Carmustine 100 mg powder and solvent for concentrate for solution for infusion

Carmustine is indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following:

• brain tumours - glioblastoma, medulloblastoma, astrocytoma and metastatic brain tumours.

• multiple myeloma - in combination with glucocorticoid such as prednisone.

• secondary therapy for Hodgkin's disease, non-Hodgkin's lymphoma,

• as conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPCT) in malignant haematological diseases (Hodgkin's disease / Non-hodgkin's lymphoma)

• tumours of the GI tract

• malignant melanoma when used in combination with other antineoplastic drugs.

Adults:

Posology of intravenous administration:

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 two daily injections 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 accordingly.

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 hematologic toxicity.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose in both monotherapy as well as in combination therapy with other myelosuppressive medicinal products. The following schedule is suggested as a guide to dosage adjustment:

Conditioning treatment prior to SCT

Carmustine is administered in combination with other chemotherapeutic agents in patients with malignant haematologic diseases before SCT at an intravenous dose of 300 - 600 mg/m².

Special patient 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 patients:

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 of concomitant disease or other drug therapy.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

In elderly patients the incidence of stomatitis (oral mucositis) is higher when high dose of carmustine is administered.

Method of administration:

For intravenous use.

Carmustine is given as a slow intravenous infusion. Carmustine should not be administered as a rapid intravenous injection.

For instructions on handling and reconstitution of the medicinal product prior to use, see section 6.6.

Carmustine is given as an intravenous infusion over 1-2 hours after the prescribed dilution protected from light.

The time of infusion should not be less than one hour otherwise it leads to burning and pain at the injected area.

There is no general limit to the duration of use of carmustine therapy. In case the tumour remains incurable or some serious or intolerable side effects appear, the carmustine therapy must be terminated.

Carmustine should not be given to individuals who:

• have demonstrated a previous hypersensitivity to the active substance (carmustine), to other nitrosoureas or to any of the excipients

• suffer from decreased circulating platelets, leucocytes or erythrocytes either from previous chemotherapy or other causes.

• higher degree of renal impairment,

• Pregnancy and lactation (see section 4.6),

• Children and adolescents.

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, haemoglobin, 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.

Ethanol

A dose of 200 mg/m² of this medicine administered to an adult weighing 70 kg will result in exposure to 123.4 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 20.57 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. Co- administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects. Because this medicine is usually given slowly over 1-2 hours, the effects of alcohol may be reduced.

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 tumours 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 follow-up. The risk-benefit ratio of carmustine therapy must be carefully weighed because of the high risk of pulmonary toxicity.

An increased risk of pulmonary toxicities has been reported with conditioning regimens and SCT in women. To date, this increased risk has been described for the treatment itself, including the conditioning regimen without carmustine (e.g. TBI or busulfan-cyclophosphamide) or with carmustine (BEAM: carmustine, etoposide, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide).

High-dose therapy with carmustine (especially at 600 mg/m²) prior to hematopoietic 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, the use of carmustine must be weighed against the risks.

Renal Toxicity

Renal changes with decrease in renal size, progressive azotaemia, 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 (hypokalaemia, hypomagnesemia and hypophosphatemia).

Comorbidities and poor disease status

Patients with comorbidities and worse 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.

In combination with:

• phenytoin – reduced activity of antiepileptic medicinal products must be reckoned in the concomitant use with chemotherapeutic medicinal products

• cimetidine – the concomitant use leads to delayed, major, suspected, increased carmustine toxic effect (due to the inhibition of carmustine metabolism)

• digoxin – the concomitant use leads to delayed, moderate, suspected, decreased effect of digoxin (due to the decreased digoxin absorption)

• melphalan – the concomitant use leads to increased risk of pulmonary toxicity

Carmustine should not normally be administered to patients who are pregnant or mothers who are breast-feeding. Male patients should be advised to use adequate contraceptive measures during the treatment with carmustine for at least 6 months.

Pregnancy

Safe use in pregnancy has not been established and therefore the benefit to risk of toxicity must be carefully weighed. Carmustine is embryotoxic in rats and rabbits and teratogenic in rats when given in doses equivalent to the human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.

Breast-feeding

It is not known whether carmustine or its metabolites excrete in the mother's milk. Breast-feeding should not be permitted during the treatment.

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.

The table includes adverse events 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 event rates observed may not reflect the rates observed in clinical practice. Adverse events 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 events are included if the incidence is > 5% higher in the treatment group.

High dose is defined as >200 mg/m².

The following table includes adverse effects of carmustine divided by groups according to MedDRA terminology with frequency of occurrence: 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):

¹Pulmonary toxicity is also manifested as pneumonitis and interstitial lung disease in post-marketing experience.

