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

Each vial of powder for concentrate for solution for infusion contains 100 mg carmustine.

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

Excipient with known effect

Each vial of solvent contains 3 ml ethanol anhydrous (that is equivalent to 2.37 g).

For full list of excipients, see section 6.1.

Powder and solvent for concentrate for solution for infusion.

Powder: lyophilized pale yellow flakes or congealed mass.

Solvent: colourless clear liquid.

The pH of ready-to-use solutions for infusion is 4.0 to 6.8.

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

• Brain tumours (glioblastoma, Brain-stem gliomas, medulloblastoma, astrocytoma and ependymoma), brain metastases;

• Secondary therapy in non-Hodgkin's lymphoma and Hodgkin's disease;

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

• Multiple myeloma – in combination with glucocorticoid such as prednisone.

Carmustine Waymade must be administered only by specialists experienced in the field of chemotherapy and under appropriate medical supervision.

Posology:

Initial doses

The recommended dose of Carmustine Waymade 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 Waymade is used in combination with other myelosuppressive medicinal products or in patients in whom bone marrow reserve is depleted, the doses should be adjusted according to the haematologic profile of the patient as shown below.

Monitoring and subsequent doses

A repeat course of Carmustine Waymade 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:

In cases where the nadir after initial dose does not fall in the same row for leucocytes and platelets (e.g. leucocytes >4,000 and platelets <25,000) the value given the lowest percentage of prior dose should be used (e.g. platelets <25,000 then a maximum of 50% of prior dose should be given).

There are no limits for the period of application of carmustine therapy. In case the tumor remains incurable or some serious or intolerable adverse reactions appear, the carmustine therapy must be terminated.

Conditioning treatment prior to HPCT

Carmustine is given in combination with other chemotherapeutic agents in patients with malignant haematological diseases before HPCT at a dose of 300 - 600 mg/m² intravenously.

Special populations:

Paediatric population

Carmustine 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 glomerular filtration rate should be monitored and the dose reduced according to this.

Renal impairment

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

Method of administration

Carmustine Waymade is for intravenous use after reconstitution and further dilution.

By reconstituting the powder with the solvent provided, a solution has to be prepared by adding additional 27 ml water for injections. The reconstituted solution is a clear, colourless to light yellowish solution. The reconstituted solution has to be further diluted with 500 ml Sodium Chloride 9 mg/ml (0.9%) solution for injection, or Dextrose 50 mg/ml (5%) solution for injection.

The resulting ready-to-use solution for infusion should then be administered immediately by intravenous drip over a one to two hours period protected from light. The duration of infusion should not be less than one hour, otherwise it leads to burning and pain in the injected 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.

Hypersensitivity to the active substance 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.

Pulmonary toxicity characterized 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 1200-1500 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).

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 (hypokalemia, 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 (see section 5.3).

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 decreased number of circulating platelets, leucocytes or erythrocytes either from previous chemotherapy or other cause the dose should be adjusted, see Table in section 4.2. Liver, kidney and lung function should be checked and monitored regularly during therapy (see section 4.8).

Repeat doses of Carmustine Waymade should not 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.

A dose of 200 mg/ m2 of this medicine administered to an adult weighing 70 kg will result in exposure to 109.7 mg/kg of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 18.3 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.

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.

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 Carmustine Waymade is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Carmustine Waymade, 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. Carmustine Waymade is contraindicated during breast-feeding. Brest-feeding must not be started during and up to seven days, after 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.

Carmustine Waymade 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.

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 reactions 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 beestimated 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).

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 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 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 agent, nitrosourea, 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

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

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.

Compatibility/ Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride container. The carmustine solution can be administered from the glass bottles or polypropylene container only.

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

Unopened vial

3 Years.

After reconstitution and dilution

After reconstitution as recommended, Carmustine Waymade is stable for 24 hours under refrigeration (2°C - 8°C) in glass container and protected from light.

The reconstituted solution further diluted with either 500 ml of Sodium Chloride 9 mg/ml (0.9%) solution or 500 ml of Dextrose 50 mg/ml (5%) solution in glass or polypropylene container. It should be stored at room temperature, protected from light and utilized within 4 hours. These solutions are also stable for 24 hours under refrigeration (2°C – 8°C) and an additional 6 hours at room temperature and 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 in a refrigerator (2°C – 8°C). Do not freeze.

Keep the powder and solvent 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.

Powder:

Type I amber glass vial (30 ml) with gray 20 mm bromobutyl rubber stopper and sealed with a blue flip-off matte top seal.

Solvent:

Type I clear glass vial (5 ml) with gray 13 mm chlorobutyl rubber stopper and sealed with a blue flip-off matte top seal.

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

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 dry flakes or dry congealed mass. 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 and every vial in the carton. For verification, hold the vial in bright light.

Reconstitution and dilution for infusion

Dissolve the 100 mg lyophilized carmustine powder with 3 ml of the supplied sterile refrigerated ethanol anhydrous solvent provided in the carton. Carmustine must be completely dissolved in ethanol anhydrous before sterile water for injections is added. Then aseptically add 27 ml of sterile water for injections to the alcohol solution. The 30 ml stock solution needs to be mixed thoroughly. Reconstitution, as recommended, results in a clear, colourless to light yellowish solution.

Examine reconstituted vials for crystals formation prior to use. If crystals are observed, they may be re-dissolved by warming the vial to room temperature with agitation. After reconstitution, Carmustine Waymade is stable for 24 hours under refrigeration (2°C – 8°C), stored in a glass container and protected from light.

The reconstituted solution must be further diluted with either 500 ml of Sodium Chloride solution 9 mg/ml (0.9%) or 500 ml of Dextrose 50 mg/ml (5%) solution. The reconstituted and diluted solution (i.e ready-to-use solution) should be mixed for at least 10 seconds before administration. The ready to use solution should be stored at room temperature in a glass or polypropylene container, protected from light and utilized within 4 hours. These solutions are also stable for 24 hours under refrigeration (2°C – 8°C) and an additional 6 hours at room temperature protected from light.

The reconstituted and diluted solution (i.e. ready-to-use solution) must be given intravenously and should be administered by intravenous drip over a one- to two-hour period and administration. Administration of the infusion should be performed using a PVC free PE infusion set or containers. During administration of the medicinal product, the container shall be of suitable glass ware or polypropylene container only. Ensure that the polypropylene containers used are PVC and DEHP free. Carmustine has a low melting point (30.5°C – 32.0°C or 86.9°F – 89.6°F). Exposure of this drug to this temperature or above will cause the drug to liquefy and appears as an oil film on the vials. This is a sign of decomposition and vials should be discarded.

Infusion of Carmustine Waymade over shorter periods of time may produce intense pain and burning at the site of injection. The injected area should be monitored during the administration (see section 4.2).

Guideline 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.

Waymade Plc

Sovereign House

Miles Gray Road

Basildon, Essex, SS14 3FR

United Kingdom

PL 06464/3116

11/11/2021

11/11/2021