Carmustine

Carmustine is a cell-cycle phase-nonspecific nitrosourea. In aqueous solution it breaks down spontaneously into reactive intermediates that alkylate and carbamoylate, and its antitumour and toxic activity is thought to come from these breakdown products. It is lipophilic and not ionised at physiological pH, so it crosses the blood–brain barrier readily.

Mechanism of Action

• Alkylation: carmustine alkylates reactive sites on nucleoproteins, which interferes with DNA and RNA synthesis and with DNA repair. It forms interstrand cross-links in DNA that prevent replication and transcription.
• Carbamoylation: it also carbamoylates lysine residues on proteins and irreversibly inactivates enzymes such as glutathione reductase. The SmPC regards this as less important than alkylation for the antitumour effect, but it may help to inhibit DNA repair.
• Reactive intermediates: the alkylating intermediates are believed to produce the antitumour effect. Opinion is divided on the carbamoylating ones: they may add to cytotoxicity by blocking DNA repair enzymes, or they may mediate some of the toxic effects.

Pharmacokinetics

• Distribution: after intravenous infusion carmustine is degraded rapidly, and no intact drug is detectable after 15 minutes. Its good lipid solubility and lack of ionisation let it cross the blood–brain barrier; radioactivity in cerebrospinal fluid is at least 50% higher than in plasma measured at the same time. After a 1-hour infusion plasma levels fall in two phases (α half-life 1–4 minutes, β half-life 18–69 minutes). DrugBank gives plasma protein binding of about 80%.
• Metabolism: the metabolites are presumed to be responsible for the antineoplastic and toxic activity. DrugBank describes rapid hepatic metabolism to active metabolites that can persist in plasma for several days.
• Elimination: about 60–70% of a dose is excreted in the urine within 96 hours and about 10% as respiratory carbon dioxide; the fate of the remainder is undetermined.
• Special populations: the SmPC gives no pharmacokinetic data for special populations; for elderly patients and renal impairment it advises dose adjustment (see Administration and Dosage).

Carmustine is indicated in adults, as a single agent or in combination with other antineoplastic agents and/or other therapeutic measures (radiotherapy, surgery), in the following malignant neoplasms:

• Brain tumours: glioblastoma, brain-stem gliomas, medulloblastoma, astrocytoma and ependymoma; brain metastases.
• Lymphomas: secondary therapy in non-Hodgkin’s lymphoma and Hodgkin’s disease.
• Gastrointestinal tract: tumours of the gastrointestinal tract.
• Malignant melanoma: in combination with other antineoplastic medicinal products.
• Conditioning before transplantation: conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPCT) in malignant haematological diseases (Hodgkin’s disease and non-Hodgkin’s lymphoma).

• Hypersensitivity to carmustine, to other nitrosoureas or to any of the excipients.
• Severe bone marrow depression.
• Severe (end-stage) renal impairment.
• Children and adolescents under 18 years.
• Breastfeeding, which includes the period up to seven days after treatment.

The SmPC table lists reactions seen during treatment, not all of which are proven to be caused by carmustine, and rates seen in trials may differ from clinical practice. Bone marrow toxicity is common and severe, and pulmonary toxicity and severe nausea and vomiting are also very common.

Very common (≥1/10): myelosuppression; ataxia, dizziness, headache; ocular toxicity (transient conjunctival flushing and blurred vision due to retinal haemorrhages); hypotension (from the alcohol content of the solvent, with high-dose therapy); phlebitis; pulmonary toxicity and interstitial fibrosis (with prolonged therapy and cumulative dose); pneumonitis; severe nausea and vomiting (high emetogenic potential); dermatitis with topical use and transient skin hyperpigmentation on accidental skin contact.

Common (≥1/100 to <1/10): acute leukaemia and bone marrow dysplasia after long-term use; anaemia; encephalopathy (high-dose therapy, dose-limiting); anorexia, constipation, diarrhoea, stomatitis; reversible hepatotoxicity, delayed by up to 60 days after administration (high-dose therapy, dose-limiting), shown by reversible rises in bilirubin, alkaline phosphatase and SGOT; alopecia; flushing (from the alcohol content of the solvent, more likely when the infusion lasts under 1–2 hours); injection site reaction.

Rare (≥1/10,000 to <1/1,000): veno-occlusive disease (high-dose therapy); interstitial fibrosis (with lower doses); renal toxicity; gynaecomastia.