Reporting of suspected adverse reactions

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 Yellow Card Scheme at http://www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

The main symptom of intoxication is myelosuppression. In addition, the following serious side effects may occur:

Liver necrosis, interstitial pneumonitis, encephalomyelitis.

A specialized antidote is not available.

Pharmacotherapeutic Group: Antineoplastic medicine, alkylating agents, nitrosoureas ATC-Code: L01AD01.

Carmustine alkylates DNA and RNA, has also been shown to inhibit several enzymes by carbamoylation of amino acids in proteins. It is thought that the antineoplastic and toxic activities of Carmustine may be due to metabolites.

Distribution

Intravenously administered Carmustine is rapidly degraded, with no drug intact detectable after 15 minutes. Because of the good lipid solubility and the lack of ionization at the physiological pH, Carmustine is very well transferred through the blood-brain barrier. Levels of radioactivity in the CSF are at least 50% higher than those measured concurrently in plasma.

The kinetic of carmustine in humans is characterized by a two-chamber model. After the intravenous infusion over 1 hour, the carmustine-plasma level drops in a biphasic manner. The half-life α accounts to 1-4 minutes and the half-life β accounts to 18-69 minutes.

Biotransformation

It is presumed that the metabolites of carmustine causes its antineoplastic and toxic activity.

Elimination

Approximately 60-70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO₂. The fate of remainder is undetermined.

Carmustine was embryotoxic and teratogenic in rats and embryotoxic in rabbits at dose levels equivalent to the human dose. Carmustine affected the fertility of male rats at doses higher than the human dose. Carmustine, at clinically relevant dose levels, was carcinogenic in rats and mice.

Powder

No excipients

Solvent

Ethanol, anhydrous

The solution for infusion is unstable in polyvinyl chloride (PVC) containers. The carmustine solution can be administered from glass bottles or polypropylene container only, using PVC-free infusion set.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial

2 years

After reconstitution and dilution

After reconstitution as recommended, Carmustine is stable up to 24 hrs at refrigerator (2°C - 8°C) and protected from light.

The reconstituted solution should be further admixed with 500 mL of sodium chloride (0.9%) solution or 500 mL glucose (5%) solution. These solutions are stable up to 4 hours at room temperature (20°C-25°C) protected from light and also at 24 hrs at 2°C -8°C protected from light.

From a microbial point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Store and transport refrigerated (2°C – 8°C).

For storage conditions after reconstitution and further dilution of the medicinal product, see section 6.3

Powder: Type I amber glass vial (30 ml) stoppered with bromobutyl rubber stopper and sealed with an aluminium flip off seal having polypropylene disc.

Solvent: Type I clear glass vial (5 ml) stoppered with bromobutyl rubber stopper and sealed with an aluminium flip off seal having polypropylene disc.

One pack contains one vial with 100 mg of powder for concentrate for solution for infusion and one vial with 3 ml solvent.

The medicinal product contains no preservative and is not intended as multiple dose vial. Reconstitution and further dilutions should be carried out under aseptic conditions.

The storage of carmustine at 27°C or higher temperature can lead to liquefaction of the substance, since carmustine has a low melting point (ca. 30.5°C to 32.0°C). An indication of the decomposition is the appearance of an oil film at the bottom of the vial, visible when the vial is held in bright light. This medicine should not be used any further. There can be physical appearances of sharp flakes in the unopened vial as far as rigid mass, however without any decomposition of carmustine.

Reconstitution and dilution for each vial of the powder for concentrate for solution for infusion

Dissolve carmustine (100 mg powder) with 3 ml of the supplied sterile refrigerated ethanol solvent in the primary packaging. Carmustine must be completely dissolved in ethanol before sterile water for injection is added. The dissolution of the powder could take up to 2 minutes. Then aseptically add 27 ml of sterile water for injection to the alcohol solution. The 30 ml stock solution needs to be mixed thoroughly.

Each ml of the reconstituted stock solution will contain 3.3 mg of carmustine in 10 % ethanol and have a pH of 4.0 to 6.8.

Reconstitution, as recommended, results in a clear colourless to yellowish solution.

The 30 ml stock solution is to be diluted immediately by adding the 30 ml stock solution to either 500 ml sodium chloride 9 mg/ml (0.9 %) solution for injection, or 500 ml 5 % glucose solution for injection.

The ready-to-use solution should be administered over 1-2 hours.

Infusion of Carmustine in less than one hour may produce intense pain and burning at the site of injection (see section 4.2).

Guidelines for the safe handling and disposal of antineoplastic agents must be observed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.