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

Cosmegen should be administered only under the supervision of a physician who is experienced in the use of a cancer chemotherapeutic agent. 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. Since Cosmegen is extremely corrosive to soft tissues, it is intended for intravenous use. 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 Cosmegen. 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 6.6 ‘Instructions for use/handling’).

If extravasation occurs during intravenous use, severe damage to soft tissue may occur (see 6.6 ‘Instructions for use/handling’).

Cosmegen, like all antineoplastic agents, is a toxic drug, and very careful and frequent observation 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. The possibility of an anaphylactoid reaction should be borne in mind.

It is extremely important to observe the patient daily for toxic side effects when combined therapy is employed, since a full course of therapy is occasionally not tolerated. If stomatitis, diarrhoea or severe haematopoietic depression appear during therapy, these drugs 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 (see 4.8 ‘Undesirable effects: Gastro-intestinal’).

Cosmegen and radiation therapy

An increased incidence of gastrointestinal toxicity and marrow suppression has been reported with combination therapy incorporating Cosmegen 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 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 Cosmegen within two months of irradiation for the treatment of right-sided Wilm’s tumor, since hepatomegaly and elevated AST levels have been noted.

In general, Cosmegen should not be concomitantly administered with radiotherapy in the treatment of Wilm’s tumor unless the benefit outweighs the risk.

Reports indicate an increased incidence of secondary primary tumours (including leukaemia) following treatment with radiation and antineoplastic agents, such as Cosmegen. 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 Cosmegen. Renal, hepatic and bone-marrow functions should be assessed frequently.

Much evidence suggests that Cosmegen potentiates the effects of X-ray therapy. The converse also appears likely: that Cosmegen may be more effective when radiation therapy is given concurrently. See 4.4 ‘Cosmegen and radiation therapy’.

Cosmegen may interfere with bio-assay procedures for the determination of antibacterial drug levels.

Dactinomycin has been shown to be teratogenic in animals and should not normally be given to pregnant women.

Cosmegen, dactinomycin should not be administered to mothers who are breast-feeding.

There are no data available. The potential side effects, fatigue and lethargy, should be taken into account (see 4.8 ‘Undesirable effects’).

Toxic effects (except nausea and vomiting) do not usually become apparent until two to four days after a course of therapy is stopped, and may not peak until one to two weeks have elapsed. Deaths have been reported. However, side effects are usually reversible on discontinuing therapy, they include the following:

Infections and infestations

Sepsis (including neutropenic sepsis) with fatal outcome, infection, pharyngitis

Metabolism and nutrition disorders

Anorexia, hypocalcemia, tumour lysis syndrome.

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

Nausea, vomiting, abdominal pain, diarrhoea, gastro-intestinal ulceration, cheilitis, dysphagia, constipation, esophagitis, proctitis, ulcerative stomatitis, ascites. Nausea and vomiting, which occur early during the first few hours after administration, may be alleviated by the administration of anti-emetics.

Hepatobiliary disorders

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 4.4 ‘Special warnings and precautions for use: Veno-occlusive disease’). Hepatic encephalopathy, pleural effusion as a complication of various hepatic disorders.

Blood and lymphatic system disorders

Anaemia (even to the point of aplastic anaemia), agranulocytosis, disseminated intravascular coagulation (DIC), leucopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia. Platelet and white blood-cell counts should be performed frequently to detect severe haemopoietic depression. If either count shows a marked decrease, dactinomycin should be withheld to allow marrow recovery. This often takes up to three weeks.

Skin and subcutaneous tissue disorders

Alopecia, rash, skin toxicity and dermatitiss, erythema multiforme, acne, 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.

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 disorders

Myalgia, growth retardation.

General disorders and administrative site conditions

Fatigue, pyrexia, malaise.

Immune system disorders

Hypersensitivity

Nervous System disorders

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

Eye disorders

Optic neuropathy

Vascular disorders

Haemorrhage, thrombophlebitis

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 haemopoietic depression, increased susceptibility of infection, absorption of toxic products from massive destruction of neoplastic tissue, impaired wound healing and superficial ulceration of the gastric mucosa. Other side effects may include oedema of the extremity involved, damage to the soft tissues of the perfused area, and potentially venous thrombosis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via

United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard

Ireland: Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Ireland, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, e-mail: medsafety@hpra.ie

Adverse events should also be reported to Recordati Rare Diseases at: +44 (0)1491 414333 or email RRDPharmacovigilance@recordati.com

Use of water containing preservatives (benzyl alcohol or parabens) to reconstitute Cosmegen for injection results in the formation of a precipitate.