CARMUSTINE

Carmustine must be administered only by specialists experienced in the field of chemotherapy and under appropriate medical supervision. Posology Initial doses The recommended dose of Carmustine as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks.

This may be given as a single dose or divided into daily infusions such as 75 to 100 mg/m2 on two successive days. When Carmustine is used in combination with other myelosuppressive medicinal products or in patients in whom bone marrow reserve is depleted, the doses should be adjusted according to the haematologic profile of the patient as shown below.

Monitoring and subsequent doses A repeat course of Carmustine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/ mm3, leukocytes above 4,000/ mm3), and this is usually in six weeks.

Blood counts should be monitored frequently and repeat courses should not be given before six weeks because of delayed haematologic toxicity. Doses subsequent to the initial dose should be adjusted according to the haematologic response of the patient to the preceding dose, in both monotherapy as well as in combination therapy with other myelosuppressive medicinal products.

g. g. platelets <25,000 then a maximum of 50% of prior dose should be given). Conditioning regimen prior to SCT Carmustine is administered in combination with other chemotherapeutic agents in patients with haematologic malignancies prior to SCT at an intravenous dose of 300 – 600 mg/m2.

Special populations Patients with impaired renal function In patients with impaired renal function, the dose of carmustine should be reduced depending on the glomerular filtration rate. Elderly In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and take into consideration concomitant disease or other therapy with other medicinal products.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and the renal function should be monitored and the dose reduced according to this. 4). Method of administration For intravenous use after reconstitution and further dilution.

By reconstituting the powder with the solvent provided, a solution has to be prepared by adding additional sterile water for injections. 9%) solution for injection, or glucose 50 mg/ml (5%) solution for injection. The resulting ready-to-use solution for infusion should then be administered immediately by intravenous drip over a one- to two-hour period protected from light.

The duration of infusion should not be less than one hour, otherwise it leads to burning and pain in the injected area. The injected area should be monitored during the administration. 6.

Summary of the safety profile The table includes adverse reactions that were presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed may not reflect the rates observed in clinical practice.

Adverse reactions are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important. When placebo-controlled trials are available, adverse reactions are included if the incidence is ≥ 5% higher in the treatment group.

High dose is defined as >200 mg/m2. Tabulated list of adverse reactions The following table includes adverse reactions of carmustine listed by MedDRA system organ class and frequency convention presented in order of decreasing seriousness: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to < 1/1,000); very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness: MedDRA system organ class Frequency Adverse reactions Clinically important side effects are in italics Infections and infestations Not known Opportunistic infections (including fatal outcome).

Common Acute leukaemias, bone marrow dysplasias; following long-term use. Neoplasms benign, malignant and unspecified (including cysts and polyps) Not known Secondary malignancies. Blood and lymphatic system disorders Common Anaemia.

Immune system disorders Not known Allergic reaction. Metabolism and nutrition disorders Not known Electrolyte disorders (hypokalaemia, hypomagnesaemia and hypophosphataemia). Very common Ataxia, dizziness, headache. Common Encephalopathy (high-dose therapy and dose- limiting).

Nervous system disorders Not known Muscular pain, status epilepticus, seizure, tonic clonic seizure (grand mal seizure). Very common Ocular toxicities, transient conjunctival flushing and blurred vision; retinal haemorrhages. Eye disorders Rare Neuroretinitis.

Very common Hypotension, due to alcohol content of diluent (high-dose therapy). Cardiac disorders Not known Tachycardia, chest pain. Vascular disorders Rare Veno-occlusive disease (high-dose therapy). Very common Pulmonary toxicity1, interstitial fibrosis (with prolonged therapy and cumulative dose* >1400 mg/m2).

Pneumonitis (for doses >450 mg/m2). Respiratory, thoracic and mediastinal disorders Rare Interstitial fibrosis (with lower doses). Very common Nausea and vomiting, severe; emetogenic potential >250 mg/m2 medium-high; starts within 2-4 hours after administration and lasts for 4-6 hours.

Common Anorexia, constipation, diarrhoea, stomatitis. Rare Gastrointestinal bleeding. Gastrointestinal disorders Not known Neutropenic enterocolitis. MedDRA system organ class Frequency Adverse reactions Hepatobiliary disorders Common Hepatotoxicity, reversible, delayed up to 60 days after administration (high-dose therapy and dose-limiting), manifested by: - bilirubin, reversible increase - alkaline phosphatase, reversible increase - SGOT, reversible increase.

Very common Dermatitis with topical use improves with reduced concentration of compounded product, hyperpigmentation, transient, with accidental skin contact. Common Alopecia, flushing (due to alcohol content of diluent; increased with administration times <1- 2 h), injection site reaction.

Skin and subcutaneous tissue disorders Not known Extravasation hazard: vesicant. Renal and urinary disorders Not known Renal failure, azotaemia, decrease in kidney volume. Reproductive system and breast disorders Not known Infertility, teratogenesis.

