Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Obvius Investment B.V. De, Cuserstraat 93, 1081 CN, Amsterdam, The Netherlands
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 and 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.
Hepatic and renal function should also be checked prior to treatment and regularly monitored during therapy (see section 4.8).
Carmustine is carcinogenic in rats and mice at doses less than the recommended human dose based on body surface area.
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. In case of a decreased number of circulating platelets, leucocytes or erythrocytes either from previous chemotherapy or other cause the dose should be adjusted, see Table 1, section 4.2. Liver, kidney and lung function should be checked and monitored regularly during therapy (see section 4.8). Repeat doses of Carmustine Obvius should not to be given more frequently than every six weeks. The bone marrow toxicity of carmustine is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior doses (see section 4.2).
Direct administration of carmustine into the carotid artery is regarded as experimental and has been associated with ocular toxicity.
This medicinal product contains 0.57 vol% ethanol (alcohol), i.e. up to 7.62 g per dose, equivalent to 11.2 ml beer or 4.65 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines, and may impair your ability to drive or use machines.
In combination with chemotherapeutic medicinal products reduced activity of antiepileptic medicinal products must be anticipated.
Concomitant use with cimetidine leads to delayed, major, suspected, increased carmustine toxic effect (due to the inhibition of carmustine metabolism).
Concomitant use with digoxin leads to delayed, moderate, suspected, decreased effect of digoxin (due to the decreased digoxin absorption).
Concomitant use with melphalan leads to increased risk of pulmonary toxicity.
Women should use effective contraception to avoid becoming pregnant while on treatment and for at least 6 months after treatment.
Male patients should be advised to use adequate contraceptive measures while on treatment with carmustine and for at least 6 months after treatment.
Carmustine should not be administered to patients who are pregnant. Safe use in pregnancy has not been established and therefore the benefit must be carefully weighed against the risk of toxicity. Carmustine is embryotoxic in rats and rabbits and teratogenic in rats when given in doses equivalent to the human dose. If Carmustine Obvius is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Carmustine Obvius, the patient should be apprised of the potential hazard to the foetus.
It is unknown whether carmustine/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Carmustine Obvius is contraindicated during breast-feeding and up to seven days post-treatment (see section 4.3).
Carmustine may impair male fertility. Males should be advised of potential risk of infertility and to seek fertility/family planning counselling prior to therapy with carmustine.
Carmustine Obvius has no or negligible influence on the ability to drive and use machines. However, the possibility will have to be taken into consideration, that the alcohol quantity in these pharmaceutical medicines can impair the ability to drive and use machines.
The table includes adverse reactions that were presented during treatment with this medicinal product but may not necessarily have a causal relationship with the medicinal product. 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.
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:
Common: Acute leukaemia, bone marrow dysplasia – following long-term use.
Very common: Myelosuppression.
Common: Anaemia.
Very common: Ataxia, dizziness, headache.
Common: Encephalopathy (high-dose therapy and dose-limiting).
Not known: Muscular pain, status epilepticus, seizure, grand mal seizure.
Very common: Ocular toxicities, transient conjunctival flushing and blurred vision due to retinal haemorrhages.
Very common: Hypotension, due to the alcohol content of the solvent (high-dose therapy).
Very common: Phlebitis.
Rare: Veno-occlusive disease (high-dose therapy).
Very common: Pulmonary toxicity, interstitial fibrosis (with prolonged therapy and cumulative dose), Pneumonitis.
Rare: Interstitial fibrosis (with lower doses).
Very common: Emetogenic potential. Nausea and vomiting-severe.
Common: Anorexia, constipation, diarrhoea, stomatitis.
Common: Hepatotoxicity, reversible, delayed up to 60 days after administration (high-dose therapy and dose-limiting), manifested by:
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 solvent; increased with administration times <1-2 h), injection site reaction.
Not known: Extravasation hazard: vesicant
Rare: Renal toxicity.
Rare: Gynecomastia.
Not known: Infertility, teratogenesis.
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.
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 capacity in these tests are at particular 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.
Long-term follow-up observation of 17 patients who survived brain tumours in childhood showed that 8 of them succumbed to pulmonary fibrosis. Two of these 8 fatalities occurred within the first 3 years of treatment and 6 of them occurred 8-13 years after treatment. The median age of patients who died on treatment was 2.5 years (1-12 years), the median age of long-term survivors on treatment was 10 years (5-16 years). All patients younger than 5 years of age at the time of treatment died from pulmonary fibrosis; neither the carmustine dose nor an additional vincristine dose or spinal radiation had any influence on the fatal outcome.
All remaining survivors available for follow-up were diagnosed with pulmonary fibrosis. Use of carmustine in children and adolescents <18 years is contraindicated, see section 4.3.
Pulmonary toxicity also manifested in the post-marketing phase as pneumonitis and interstitial lung disease. Pneumonitis is seen for doses >450 mg/m2 and interstitial lung disease is seen with prolonged therapy and cumulative dose >1,400 mg/m2.
The emetogenic potential is high at doses >250 mg/m2 and high to moderate in doses ≤250 mg/m2. Nausea and vomiting are severe and begins within 2-4 h of administration and lasts for 4-6 h.
Renal toxicity is rare, but occurs for cumulative doses <1,000 mg/m2.
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 the national reporting system listed in Appendix V.
The intravenous solution is unstable in polyvinyl chloride containers. All plastic coming into contact with the carmustine solution for infusion (e.g. infusion set, etc.) should be PVC-free polyethylene plastic, otherwise glass ware should be used.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
