4.4 Special Warnings and Precautions for Use

Cosmegen should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Due to the toxic properties of dactinomycin (e.g. corrosivity, carcinogenicity, mutagenicity, teratogenicity), special handling procedures should be reviewed prior to handling and followed diligently.
Cosmegen is highly toxic and both powder and solution must be handled and administered with care. This drug is extremely corrosive to soft tissue. If extravasation occurs during intravenous use, severe damage to soft tissue will occur (see Section 4.2 Dose and Method of Administration, Special handling).
As with all antineoplastic agents, dactinomycin is a toxic drug and very careful and frequent observations of the patient for adverse reactions is necessary. These reactions may involve any tissue of the body most commonly the haematopoietic system resulting in myelosuppression. As such, live virus vaccines should not be administered during therapy with Cosmegen. The possibility of an anaphylactoid reaction should be borne in mind.

Veno-occlusive disease.

Veno-occlusive disease (primarily hepatic) may result in fatality, particularly in children younger than 48 months (see Section 4.8 Adverse Effects (Undesirable Effects), Hepatic).

Cosmegen and radiation therapy.

An increased incidence of gastrointestinal toxicity and marrow suppression has been reported when dactinomycin was given with X-ray therapy. 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 Cosmegen causes erythema and vesiculation, which progress more rapidly through the stages of tanning and desquamation. Healing may occur in four to six weeks rather than two to three months. Erythema from previous radiation therapy may be reactivated by Cosmegen 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 Cosmegen and radiation therapy are used or if the patient is particularly sensitive to such combined therapy.
Particular caution is necessary when administering dactinomycin in the first two months after irradiation for the treatment of right-sided Wilms' tumour, since hepatomegaly and elevated AST levels have been noted. In general, Cosmegen should not be concomitantly administered with radiotherapy in the treatment of Wilms' tumour unless the benefit outweighs the risk.
Nausea and vomiting due to dactinomycin make it necessary to give this drug intermittently. It is extremely important to observe the patient daily for toxic side effects when multiple chemotherapy is employed, since a full course of therapy occasionally is not tolerated. If stomatitis, diarrhoea, or severe haematopoietic depression appear during therapy, these drugs should be discontinued until the patient has recovered.
Recent reports indicate an increased incidence of second primary tumours (including leukaemia) following treatment of radiation and antineoplastic agents, such as dactinomycin. Multi-modal therapy creates the need for careful, long-term observation of cancer survivors.

Cosmegen and regional perfusion therapy.

Complications of the perfusion technique are related mainly to the amount of drug that escapes into the systemic circulation and may consist of haematopoietic depression, absorption of toxic products from massive destruction of neoplastic tissue, increased susceptibility to infection, impaired wound healing and superficial ulceration of the gastric mucosa. Other side effects may include oedema of the extremity involved, damage to soft tissues of the perfused area and (potentially) venous thrombosis.

Use in the elderly.

Clinical studies of Cosmegen did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, a published meta-analysis of all studies performed by the Eastern Cooperative Oncology Group (ECOG) over a 13-year period suggests that administration of Cosmegen to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients.

Paediatric use.

The greater frequency of toxic effects of dactinomycin in infants suggests that this drug should be given to infants only over the age of 6 to 12 months.

Effects on laboratory tests.

Many abnormalities of renal, hepatic and bone marrow function have been reported in patients with neoplastic disease and receiving dactinomycin. It is advisable to check renal, hepatic and bone marrow function frequently.
It has been reported that dactinomycin may interfere with bioassay procedures for the determination of antibacterial drug levels.

4.5 Interactions with Other Medicines and Other Forms of Interactions

None known.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Cosmegen has been shown to cause malformations and embryotoxicity in the rat, rabbit and hamster when given in doses of 50-100 microgram/kg intravenously (3-7 times the maximum recommended human dose).
(Category D)
There are no adequate and well-controlled studies in pregnant women. Cosmegen should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cosmegen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Toxic effects (excepting nausea and vomiting) usually do not become apparent until two to four days after a course of therapy is stopped and may not be maximal before one to two weeks have elapsed. Deaths have been reported. However, adverse reactions are usually reversible on discontinuation of therapy. They include the following.

Miscellaneous.

Sepsis (including neutropenic sepsis) with fatal outcome, malaise, fatigue, pyrexia, proctitis, hypocalcaemia, infection.

Lung.

Pneumonitis, pneumothorax (observed as a result of antitumor effect of chemotherapy including dactinomycin).

Oral.

Cheilitis, dysphagia, oesophagitis, ulcerative stomatitis, pharyngitis.

Gastrointestinal.

Anorexia, nausea, vomiting, abdominal pain, diarrhoea, tumour lysis syndrome, constipation, gastrointestinal ulceration, ascites. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by giving antiemetics.

Hepatic.

Liver toxicity including liver function test abnormalities, hepatomegaly, hepatitis and hepatic failure with reports of death. Hepatic veno-occlusive disease, which may be associated with intravascular clotting disorder and multi-organ failure, has been reported in patients receiving Cosmegen as part of a multidrug chemotherapy regimen (see Section 4.4 Special Warnings and Precautions for Use, Veno-occlusive disease). Hepatic encephalopathy, pleural effusion as a complication of various hepatic disorders.

