Chemical formula: C₅H₉Cl₂N₃O₂ Molecular mass: 214.05 g/mol PubChem compound: 2578
Carmustine interacts in the following cases:
For patients with renal impairment the dose of carmustine should be reduced if the glomerular filtration rate is reduced.
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.
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.
In combination with chemotherapeutic medicinal products reduced activity of antiepileptic medicinal products must be anticipated.
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 is used during pregnancy, or if the patient becomes pregnant while taking (receiving) carmustine, 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 is contraindicated during breast-feeding and up to seven days post-treatment.
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 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 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.
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.
The spectrum of undesirable effects observed in patients with newly-diagnosed high-grade malignant glioma and recurrent malignant gliomas was generally consistent with that encountered in patients undergoing craniotomy for malignant gliomas.
Very common (≥1/10), common (≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100) adverse reactions reported in patients receiving carmustine implant during the clinical trials are listed below.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following data are the most frequently occurring adverse events observed in 5% or more of the 120 newly-diagnosed malignant glioma patients receiving carmustine implant during the trial.
Common Adverse Events Observed in ≥5% of Patients Receiving carmustine implant at Initial Surgery:
Common: Diabetes mellitus
Very common: Healing abnormal
Common: Peripheral oedema
Very common: Hemiplegia, convulsion, confusion, brain oedema, aphasia, depression, somnolence, speech disorder
Common: Amnesia, intracranial hypertension, personality disorder, anxiety, facial paralysis, neuropathy, ataxia, hypoesthesia, paresthesia, thinking abnormal, abnormal gait, dizziness, grand mal convulsion, hallucinations, insomnia, tremor
Common: Conjonctival oedema, abnormal vision, visual field defect
Very common: Deep thrombophlebitis
Common: Pulmonary embolism, haemorrhage
Common: Pneumonia
Very common: Nausea, vomiting, constipation
Common: Diarrhoea
Very common: Rash, alopecia
Common: Urinary tract infection, urinary incontinence
Very common: Aggravation reaction, headache, asthenia, infection, fever, pain
Common: Abdominal pain, back pain, face oedema, chest pain, abscess, accidental injury
Intracranial hypertension was present in more carmustine implant-treated patients than in Placebo patients (9.2% vs. 1.7%). It was typically observed late, at the time of tumour recurrence, and was unlikely to be associated with carmustine implant use.
CSF leak was more common in carmustine implant-treated patients than in placebo patients. However intracranial infections and other healing abnormalities were not increased.
The following post-operative adverse events were observed in 4% or more of the 110 patients receiving carmustine implant at recurrent surgery in a controlled clinical trial. Except for nervous system effects, where there is a possibility that the placebo implants could have been responsible, only events more common in the carmustine implant group are listed. These adverse events were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.
Common Adverse Events in ≥4% of Patients Receiving carmustine implant at Recurrent Surgery:
Common: Anaemia
Very common: Healing abnormal
Common: Hyponatraemia
Very common: Convulsion, hemiplegia, headache, somnolence, confusion
Common: Aphasia, stupor, brain oedema, intracranial hypertension, meningitis or abscess
Common: Deep thrombophlebitis, Pulmonary embolism
Common: Pneumonia
Common: Nausea, nausea and vomiting, oral moniliasis
Common: Rash
Very common: Urinary tract infection
Very common: Fever
Common: Infection, pain
The following adverse events, not listed in the table above, were reported in less than 4% but at least 1% of patients treated with carmustine implant in all studies. The events listed were either not present pre-operatively or worsened post-operatively. Whether carmustine implant caused these events cannot be determined.
Common Adverse Events in 1% to 4% of Patients Receiving carmustine implant:
Common: Thrombocytopenia, leukocytosis
Common: Hyponatraemia, hyperglycaemia, hypokalaemia
Common: Hydrocephalus, depression, abnormal thinking, ataxia, dizziness, insomnia, hemiplegia, coma, amnesia, diplopia, paranoid reaction
Uncommon: Cerebral haemorrhage, cerebral infarct
Common: Visual defect, eye pain
Common: Hypertension, hypotension
Common: Infection, aspiration pneumonia
Common: Diarrhoea, constipation, dysphagia, gastrointestinal haemorrhage, faecal incontinence
Common: Rash
Common: Infection
Common: Urinary incontinence
Common: Peripheral oedema, neck pain, accidental injury, back pain, allergic reaction, asthenia, chest pain, sepsis
The following four categories of adverse events are possibly related to treatment with carmustine implant.
In the initial surgery trial, the incidence of seizures within the first 5 days after implantation was 2.5% in the carmustine implant group.
In the surgery for recurrent disease trial, the incidence of post-operative seizures was 19% in patients receiving carmustine implant. 12/22 (54%) of patients treated with carmustine implant experienced the first new or worsened seizure within the first five post-operative days. The median time to onset of the first new or worsened post-operative seizure was 3.5 days in patients treated with carmustine implant.
Development of brain oedema with mass effect (due to tumour recurrence, intracranial infection, or necrosis) may necessitate re-operation and, in some cases, removal of carmustine implant or its remnants.
The following healing abnormalities have been reported in clinical trials of carmustine implant: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak.
In the initial surgery trial, cerebrospinal fluid leaks occurred in 5% of carmustine implant recipients. During surgery, a water-tight dural closure should be obtained to minimise the risk of cerebrospinal fluid leak.
In the initial surgery trial, the incidence of brain abscess or meningitis was 5% in patients treated with carmustine implant.
In the recurrent setting, the incidence of brain abscess or meningitis was 4% in patients treated with carmustine implant.
In a published clinical study, cyst formation after carmustine implant treatment has been reported. This reaction occurred in 10% of the patients observed in the study, however, the formation of cysts is possible after resection of a malignant glioma.
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