General disorders and administration site conditions Very rare Thrombophlebitis. 1Pulmonary toxicity is also manifested as pneumonitis and interstitial lung disease in post-marketing experience. * An increased risk for pulmonary toxicities upon treatment with conditioning regimes and SCT for females has been reported.

g. TBI or busulfan-cyclophosphamide) or with carmustine (BEAM: carmustine, etopside, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide). Description of selected adverse reactions Myelosuppression Myelosuppression is very common and begins 7-14 days of administration with recovery 42-56 days of administration.

The myelosuppression is dose and cumulative dose related, and often biphasic. Thrombocytopenia is generally more pronounced than leukopenia, but both are dose-limiting adverse effects. Anaemia is common but is usually less pronounced.

Eye disorders Rapid intravenous infusion may cause conjunctival bleeding within 2 hours, lasting approximately 4 hours. Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis (with fatal outcome), pulmonary infiltration Pulmonary toxicity has been observed in up to 30% of patients.

In cases where pulmonary toxicity started early (within 3 years of treatment), pulmonary infiltrates and/or pulmonary fibrosis occurred, some of which were fatal. The patients were between 22 months and 72 years old. Risk factors include smoking, respiratory disease, existing radiographic abnormalities, sequential or concomitant thoracic radiation, as well as combination with other active substances that can cause lung damage.

The incidence of adverse reactions is probably dose-related; cumulative doses of 1200-1500 mg/m2 have been associated with an increased likelihood of pulmonary fibrosis. During treatment, lung function tests (FVC, DLCO) should be performed regularly.

Patients showing a baseline value of <70% of expected forced vital capacity or carbon monoxide diffusion […]

Pulmonary toxicity characterised by pulmonary infiltrates and/or fibrosis has been reported to occur with a frequency ranging up to 30%. This may occur within 3 years of therapy. The adverse reaction frequency appears to be dose related with cumulative doses of 1,200 -1,500 mg/m2 being associated with increased likelihood of lung fibrosis.

Risk factors include smoking, the presence of a respiratory condition, pre-existing radiographic abnormalities, sequential or concomitant thoracic irradiation and association with other agents that cause lung damage. Baseline pulmonary function studies and chest X-ray should be conducted along with frequent pulmonary function tests during treatment.

Patients with a baseline below 70% of the predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk. In patients having received carmustine in childhood or adolescence, cases of extremely delayed-onset pulmonary fibrosis (up to 17 years after treatment) have been described.

3. 8). An increased risk of pulmonary toxicities has been reported with conditioning regimens and SCT in women. g. TBI or busulfan, cyclophosphamide) or with carmustine (BEAM: carmustine, etopside, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide).

High-dose therapy with carmustine (especially with 600 mg/m2) prior to haematopoietic stem cell transplantation has been shown to increase the risk for incidence and severity of pulmonary toxicities. Therefore, in patients with other risks for pulmonary toxicities, use of carmustine needs to be weighed against the risks.

High-dose therapy High-dose therapy with carmustine increases the risk and severity of infections, cardiac, hepatic, gastrointestinal, and renal toxicity, as well as nervous system disorders and electrolyte disturbances (hypokalaemia, hypomagnesemia and hypophosphatemia).

Comorbidities and poor disease status Patients with comorbidities and poorer disease status are at higher risk for adverse events. This is especially important for elderly patients. Carmustine is carcinogenic in rats and mice at doses less than the recommended human dose based on body surface area.

Bone marrow toxicity Delayed and cumulative bone marrow toxicity is a common and severe toxic adverse reaction of carmustine. Complete blood count should be monitored frequently for at least six weeks after a dose. 2. 8). Repeat doses of Carmustine should not to be given more frequently than every six weeks.

Myelosuppression is very common and begins 7-14 days of administration with recovery 42-56 days of administration. The myelosuppression is dose and cumulative dose related, and often biphasic. Thrombocytopenia is generally more pronounced than leukopenia, but both are dose-limiting adverse effects.

Anaemia is common but is usually less pronounced. 2). Women of childbearing potential/contraception in males and females Women of childbearing potential should use effective contraception to avoid becoming pregnant while on treatment and for at least 6 months after treatment.

6) Parenteral administration The intra-arterial compatibility has not been tested. Severe tissue damage can be expected in case of inadvertent intra-arterial administration. Experimental direct injection of carmustine to the carotid artery has been associated with ocular toxicity.

8). Given the possibility of extravasation, close monitoring of the infusion site is recommended for possible infiltration during administration. A special method for handling extravasation is currently unknown. Accidental contact of the reconstituted infusion solution with the skin has resulted in burns and excessive pigmentation in the affected areas.

Local soft tissue toxicity resulting from extravasation of carmustine has been reported. 7 mg/100 ml. For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml. g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects.

Because this medicine is usually given slowly over 6 hours, the effects of alcohol may be reduced.

1. - Severe bone marrow depression or myelosuppression. - Severe (end-stage) renal impairment. - Children and adolescents. 6).