COSMEGEN Lyophilised powder for solution for injection Ref.[8698] Active ingredients: Dactinomycin

Toxic reactions due to Cosmegen are frequent and may be severe (see 4.8 ‘Undesirable effects’), thus limiting the amount that may be administered in many cases. However, the severity of toxicity varies markedly and is only partly dependent on the dosage used.

Posology

Intravenous use

The dosage of Cosmegen will vary with 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 reduce the usual dosage suggested below when additional chemotherapy or radiation therapy is used concurrently or has been employed previously.

The dosage of Cosmegen is calculated in micrograms. The dose intensity per-two-week cycle for adults or children should not exceed 15 micrograms per kg per day or 400-600 micrograms per square meter of body surface daily, intravenously, for 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.

As there is a greater frequency of toxic effects of Cosmegen in infants, Cosmegen should only be given to infants under the age of 12 months, when the benefit outweighs the risk.

A wide variety of single agent and combination chemotherapy regimens with Cosmegen may be employed. Because chemotherapeutic regimens are constantly changing, dosing and administration should be performed under the direct supervision of physicians familiar with current oncologic practices and new advances in therapy. The following suggested regimens are based upon a review of current literature concerning therapy with Cosmegen and are on a per-cycle basis.

Wilms’s Tumor

Regimens of 45 micrograms per kg intravenously administered in various combinations and schedules with other chemotherapeutic agents.

Rhabdomyosarcoma

Regimens of 15 micrograms per kg intravenously daily for five days administered in various combinations and schedules with other chemotherapeutic agents.

Ewing’s Sarcoma

Regimens of 1.25 milligrams per m2 intravenously administered in various combinations and schedules with other chemotherapeutic agents.

Testicular carcinoma

1,000 micrograms per m2 intravenously on Day 1 as part of a combination regimen with cyclophosphamide, bleomycin, vinblastine, and cisplatin.

Gestational trophoblastic neoplasia

12 micrograms per kg intravenously daily for five days as a single agent.

500 micrograms intravenously on Days 1 and 2 as part of a combination regimen with etoposide, methotrexate, folinic acid, vincristine, cyclophosphamide and cisplatin.

Elderly patients

The general considerations already outlined also apply to elderly patients. Administration of Cosmegen to elderly patients may be associated with an increased risk of myelosuppression compared to younger patients.

Regional perfusion in locally recurrent and locoregionally metastatic melanoma

The dosage schedules and the technique itself vary from one investigator to another, and the published literature should, therefore, be consulted for details. In general the following doses are suggested:

For a lower extremity or pelvis – 50 micrograms per kg bodyweight.

For an upper extremity – 35 micrograms per kg bodyweight.

It may be advisable to use lower doses in obese patients, or when previous chemotherapy or radiation therapy has been employed.

Method of administration

When reconstituted, the solution of dactinomycin can be added to an infusion solution of 5% dextrose injection or sodium chloride injection, either directly or into the tubing of a running intravenous infusion.

Although reconstituted Cosmegen 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 Cosmegen 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.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

In the event of overdosage, dactinomycin therapy should be withdrawn immediately. Limited information is available on overdosage in humans. Manifestations of overdose have included nausea, vomiting, diarrhoea, mucositis including stomatitis, gastro-intestinal ulceration, severe skin disorders including skin exfoliation, exanthema, desquamation and epidermolysis, severe haemopoietic depression, veno-occlusive disease, acute renal failure, sepsis (including neutropenic sepsis) with fatal outcome and death. Treatment should be symptomatic and supportive. There is no known antidote. It is advisable to check skin and mucous membrane integrity as well as renal, hepatic and bone-marrow functions frequently.

The shelf-life is 36 months.

Store below 25°C. Do not freeze. Keep the vial in the outer carton in order to protect from light.

Glass vials containing 500 micrograms dactinomycin with 20 mg mannitol.

Reconstitution and administration

Cosmegen is reconstituted by adding 1.1 ml of water for Injections Ph Eur without preservative to the vial. For injection, 1.0 ml of the reconstituted solution, which will contain 500 micrograms of dactinomycin, is withdrawn into the syringe. Only Water for Injections Ph Eur (which does not contain preservatives) should be used. Other injection fluids may cause precipitation. Cosmegen should be inspected for particulate matter and discoloration, whenever possible. The reconstituted solution is clear and gold-coloured.

Studies conducted on dactinomycin lyophilized powder for injection demonstrate that drug product diluted at concentrations of 10 mcg/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 10 mcg/mL and stored at ambient room temperature showed significantly lower recoveries. Therefore, only drug product diluted at concentrations greater than 10 mcg/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 Cosmegen 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 drugs have been published and should be considered.

Accidental contact measures

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 (see 4.4 ‘Special warnings and precautions for use’).

Care in the administration of Cosmegen will reduce the chance of perivenous infiltration (See 4.4 ‘Special warnings and precautions for use’ and 4.8 ‘Undesirable effects’). It may also decrease the chance of local reactions such as urticaria and erythematous streaking. On intravenous administration of Cosmegen, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be terminated and restarted in another vein. If extravasation is suspected, intermittent application of ice to the site for 15 minutes 4 times daily for 3 days may be useful. The benefit of local administration of drugs has not been clearly established. Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended. Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.