This information is intended for use by health professionals

1. Name of the medicinal product

Carmustine Obvius 100 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 100 mg carmustine.

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

Excipient with known effect

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for concentrate for solution for infusion.

Powder: white to almost white powder or lyophilisate.

Solvent: colourless clear liquid.

The pH and osmolarity of ready-to-use solutions for infusion are:

pH 4.0 to 5.0 and 385-397mOsm/l (if diluted in glucose 50 mg/ml [5%] solution for injection), and

pH 4.0 to 6.8 and 370-378mOsm/l (if diluted in sodium chloride 9 mg/ml [0.9%] solution for injection).

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Carmustine Obvius 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 Obvius 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 daily infusions such as 75 to 100 mg/m2 on two successive days.

When Carmustine Obvius 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 Obvius 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 haematologic toxicity.

Doses subsequent to the initial dose should be adjusted according to the haematologic 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:

Table 1

Nadir after prior dose

Percentage of prior dose to be given

Leucocytes/mm3

Platelets/mm3

>4,000

>100,000

100%

3,000 – 3,999

75,000 - 99,999

100%

2,000 – 2,999

25,000 - 74,999

70%

<2,000

<25,000

50%

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.

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

Renal impairment

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

Method of administration

Carmustine Obvius 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. Reconstitution and dilution, as recommended, results in a clear, colourless to light yellow stock solution which has to be further diluted with 500 ml 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 administered 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, 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.

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.

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

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, see Table 1, section 4.2. Liver, kidney and lung function should be checked and monitored regularly during therapy (see section 4.8). Repeat doses of Carmustine Obvius should not to 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.

This medicinal product contains 0.57 vol% ethanol (alcohol), i.e. up to 7.62 g per dose, equivalent to 11.2 ml beer or 4.65 ml wine per dose. Harmful for those suffering from alcoholism. To be taken into account in high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines, and may impair your ability to drive or use machines.

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. If Carmustine Obvius is used during pregnancy, or if the patient becomes pregnant while taking (receiving) Carmustine Obvius, 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 Obvius 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

Carmustine Obvius 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:

MedDRA system organ class

Frequency

Adverse reactions

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

Acute leukaemia, bone marrow dysplasia - following long-term use.

Blood and lymphatic system disorders

Very common

Myelosuppression.

Common

Anaemia.

Nervous system disorders

Very common

Ataxia, dizziness, headache.

Common

Encephalopathy (high-dose therapy and dose-limiting).

Not known

Muscular pain, status epilepticus, seizure, grand mal seizure.

Eye disorders

Very common

Ocular toxicities, transient conjunctival flushing and blurred vision due to retinal haemorrhages.

Cardiac disorders

Very common

Hypotension, due to the alcohol content of the solvent (high-dose therapy).

Vascular disorders

Very common

Phlebitis.

Rare

Veno-occlusive disease (high-dose therapy).

Respiratory, thoracic and mediastinal disorders

Very common

Pulmonary toxicity, interstitial fibrosis (with prolonged therapy and cumulative dose)

Pneumonitis.

Rare

Interstitial fibrosis (with lower doses).

Gastrointestinal disorders

Very common

Emetogenic potential.

Nausea and vomiting - severe

Common

Anorexia, constipation, diarrhoea, stomatitis.

Hepatobiliary disorders

Common

Hepatotoxicity, reversible, delayed up to 60 days after administration (high-dose therapy and dose-limiting), manifested by:

- bilirubin, reversible increase

- alkaline phosphatase, reversible increase

- SGOT, reversible increase.

Skin and subcutaneous tissue disorders

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

Renal and urinary disorders

Rare

Renal toxicity.

Reproductive system and breast disorders

Rare

Gynecomastia.

Not known

Infertility, teratogenesis.

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 national reporting system listed in Appendix V.

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

Carmustine Obvius 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 α is 1-4 minutes and the half-life β 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. Pharmaceutical particulars
6.1 List of excipients

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 and dilution

After reconstitution and dilution, the solution should be administered within 3 hours after reconstitution and dilution of the product. The solution should be protected from light until end of administration.

6.4 Special precautions for storage

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

Keep the vial and ampoule 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

Powder

Brown type I hydrolytic glass vial (50 ml) with light grey 20 mm bromobutyl rubber stopper and sealed with a dark red aluminium flip-off cap.

Solvent

Clear type I glass ampoule (5 ml).

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

6.6 Special precautions for disposal and other handling

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 more heavy and lumpy 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 and every vial in the carton. For verification, hold the vial in bright light.

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

Dissolve the Carmustine (100 mg powder) with 3 ml of the 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 27 ml of sterile water for injection to the alcohol solution. The 30 ml stock solution needs to be mixed thoroughly. Reconstitution, as recommended, results in a clear, colourless to light yellow stock solution.

The 30 ml stock solution is to be diluted immediately by adding the 30 ml stock solution to either 500 ml 5% glucose or 500 ml sodium chloride 9 mg/ml (0.9%) solution for injection in glass containers. The 530 ml 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 and administration should be finalised within 3 hours from reconstitution of the product.

Administration of the infusion should be performed using a PVC free PE infusion set. During administration of the medicinal product, the container shall be of suitable glass ware. Further, the ready-to-use solution 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 20-22°C as Carmustine degrades faster at higher temperatures.

Infusion of Carmustine Obvius 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.

7. Marketing authorisation holder

Obvius Investment B.V. De

Cuserstraat 93

1081 CN Amsterdam

The Netherlands

8. Marketing authorisation number(s)

EU/1/18/1278/001

9. Date of first authorisation/renewal of the authorisation

19.07.2018

10. Date of revision of the text