BICARLOG 300 MG POWDER AND SOLVENT FOR CONCENTRATE FOR SOLUTION FOR INFUSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bicarlog 300 mg powder and solvent for concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder for concentrate for solution for infusion contains 300 mg carmustine.

Each vial of solvent contains 9 ml ethanol anhydrous (equivalent to7.11 g).

After reconstitution and dilution (see section 6.6), one mL of solution contains 3.3 mg carmustine.

Excipient with known effect

Solvent vial contains ethanol anhydrous.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder and solvent for concentrate for solution for infusion.

Powder: Pale yellow dry flakes or dry congealed mass.

Solvent: Clear, colourless solution.

The pH and osmolality of diluted ready-to-use solutions for infusion are pH: 3.2 to 7.0 diluted in normal saline or 5% glucose solution for injection. Osmolality: 340 to 400 mOsmol/l (diluted in glucose 50 mg/ml [5%] solution for injection or sodium chloride 9 mg/ml [0.9%] solution for injection).

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Bicarlog is indicated, in combination with other chemotherapy medicinal products with or without total body irradiation (TBI), as conditioning treatment prior to autologous haematopoietic progenitor cell transplantation (HPCT) in Lymphomas (Hodgkin’s disease and Non-Hodgkin’s lym­phoma).

4.2 Posology and method of administration

Bicarlog administration must be supervised by a physician experienced in conditioning treatment prior to haematopoietic progenitor cell transplantation.

Posology

Bicarlog is administered in combination with other chemotherapeutic medicinal products, prior to autologous HPCT at a dose of 300 mg/m2 to 600 mg/m2 intravenously.

Special , populations

Paediatric population

Bicarlog is contraindicated in children and adolescents aged <18 years (see section 4.3).

Elderly

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 take into consideration concomitant disease or therapy with other medicinal products. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and the glomerular filtration rate should be monitored and the dose reduced according to this.

Renal impairment

For patients with renal impairment the dose of Bicarlog should be reduced if the glomerular filtration rate is reduced.

Method of administration

Bicarlog is for intravenous use after reconstitution and further dilution.

After reconstituting the powder with the solvent provided, a stock solution has to be prepared by adding sterile water for injections. Reconstitution and dilution, as recommended, results in a clear, colourless to yellowish stock solution. The stock solution has to be further diluted with sodium chloride 9 mg/ml (0.9%) solution for injection, or glucose 50 mg/ml (5%) solution for injection.

The resulting ready-to-use solution for infusion should then be given immediately by intravenous drip over a one- to two-hour period protected from light. The duration of infusion should not be less than one hour to avoid burning and pain in the injection area. The injected area should be monitored during the administration.

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance, to other nitrosoureas or to any of the excipients listed in section 6.1.

Severe bone marrow depression.

Severe (end-stage) renal impairment.

Children and adolescents

Breast-feeding.

4.4 Special warnings and precautions for use

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.

An increased risk for pulmonary toxicities upon treatment with conditioning regimes and HPCT for females has been reported. So far, this increased risk is described for the treatment itself including conditioning regimes without carmustine (e.g. TBI or busulfan-cyclophosphamide) or with carmustine (BEAM: carmustine, etopside, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide). A direct connection to carmustine can therefore not be stated.

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

Upon high-dose therapy with carmustine, the risk and severity for infections, cardiac, hepatic, gastrointestinal, and renal toxicity, diseases of the nervous system and electrolyte abnormalities (hypokalaemia, hypomagnesemia and hypophosphate­mia) rises.

Patients with comorbidities and worse disease status have a higher risk for adverse events. This needs to be respected especially for elderly patients.

Hepatic and renal function should also be checked prior to treatment and regularly monitored during therapy (see section 4.8).

Neutropenic enterocolitis can occur as therapy-related adverse event upon treatment with chemotherapeutic agents.

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. Liver, kidney and lung function should be checked and monitored regularly during therapy (see section 4.8). The bone marrow toxicity of carmustine is cumulative.

Direct administration of carmustine into the carotid artery is regarded as experimental and has been associated with ocular toxicity.

A dose of 600 mg/m2 of this medicine administered to an adult weighing 70 kg would result in exposure to 370 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 61.7 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 6 hours, the effects of alcohol may be reduced.

