SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

BiCNU 100 mg-Powder and solvent for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial of powder contains 100 mg carmustine.

Each vial of solvent contains 3 ml dehydrated alcohol (that is equivalent to 2,37 g). For excipients, see 6.1

3    PHARMACEUTICAL FORM

Powder and solvent for solution for infusion.

Yellowish powder for reconstitution.

Appearance of solution: colorless to light yellow pH: 4.0 to 6.8

The osmolarity of the solution for infusion that is reconstituted with dehydrated ethanol and sterilized water is 15.6 mOsmol/l. The solution for infusion that is diluted with physiological saline or with 5% glucose solution is isotonic with the plasma.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

•    Brain tumors - glioblastoma, medulloblastoma, astrocytoma and metastatic brain tumors.

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

•    Hodgkin’s disease - as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

•    Non-Hodgkin’s lymphomas - as secondary therapy in combination with other approved drugs in patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

4.2 Posology and method of administration

Adults:

Posology of intravenous administration:

The recommended dose of BiCNU 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 BiCNU 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 BiCNU 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:

Nadir after Prior Dose		Percentage of prior dose to be given
Leucocytes/ mm3	Platelets/ mm3
>4000	>100,000	100
3000 - 3999	75,000 - 99,999	100
2000 - 2999	25,000 - 74,999	70
<2000	<25,000	50

Children:

BiCNU should be used with extreme caution in children due to the high risk of pulmonary toxicity (see Warnings).

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 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.

Method of administration:

Following reconstitution (please, see Section 6.6) with sterile diluent (3 ml vial provided) and dilution with water for injection, BiCNU should be administered by intravenous drip over one to two hour period. The time of infusion should not be less than one hour otherwise it leads to burning and pain at the injected area. The injected area should be monitored during the administration.

There are no limits for the period of application of carmustine therapy. In case the tumor remains uncurable or some serious or untolerable side effects appear, the carmustine therapy must be terminated.

4.3 Contraindications

BiCNU 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.

4.4 Special warnings and precautions for use

BiCNU may be administered only by specialists experienced in the field of chemotherapy.

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.

Cases of late pulmonary fibrosis, occurring up to 17 years after treatment have also been reported. In a long-term follow-up of 17 patients who survived childhood brain tumors eight (47%) died of lung fibrosis. Of these eight deaths, two occurred within 3 years of treatment and 6 occurred 8-13 years after treatment. Of the patient who died, the median age at treatment was 2.5 years (range 1-12); the median age of the long survivors was 10 years (5-16 years at treatment). All five patients treated under the age of 5 years have died of pulmonary fibrosis. In this study the dose of BiCNU did not influence fatal outcome nor did co-administration of vincristine or spinal irradiation. Of the remaining survivors available for follow up, evidence of lung fibrosis was detected in all patients. The risk and benefit of BiCNU therapy must be carefully considered especially in young patients, due to extremely high risk of pulmonary toxicity.

BiCNU is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximately those employed clinically.

Bone marrow toxicity is a common and severe toxic effect of BiCNU. Complete blood count should be monitored frequently for at least six weeks after a dose. In addition to this, the liver, kidney and lung function should be examined and monitored regularly during the carmustine therapy. Repeat doses of BiCNU should not to be given more frequently than every six weeks.

The bone marrow toxicity of BiCNU is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior dose (see section 4.2).

This medicinal product contains 0.57 vol% ethanol (alcohol), it means 7.68 g per dose. This corresponds to 11.32 ml of beer or 4.72 ml wine per dose.

These amounts arise from a calculated example with 320 mg of carmustine (200 mg/m² for 1.6 m²) dissolved in 9.6 ml (sterile dehydrated ethanol) and a volume of 1696 ml (see section 6.6).

For patients addicted to alcohol, this quantity can be harmful to health.

This must be considered in pregnant and breast-feeding women as well as in high-risk groups (patients with liver disease or epilepsy).

The alcohol content in this medicinal product may alter the effects of other drugs.

The alcohol content in this medicinal product may impair the ability to drive and the ability to use machines.

4.5 Interaction with other medicinal products and other forms of interaction

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

4.6 Fertility, pregnancy and lactation

BiCNU 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. BiCNU 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 fetus. 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.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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 BiCNU 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):

MedDRA system organ class	Frequency	Adverse effects
Clinically important side effects are in italics
Neoplasms benign, malignant and unspecified (including cysts and p°iyps)	common	Acute leukemias, bone marrow dysplasias; following long-term use.
Blood and lymphatic system disorders	common	Anaemia.
	very common	Myelosuppression; onset 7-14 days, nadir 21-35 days, recovery 42-56 days; cumulative, dose related, delayed and often biphasic.
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	Ocular toxicities, transient conjunctival

MedDRA system organ class	Frequency	Adverse effects
Clinically important side effects are in italics
	common	flushing and blurred vision; retinal haemorrhages.
Cardiac disorders	very common	Hypotension, due to alcohol content of diluent (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 2 > 1400 mg/m ) Pneumonitis (for doses >450mg/m2).
	rare	Interstitial fibrosis (with lower doses).
Gastrointestinal disorders	very common	emetogenic potential: >250 mg/m2 high; <250 mg/m2 high-moderate
	very common	Nausea and vomiting, severe; begins within 2-4 h of administration and lasts for 4-6 h.
	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	not known	extravasation hazard: vesicant
	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 diluent; increased with administration times <1-2 h), injection site reaction.
Renal and urinary disorders	rare	Renal toxicity (for cumulative doses <1,000 mg/m2).
Reproductive system and breast disorders	rare	Gynecomastia.
	not known	Infertility, teratogenesis.

