Special Warning : אזהרת שימוש

4.4    Special warnings and precautions for use
Carmustine should be used only by physicians with specific experience in the field of chemotherapy.

Myelosuppression
Delayed and cumulative bone marrow depression (especially thrombocytopenia and leukopenia) that can lead to bleeding and severe infections in patients already at risk is a common and severe toxic side effect of carmustine. Hematologic parameters (leukocytes, granulocytes,
hemoglobin, platelets) should be checked prior to initiation of therapy and monitored regularly during therapy until at least 6 weeks after administration of a dose (see section 4.2). Repeated doses of carmustine should not be given more frequently than every 6 weeks.

The most common and dose-limiting adverse reaction is reversible and delayed-onset myelosuppression, which usually occurs after 4 to 6 weeks and whose severity depends on the dose. The myelosuppressive effect of carmustine is cumulative.

The lowest platelet count is observed after 4 to 5 weeks, and the lowest leukocyte count is observed 5 to 6 weeks after the start of treatment.
Thrombocytopenia is generally more severe than leukocytopenia, but both side effects may be dose-limiting.

Monitoring Organ Functions
In addition, hepatic, renal, and pulmonary functions should be assessed prior to treatment and monitored regularly during therapy (see Section 4.8).
Intra-arterial administration
I.a. tolerability has not been evaluated. Severe tissue damage is to be expected in case of accidental i.a. administration.
Direct application of carmustine into the carotid artery should be considered experimental and has been associated with ocular toxicity.

Pulmonary Toxicity
Pulmonary toxicity has been observed in up to 30% of patients. Early-onset pulmonary toxicity (within 3 years of treatment) resulted in pulmonary infiltrates and/or pulmonary fibrosis, which in some cases was fatal. Patients ranged in age from 22 months to 72 years. Risk factors included smoking, respiratory disease, existing radiographic abnormalities, sequential or concurrent chest irradiation, and combination with other agents that may cause lung injury. The incidence of adverse reactions is likely dose-dependent.
Cumulative doses of 1200-1500 mg/m2 have been associated with an increased likelihood of pulmonary fibrosis. Spirometry (FVC, DLCO) should be performed regularly during treatment. Patients who have a baseline spirometry value of <70% of the expected forced expiratory vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk.

Cases of very late-onset pulmonary fibrosis (up to 17 years after treatment) have been observed in patients who received carmustine in childhood or adolescence.

A long-term follow-up of 17 patients who survived childhood brain tumors showed that 8 of them died of pulmonary fibrosis. Two of these 8 deaths occurred within the first 3 years of treatment and 6 within 8-13 years of treatment. The mean age (at the time of treatment) of the patients who died was 2.5 years (1-12 years) and the mean age of the long-term survivors was 10 years (5-16 years). All patients younger than 5 years at the time of treatment died of pulmonary fibrosis. Neither the carmustine dose nor additional administration of vincristine or spinal irradiation affected the fatal outcome.

Pulmonary fibrosis was found in all remaining survivors available for followup.
The risk-benefit ratio of carmustine therapy must be carefully weighed because of the high risk of pulmonary toxicity.

Renal Toxicity
Renal changes with decrease in renal size, progressive azotemia, and renal failure have been observed after high-cumulative doses and after long-term treatment with carmustine and related nitrosoureas.

Liver Toxicity
Hepatic necrosis may occur after administration of doses higher than those recommended in the dosing instructions.

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 (hypokalemia,
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.
Local Toxicity
Reactions at the site of administration may occur during administration of carmustine (see section 4.8). Considering the possibility of extravasation, close monitoring of the infusion site is recommended due to possible infiltration during administration. A specific method for managing extravasation is not currently known.
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.
Infiltration of carmustine may cause swelling, pain, erythema, burning, and skin necrosis.

Important information about other components:
Ethanol
This drug contains 0.57% ethanol (alcohol) by volume, or up to 7.68 g per dose. This is equivalent to 11.32 ml of beer or 4.72 ml of wine per dose. These amounts are derived from a calculated example of 320 mg carmustine (200 mg/m2 BSA for 1.6 m2) dissolved in 9.6 ml (sterile absolute ethanol) and a final infusion volume of 1696 ml (see Section 6.6). Health risk for patients suffering from alcoholism. Should be considered in pregnant or lactating women and in children and patients at increased risk due to liver disease or epilepsy. The amount of alcohol in this medicine may affect the effectiveness of other medicines. The amount of alcohol in this medicine may impair the ability to drive and operate machinery.

Effects on Driving

  4.7     Effects on ability to drive and use machines

No studies have been undertaken on the consequences the medicine on the competency to drive and the ability to operate machines. However the possibility will have to be taken into consideration, that the alcohol quantity in these pharmaceutical medicines can impair the competency to drive and the ability to operate machines.