4.5 Interaction with other medicinal products and other forms of interaction

Phenytoin and dexamethasone

In combination with chemotherapeutic medicinal products reduced activity of antiepileptic medicinal products must be anticipated.

Cimetidine

Concomitant use with cimetidine leads to delayed, major, suspected, increased carmustine toxic effect (due to the inhibition of carmustine metabolism).

Digoxin

Concomitant use with digoxin leads to delayed, moderate, suspected, decreased effect of digoxin (due to the decreased digoxin absorption).

Melphalan

Concomitant use with melphalan leads to increased risk of pulmonary toxicity.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/con­traception in males and females 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.

Pregnancy

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 (see section 5.3). If Bicarlog is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Bicarlog, the patient should be apprised of the potential hazard to the foetus.

Breast-feeding

It is unknown whether carmustine/me­tabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Bicarlog is contraindicated during breast-feeding and up to seven days post-treatment (see section 4.3).

Fertility

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.

4.7 Effects on ability to drive and use machines

Bicarlog 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.

4.8 Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

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:

* An increased risk for pulmonary toxicities upon treatment with conditioning regimes and HPCT for females has been reported. So far, this increased risk is described for the treatment itself including conditioning regimes without carmustine (e.g. TBI or busulfan-cyclophosphamide) or with carmustine (BEAM: carmustine, etopside, cytarabine and melphalan or CBV: cyclophosphamide, carmustine and etoposide). A direct connection to carmustine can therefore not be stated.

Description of selected adverse reactions

Myelosuppression

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.

Respiratory, thoracic and mediastinal disorders

Pulmonary fibrosis (with fatal outcome), pulmonary infiltration

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.

Emetogenic potential

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

Renal toxicity is rare, but occurs for cumulative doses < 1,000 mg/m2.

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

4.9 Overdose

The main symptom of intoxication is myelosuppression. In addition, the following serious adverse reactions may occur: liver necrosis, interstitial pneumonitis, encephalomyelitis. A specialized antidote is not available.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, nitrosoureas,

ATC code: L01AD01

Mechanism of action

Carmustine is a cell-cycle phase nonspecific antineoplastic agent of the nitrosourea type, which exerts tumor cytotoxicity via multiple mechanisms. As an alkylating agent, it can alkylate reactive sites on nucleoproteins, thus interfering with DNA and RNA synthesis and DNA repair. It is able to form interstrand crosslinks in DNA, which prevents DNA replication and transcription. In addition, carmustine is known to carbamoylate lysine residues on proteins causing irreversible inactivation of enzymes including glutathione reductase. The carbamoylating activity of carmustine is generally considered less significant than the alkylating activity in its action on tumors, but carbamoylation may serve to inhibit DNA repair.

Pharmacodynamic effects

The antineoplastic and toxic activities of carmustine may be due to its metabolites. Carmustine and related nitrosoureas are unstable in aqueous solutions and degrade spontaneously to reactive intermediates that are capable of alkylation and carbamoylation. The alkylating intermediates are believed to be responsible for the antitumor effect of carmustine. However, opinion is divided over the role of the carbamoylating intermediates as mediators of the biological effects of the nitrosoureas. On one hand, their carbamoylating activity was reported to contribute to the cytotoxic properties of their parent drugs by inhibiting DNA repair enzymes. On the other hand, it has been speculated that the carbamoylating species may mediate some of toxic effects of carmustine.

Carmustine crosses the blood-brain barrier readily because of its lipophilic nature.

Paediatric population

Bicarlog should not be used in children and adolescents due to high risk of pulmonary toxicity.

5.2 Pharmacokinetic properties

Distribution

Intravenously administered carmustine is rapidly degraded, with no substance intact detectable after 15 minutes. Because of the good lipid solubility and the lack of ionisation at the physiological pH, carmustine is very well transferred through the blood-brain barrier. Levels of radioactivity in the cerebrospinal fluid are at least 50% higher than those measured concurrently in plasma. The kinetic of carmustine in humans is characterised by a two-chamber model. After the intravenous infusion over 1 hour, the carmustine-plasma level drops in a biphasic manner. The half-life a is 1–4 minutes and the half-life P is 18–69 minutes.