Not known: opportunistic infections (including fatal); muscular pain, status epilepticus, seizure, grand mal seizure; tachycardia; electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypophosphataemia); infertility and teratogenesis; extravasation hazard (carmustine is a vesicant).

Myelosuppression begins 7–14 days after a dose, with recovery at 42–56 days; it depends on the dose and the cumulative dose and is often biphasic. Pulmonary toxicity has been seen in up to 30% of patients, with some fatal cases of infiltrates or fibrosis; fibrosis up to 17 years after treatment in childhood has been described. Pneumonitis is seen at doses above 450 mg/m², and interstitial lung disease with prolonged therapy and cumulative doses above 1,400 mg/m². Nausea and vomiting start within 2–4 hours of the dose and last 4–6 hours; the emetogenic potential is high above 250 mg/m² and high to moderate at 250 mg/m² or less.

• Phenytoin and dexamethasone: in combination with chemotherapy, a reduced activity of antiepileptic medicines must be anticipated.
• Cimetidine: concomitant use is suspected to increase carmustine toxicity (delayed onset, rated major) because cimetidine inhibits carmustine metabolism.
• Digoxin: concomitant use is suspected to reduce the effect of digoxin (delayed onset, rated moderate) by decreasing its absorption.
• Melphalan: increases the risk of pulmonary toxicity.
• Other myelosuppressive medicines: the carmustine dose is adjusted to the patient’s blood counts when it is combined with them.
• Lung-toxic agents and thoracic irradiation: other agents that damage the lung, and sequential or concomitant chest radiotherapy, add to the risk of pulmonary toxicity.
• Medicines containing ethanol or propylene glycol: may lead to accumulation of ethanol and adverse effects.
• Echinacea: DrugBank advises avoiding it.

Carmustine medac must be administered only by specialists experienced in chemotherapy and under appropriate medical supervision. It is given intravenously after reconstitution and further dilution.

Recommended Dose

• Single agent in previously untreated patients: 150–200 mg/m² intravenously every 6 weeks. This may be given as one dose or divided into daily infusions, for example 75–100 mg/m² on two successive days.
• With other myelosuppressive medicines, or when bone marrow reserve is depleted: adjust the dose to the patient’s haematological profile (see below).
• Conditioning before autologous HPCT: 300–600 mg/m² intravenously, in combination with other chemotherapeutic agents, in patients with malignant haematological diseases.
• Duration: the SmPC sets no limit on how long carmustine may be given. Treatment must be stopped if the tumour remains incurable or serious or intolerable adverse reactions occur.

Repeat Courses and Dose Adjustment

A repeat course is not given until circulating blood elements have recovered (platelets above 100,000/mm³ and leucocytes above 4,000/mm³), which usually takes six weeks. Blood counts are checked frequently, and courses are not repeated before six weeks because of delayed haematological toxicity. Each dose after the first follows the lowest counts (nadir) after the previous dose, in monotherapy and in combination with other myelosuppressive medicines:

• Leucocytes above 4,000/mm³ and platelets above 100,000/mm³: 100% of the prior dose.
• Leucocytes 3,000–3,999/mm³ and platelets 75,000–99,999/mm³: 100%.
• Leucocytes 2,000–2,999/mm³ and platelets 25,000–74,999/mm³: 70%.
• Leucocytes below 2,000/mm³ and platelets below 25,000/mm³: 50%.

If the leucocyte and platelet nadirs fall in different rows, the row with the lowest percentage applies (for example, platelets below 25,000/mm³ means at most 50% of the prior dose).

Preparation and Infusion

• Reconstitute the powder with the solvent supplied, then add a further 27 mL of water for injections. This gives a clear, colourless to light yellow stock solution, which is diluted further in 500 mL of sodium chloride 9 mg/mL (0.9%) or glucose 50 mg/mL (5%) solution for injection.
• Give the ready-to-use solution immediately as an intravenous drip over one to two hours, protected from light. An infusion shorter than one hour causes burning and pain in the injected area, which is watched during administration.
• The SmPC (section 6.6) holds the full reconstitution and dilution instructions.

