Carmustine  is  indicated  as  palliative  therapy  as  a  single  agent  or  in  established combination therapy with other approved chemotherapeutic agents in the following:
•     Brain      tumours      -      glioblastoma,      Brain-stem      gliomas,      
ependymoma medulloblastoma, astrocytoma and metastatic brain tumours.
•     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 whfoail 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 therapyo, r who fail to 
respond to primary therapy.
 

BiCNU 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 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 injections such as 75 to 100 mg/m2 on two successive days.
When Carmustine is used in combination with other myelosuppressive medicinal products or in patients in whom bone marrow reserve is depleted, the doses should be adjusted according to the haematologic profile of the patient as shown below.
Monitoring and subsequent doses
A repeat course of Carmustine should not be given until circulating blood elements have returned to acceptable levels (platelets above 100,000/ mm3, leukocytes above 4,000/ mm3), and this is usually in six weeks. Blood counts should be monitored frequently and repeat courses should not be given before six weeks because of delayed hematologic toxicity.
Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose, in both monotherapy as well as in combination therapy with other myelosuppressive medicinal products. The following schedule is suggested as a guide to dosage adjustment:
Table 1

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).
Special populations 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 therapy with other medicinal productsBecause elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored and the dose reduced according to this.

Paediatric population
Carmustine is contraindicated in children and adolescents aged <18 years (see section 4.3) due to the high risk of pulmonary toxicity (see Section 4.4).
Renal impairment
For patients with renal impairment the dose of Carmustine should be reduced if the glomerular filtration rate is reduced.

Method of administration:
Carmustine is for intravenous use after reconstitution and further dilution.
Following reconstitution (see section 6.6) with the sterile solvent provided (3 ml vial) and sterile water for injection, and further dilution with 500 ml with sodium chloride
9 mg/ml (0.9%) solution for injection, or 500 ml with 5% glucose solution for injection, carmustine should be administered immediately by intravenous drip over one- to two-hour period. 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.
There are no limits for the period of application of carmustine therapy. In case the tumour remains incurable or some serious or intolerable side effects appear, the carmustine therapy must be terminated.

Hypersensitivity to the active substance, to other nitrosoureas or to any of the excipients listed in section 6.1. Severe bone marrow depression or myelosuppression. Severe (end-stage) renal impairment. Children and adolescents. Pregnancy and breast-feeding.

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 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.
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
Delayed and cumulative 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.In addition to this, the liver, kidney and lung function should be examined and monitored regularly during the carmustine therapy (see section 4.8). Repeat doses of Carmustine 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 dose (see section 4.2).
Alcohol
This medicinal product contains 0.57 vol% ethanol (alcohol), i.e. up to 7.68 g per dose, equivalent 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, and may impair the ability to drive and to use machines.
Parenteral administration
The intra-arterial compatibility has not been tested. Severe tissue damage can be expected in case of inadvertent intra-arterial administration.
Experimental direct injection of Carmustine to the carotid artery has been associated with ocular toxicity.
During administration of carmustine, administration site reactions may occur (see section 4.8). Given the possibility of extravasation, close monitoring of the infusion site is recommended for possible infiltration during administration. A special method for handling extravasation is currently unknown.

Dexamethasone

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

Phenytoin 
BiCNU when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

Phenobarbital
Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of BiCNU. Consider alternative drugs to phenobarbital.
Cimetidine
Concomitant use leads to delayed, major, suspected, increased carmustine toxic effect (due to the inhibition of carmustine metabolism) or increased myelotoxicity (e.g. leukopenia and neutropenia)

Chemotherapy
Carmustine do not affect the pharmacokinetics of ondansetron.
Digoxin
Concomitant use leads to delayed, moderate, suspected, decreased effect of digoxin (due to the decreased digoxin absorption)
Melphalan
Concomitant use leads to increased risk of pulmonary toxicity
Thrombopenia and leukopenia can be expected when combined with other myelosuppressive drugs, e.g. Methotrexate, cyclophosphamide, procarbazine, chlormethine (nitrogen mustard), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin) - or in patients whose bone marrow reserve is depleted due to the disease itself or previous therapy
There is a possibility of cross resistance with other alkylating substances, e.g. Chloromethine and cyclophosphamide.

Women of childbearing potential/contraception in males and females
Women of childbearing potential 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 during the 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 to risk of toxicity must be carefully weighed. Carmustine is embryotoxic in rats and rabbits and teratogenic in rats when given in doses equivalent to the human dose. If carmustine is used during pregnancy, or if the patient becomes pregnant while taking (receiving) carmustine, the patient should be apprised of the potential hazard to the fetus.
Breast-feeding
It is unknown whether carmustine/metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
BiCNU 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.
 