Haematological.

Anaemia (even to the point of aplastic anaemia), agranulocytosis, disseminated intravascular coagulation (DIC), leukopenia, neutropenia, febrile neutropenia, thrombocytopenia, pancytopenia, reticulocytopenia. Platelet and white cell counts should be done daily to detect severe haematopoietic depression. If either count markedly decreases, the drug should be withheld to allow marrow recovery. This often takes up to three weeks.

Dermatological.

Alopecia, rash, skin toxicity and dermatitis, acne, erythema multiforme, flare-up of erythema or increased pigmentation of previously irradiated skin. Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) have been observed from postmarketing experience.

Soft tissues.

Dactinomycin is extremely corrosive. If extravasation occurs during intravenous use, severe damage to soft tissues will occur. In at least one instance, this has led to contracture of the arms. Epidermolysis, erythema and oedema, at times severe, have been reported with regional limb perfusion.

Musculoskeletal and connective tissue.

Myalgia, growth retardation.

Immune system.

Hypersensitivity.

Nervous system.

Peripheral neuropathy was commonly observed in patients receiving combination chemotherapy regimens that included dactinomycin. Lethargy.

Eye.

Optic neuropathy.

Vascular.

Haemorrhage, thrombophlebitis.

Laboratory tests.

Many abnormalities of renal, hepatic and bone marrow function have been reported in patients with neoplastic disease and receiving Cosmegen. Renal, hepatic, and bone marrow functions should be assessed frequently.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Manifestations of overdose in patients have included nausea, vomiting, diarrhoea, mucositis including stomatitis, gastrointestinal ulceration, severe skin disorders including skin exfoliation, exanthema, desquamation and epidermolysis, severe haematopoietic depression, veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome and death. No specific information is available on the treatment of overdosage with Cosmegen. Treatment is symptomatic and supportive. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic, and bone marrow functions frequently.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or National Poisons Centre on 0800 POISON (0800 764766) in New Zealand.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cosmegen (dactinomycin) is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces. Dactinomycin is the principle component of the mixture of actinomycins produced by Streptomyces parvulus. Generally, the actinomycins exert an inhibitory effect on Gram-positive and Gram-negative bacteria and on some fungi. The toxic properties of the actinomycins in relation to antibacterial activity preclude their use as antibiotics in the treatment of infectious diseases; however, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumour implant. This cytotoxic action is the basis for their use in the palliative treatment of certain types of cancer.
Unlike other species of Streptomyces, this organism yields an essentially pure substance that contains only traces of similar compounds differing in the amino acid content of the peptide side chains.

Clinical trials.

In the National Wilms' Tumour study, combination therapy with dactinomycin and vincristine together with surgery and radiotherapy, was shown to have significantly improved the prognosis of patients in groups II and III. Dactinomycin and vincristine were given for a total of seven cycles, so that maintenance therapy continued for approximately 15 months.

5.2 Pharmacokinetic Properties

Results of a study in patients with malignant melanoma indicate that dactinomycin (3H-dactinomycin) is minimally metabolised, is concentrated in nucleated cells, and does not penetrate the blood brain barrier. Approximately 30% of the dose was recovered in urine and faeces in one week. The terminal plasma half-life for radioactivity was approximately 36 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Dactinomycin has been shown to be mutagenic in a number of test systems in vitro and in vivo including human fibroblasts and leukocytes, and HeLa cells. DNA damage and cytogenetic effects have been demonstrated in the mouse and the rat.

Carcinogenicity.

The International Agency on Research on Cancer has judged that dactinomycin is a positive carcinogen in animals. Local sarcomas were produced in mice and rats after repeated subcutaneous and intraperitoneal injection. Mesenchymal tumours occurred in male F344 rats given intraperitoneal injections of 0.05 mg/kg, 2 to 5 times per week for 18 weeks. The first tumour appeared at 23 weeks.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial contains 500 micrograms (0.5 milligram) of dactinomycin and 20.0 milligrams of mannitol.

6.2 Incompatibilities

Do not use water for injections containing a preservative (benzyl alcohol or parabens) to reconstitute Cosmegen powder for injection because this will result in the formation of a precipitate.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a dry place below 25°C. Protect from light.

6.5 Nature and Contents of Container

Injection Cosmegen is a lyophilised powder and is supplied as follows: glass vials containing 500 micrograms (0.5 milligram) of dactinomycin with 20.0 milligrams of mannitol. In the dry form the compound is an amorphous yellow powder. The solution is clear and gold-coloured.
Cosmegen is supplied in packs of 1 vial.

6.6 Special Precautions for Disposal

Unwanted made-up solution and open empty vials.

Trisodium phosphate 5% for 30 minutes will destroy Cosmegen.

Unopened vials.

Incinerate at high temperature (982°C-1204°C). Allow incinerator to cool. Scrape off the clinkers and re-incinerate them.

6.7 Physicochemical Properties

Chemical structure.

The molecular formula is C₆₂H₈₆N₁₂O₁₆.
The structural formula is:

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