Special Populations

• Children and adolescents: contraindicated under 18 years.
• Elderly: choose the dose cautiously, usually starting at the low end of the range, because decreased hepatic, renal or cardiac function and concomitant diseases or medicines are more frequent. Monitor the glomerular filtration rate and reduce the dose accordingly.
• Renal impairment: reduce the dose if the glomerular filtration rate is reduced. Severe (end-stage) renal impairment is a contraindication.
• Hepatic impairment: the SmPC gives no dose recommendation; liver function is checked before and regularly during treatment.

Pulmonary Toxicity

Pulmonary infiltrates and/or fibrosis have been reported in up to 30% of patients, sometimes within 3 years of treatment. The risk is dose-related, and cumulative doses of 1,200–1,500 mg/m² make lung fibrosis more likely. Other risk factors are smoking, a respiratory condition, pre-existing radiographic abnormalities, thoracic irradiation and other agents that damage the lung. A baseline pulmonary function test and chest X-ray are done before treatment, with frequent pulmonary function tests during it. A baseline forced vital capacity or carbon monoxide diffusing capacity (DLCO) below 70% of the predicted value carries a particular risk. Women have a higher risk of pulmonary toxicity with conditioning regimens before HPCT, and high-dose carmustine (especially 600 mg/m²) increases its incidence and severity, so the benefit is weighed against the risk in patients with other risk factors.

Bone Marrow Toxicity

Bone marrow toxicity is common, severe and cumulative. A complete blood count is checked frequently for at least six weeks after a dose, the next dose is based on the nadir counts, and repeat doses are not given more often than every six weeks.

High-Dose Therapy and Organ Function

With high-dose carmustine the risk and severity of infections, cardiac, hepatic, gastrointestinal and renal toxicity, nervous system disease and electrolyte abnormalities (hypokalaemia, hypomagnesaemia, hypophosphataemia) rise. Patients with comorbidities and a worse disease status, especially elderly patients, are at higher risk. Liver, kidney and lung function are checked before treatment and monitored regularly. Neutropenic enterocolitis can occur with chemotherapy.

Carcinogenicity and Administration Route

Carmustine is carcinogenic in rats and mice at doses below the recommended human dose per body surface area, and acute leukaemia and bone marrow dysplasia are reported after long-term use. Direct administration into the carotid artery is regarded as experimental and has been associated with ocular toxicity.

Ethanol Content

Each solvent ampoule contains 3 mL of anhydrous ethanol (2.37 g). A 600 mg/m² dose in a 70 kg adult would give an ethanol exposure of about 370 mg/kg, which may raise the blood alcohol concentration by about 61.7 mg/100 mL; for comparison, a glass of wine or 500 mL of beer gives about 50 mg/100 mL. The alcohol can cause hypotension and flushing (see Side Effects) and may impair the ability to drive.

Pregnancy, Breastfeeding and Fertility

• Contraception: women should use effective contraception to avoid pregnancy during treatment and for at least 6 months afterwards, and men should be advised to use adequate contraceptive measures for the same period.
• Pregnancy: carmustine should not be given to pregnant patients. Safe use in pregnancy has not been established, so benefit must be weighed carefully against the risk of toxicity. It is embryotoxic in rats and rabbits and teratogenic in rats at doses equivalent to the human dose. A patient who is or becomes pregnant during treatment must be told of the potential hazard to the foetus.
• Breastfeeding: contraindicated during treatment and for up to seven days afterwards; excretion into human milk is unknown.
• Fertility: carmustine may impair male fertility. Men should be told of the risk of infertility and seek fertility or family-planning counselling before treatment.

Effect on Driving

Carmustine medac has no or negligible influence on the ability to drive and use machines. The alcohol in the solvent may, however, impair it.

Store and transport refrigerated at 2–8 °C. The SmPC requires refrigeration during transport as well as storage, so the cold chain must stay unbroken until the product reaches the administering hospital. Keep the vial and the solvent ampoule in the outer carton to protect them from light. For the reconstituted and diluted solution, see Shelf Life.

• Unopened vial: 3 years.
• After reconstitution and dilution: administer within 3 hours, protecting the solution from light until the end of administration.

Prescription only (Rx): a medicinal product subject to restricted medical prescription. Carmustine medac is given as an intravenous infusion by specialists experienced in chemotherapy under appropriate medical supervision, so it is supplied to the hospital or clinic that administers it, with refrigerated (2–8 °C) transport. One pack holds one vial of 100 mg powder and one ampoule of 3 mL solvent.