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 ability to drive and use machines.

Summary of the safety profile

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

 

 

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 class	system	organ	Frequency	Adverse reactions
Clinically important side effects are in italics
Infections and Infestations			Unknown	Opportunistic outcome)	infections	(including	fatal
Neoplasms benign, malignant and unspecified (including cysts and polyps)			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.
Immune system disorders			not known	Allergic reaction

 

MedDRA    system    organ class	Frequency	Adverse reactions
Clinically important side effects are in italics
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;     retinal haemorrhages.
	not known	Neuroretinitis
Cardiac disorders	very common	Hypotension, due to alcohol content of diluent (high-dose therapy)
	not known	Tachycardia, chest pain
Vascular disorders	very common	Phlebitis, hypotension
	rare	Veno-occlusive disease (high-dose therapy).
Respiratory,    thoracic    and mediastinal disorders	very common	Pulmonary toxicity1,interstitial fibrosis (with prolonged   therapy   and   cumulative   dose >   1400   mg/m2)   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.
	unknown	Gastrointestinal bleeding
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	not known	renal failure, azotemia, decrease in kidney volume
	rare	Renal toxicity (for cumulative doses <1,000 mg/m2).
Reproductive    system    and breast disorders	rare	Gynecomastia.
	not known	Infertility, teratogenesis.

 

MedDRA    system    organ class	Frequency	Adverse reactions
Clinically important side effects are in italics
General      disorders      and administration site conditions	common	Burning sensation at injection site

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

 

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. Thrombocytopenia is generally more pronounced than leukopenia, but both are dose-limiting adverse effects. Anaemia is common but is usually less pronounced.

Eye disorders

 

 

Rapid intravenous infusion may cause conjunctival bleeding within 2 hours, lasting approximately 4 hours.

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. Renal changes with decreased kidney volume, progressive azotemia, and renal failure have been reported after high cumulative doses and after long term therapy with carmustine and related nitrosoureas. Renal impairment was also occasionally observed after low total doses.

Reporting of suspected adverse reaction

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 stated below:

To report any side effect(s): The National Pharmacovigilance Centre (NPC): Fax: +966-11-205-7662 SFDA Call Center: 19999 E-mail: npc.drug@sfda.gov.sa Website: https://ade.sfda.gov.sa

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. There are no known myelo-protective substances. Bone marrow transplantation could be an effective measure

 

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, nitrosoureas, ATC code: L01AD01

Mechanism of action

Carmustine (1,3-bis (2-chloroethyl) -1-nitrosourea) 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 tumours, 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 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 remain 20-30% is undetermined.

 

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 slightly higher than the human dose. Carmustine, at clinically relevant dose levels, was carcinogenic in rats and mice with a marked increase in the incidence of tumours.

Powder

No excipients

Solvent

Ethanol, anhydrous

Compatibility/ Incompatibility with Containers

The solution for infusion is unstable in polyvinyl chloride containers. The carmustine solution can be administered from 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 when stored in a refrigerator (2°C-8°C) protected from light. After reconstitution and dilution After reconstitution as recommended, carmustine 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 4 hours at room temperature and be protected from light. These solutions are also stable for 24 hours under refrigeration (2°C-8°C) and an additional 3 hours at room temperature protected from light.

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

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

Alternatively, Carmustine can be transported   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 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. For verification, hold the vial in bright 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 a dark grey bromobutyl rubber stopper and sealed with a polypropylene cap.

Solvent

Type I clear glass vial (5 ml) with a grey bromobutyl rubber stopper and sealed with a polypropylene cap.

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

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.

The medicinal product is for single use only.

Reconstitution and dilution for each vial of the powder for concentrate for solution for infusion should be prepared as follows

Dissolve carmustine (100 mg powder) with 3 ml of the supplied sterile solvent and then aseptically add 27 ml of sterile water for injection to the alcohol solution. The 30 ml stock solution needs to be mixed thoroughly.

Each ml of the reconstituted solution will contain 3.3 mg of carmustine in 10% ethanol and have a pH of 5.6 to 6.0.

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

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

The reconstituted and diluted solution ( i.e. the ready-to-use solution) must be given intravenously and should be administered by i.v. drip over 1-2 hours.

Infusion of Carmustine 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.

Carmustine 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.

These active substances occur in the environment. Any unused medicinal product or waste material should be disposed in accordance with local requirements.

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