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: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: Antineoplastic medicine, alkylating agent, nitrosourea ATC-Code: L01AD01

BiCNU 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 BiCNU may be due to metabolites.

5.2 Pharmacokinetic properties

Distribution

Intravenously administered BiCNU 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, BiCNU 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 a accounts to 1-4 minutes and the half life P accounts to 18-69 minutes.

Metabolism

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.

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 fertlility 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

Dehydrated Alcohol

6.2 Incompatibilities

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.

The pharmaceutical medicine should be used based on the instructions in Section 6.6 and not mixed up with other pharmaceutical medicines.

6.3 Shelf life

2 Years.

After reconstitution as recommended, BiCNU is stable for 24 hours under refrigeration (2°C - 8°C) in glass container.

The reconstituted solution further diluted with 500 ml sodium chloride for injection or 5% glucose for injection, in glass or polypropylene containers, results in a solution which should be utilized within 8 hours at room temperature and be protected from light. These solutions are also stable 24 hours under refrigeration (2-8°C) and an additional 6 hours at room temperature protected from light.

6.4 Special precautions for storage

Store in a refrigerator (2⁰C-8⁰C).

The original package should be protected from light.

Alternatively, BiCNU can be transported using dry ice and stored in a refrigerator at (2°C to 8°C). By following the recommended storage conditions it is possible to avoid any decomposition of the unopened vial until the date of expiry mentioned on the packaging.

The dry frozen product does not contain any preservatives and is suitable only for one use. There can be physical appearances of sharp flakes in the unopened vial as far as rigid mass, however without any decomposition of carmustine. 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. This medicine 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. Carmustine appears with small quantities of dried flakes or dried rigid mass.

6.5 Nature and contents of container

Powder: Type I amber glass vial (30 ml) sealed with a dark grey bromobutyl lyo rubber stopper and aluminium seal having polypropylene cap.

Diluent: Type I glass vial (5 ml) sealed with a grey bromobutyl rubber stopper with an aluminium seal having polypropylene cap.

6.6 Special precautions for disposal

IMPORTANT NOTE: The lyophilized dosage formulation contains no preservative and is not intended as multiple dose vial. Reconstitution and further dilutions should be carried out under aseptic conditions.

Preparation of intravenous solution:

Dissolve BiCNU with 3 ml of the supplied sterile diluent and then aseptically add 27 ml of sterile water for injection to the alcohol solution. Each ml of resulting solution will contain 3.3 mg of BiCNU in 10% ethanol and has a pH of 5.6 to 6.0.

Reconstitution as recommended results in a clear colourless solution which may be further diluted to 500 ml sodium chloride for injection, or 5% glucose for injection. The reconstituted solution must be given intravenously and should be administered by

i.v. drip over one to two hour period. Injection of BiCNU over shorter periods of time may produce intense pain and burning at the site of injection.

NOTE: Reconstituted vials stored under refrigeration should be examined for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation.

BiCNU has a low melting point (approximately 30.5-32.0^oC or 86.9-89.6^oF). Exposure of this drug to this temperature or above will cause the drug to liquefy and appear as an oil film in the bottom of the vials. This is a sign of decomposition and vials should be discarded.

Guidelines for the safe handling of the antineoplastic agents:

1.    Trained personnel should reconstitute the drug.

2.    This should be performed in a designated area.

3.    Adequate protective gloves should be worn.

4.    Precautions should be taken to avoid the drug accidentally coming into contact with eyes. In the event of contact with the eyes, flush with copious amount of water and/or saline.

5.    The cytotoxic preparation should not be handled by pregnant staff.

6.    Adequate care and precaution should be taken in the disposal of items (syringes, needles etc.) used to reconstitute cytotoxic drugs. Excess material and body waste may be disposed of by placing in double sealed polythene bags and incinerating at a temperature of 1,000^oC. Liquid waste may be flushed with copious amounts of water.

7.    The work surface should be covered with disposable plastic-backed absorbent paper.

8.    Use Luer-Lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduce by the use of a venting needle.

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

7 MARKETING AUTHORISATION HOLDER

Creative Pharma Solutions, s.r.o.,

Italska 17 120 00 Prague 2 Czech Republic

8    MARKETING AUTHORISATION NUMBER(S)

PL 43021/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/08/2015

10    DATE OF REVISION OF THE TEXT

21/08/2015