Biotransformation

It is presumed that the metabolites of carmustine cause 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 the remainder is undetermined.

5.3 Preclinical safety data

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.

6.1

Powder

No excipients.

Solvent

Ethanol, anhydrous.

6.2 Incompatibilities

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.

6.3 Shelf life

Unopened vial 2 years.

After reconstitution (reconstituted stock solution)

Chemical and physical in-use stability of reconstituted stock solution has been demonstrated for 24 hours at 2 to 8°C.

After dilution (solution after dilution for infusion)

Chemical and physical in-use stability of solution after dilution for infusion in sodium chloride solution for injection or 5% glucose solution for injection at final concentration of 0.2 mg/ml and stored in a glass or polypropylene container has been demonstrated for 6 hours at 20 to 25°C, protected from light. These solutions will also remain stable for 24 hours in cold storage (2 to 8 °C) and a further 4 hours at 20 to 25 °C, protected from light.

From a microbiological point of view, unless the method of opening, reconstitution and 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 user.

The solution should be protected from light until the end of administration.

6.4 Special precautions for storage

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

Keep the vials in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

solvent

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

The carmustine powder for concentrate for solution for infusion contains no preservative and is not intended as a multiple dose vial. Reconstitution and further dilutions should be carried out under aseptic conditions.

The dry frozen product does not contain any preservatives and is suitable only for one use. The lyophilisate can appear as a fine powder, however handling can cause it to appear as a heavier and lumpier lyophilisate than as a powdery lyophilisate due to the mechanical instability of the freeze drying cake. The presence of an oily film can be an indication of melting of the medicinal product. Such products are not accepted for use due to the risk of temperature excursions to more than 30°C. This medicinal product should not be used any further. When you are not clear about the fact whether the product is adequately cooled, then you should immediately inspect each vial in the carton. For verification, hold the vial in bright light.

Reconstitution and dilution of the Bicarlog 50 mg powder for concentrate for solution for infusion

Dissolve carmustine (50 mg powder) with 1.5 ml of supplied sterile refrigerated ethanol solvent in the primary packaging (brown glass vial). Carmustine must be completely dissolved in ethanol before sterile water for injections is added. Then aseptically add 13.5 ml of sterile water for injection to the alcohol solution. The 15 ml stock solution needs to be mixed thoroughly.

One ml of the reconstituted stock solution contains 3.3 mg carmustine in 10% ethanol. Reconstitution, as recommended, results in a clear, colourless to yellowish stock solution, which should be further diluted immediately to either 250 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection to get final concentration of 0.2 mg/ml. The diluted solution (i.e. the ready-to-use solution) should be mixed for at least 10 seconds before administration. The Ready-to-Use solution should be administered over 1–2 hours.

Reconstitution and dilution of Bicarlog 300 mg powder for concentrate for solution for infusion

Dissolve carmustine (300 mg powder) with 9 ml of supplied sterile refrigerated ethanol solvent in the primary packaging (brown glass vial). Carmustine must be completely dissolved in ethanol before sterile water for injections is added. Then aseptically add 81 ml of sterile water for injection to the alcohol solution. The 90 ml stock solution needs to be mixed thoroughly.

One ml of the reconstituted stock solution contains 3.3 mg carmustine in 10% ethanol. Reconstitution, as recommended, results in a clear, colourless to yellowish stock solution, which should be further diluted immediately to either 1500 ml sodium chloride 9 mg/ml (0.9%) solution for injection or 5% glucose solution for injection to get final concentration of 0.2 mg/ml. The diluted solution (i.e. the ready-to-use solution) should be mixed for at least 10 seconds before administration. The Ready-to-Use solution should be administered over 1–2 hours.

Administration of the infusion should be performed using a PVC free PE infusion set. During administration of the medicinal product, the glass or polypropylene container shall be used. Further, the ready-to-use solution needs to be protected from light (e.g. using alu-foil wrapped around the container of the ready-to-use solution) and preferably kept at temperatures below 20–25°C as Carmustine degrades faster at higher temperatures.

Infusion of Bicarlog 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.

Accord Healthcare Limited Sage House, 319 Pinner Road, North Harrow, Middlesex HA14HF, United Kingdom