Stenar 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, 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 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.

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

Adults:

Posology of intravenous administration:

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 two daily injections such as 75 to 100 mg/m² on two successive days.

 

When Stenar 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 Stenar 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%

 

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 patient populations

Patients with impaired renal function

In patients with impaired renal function, the dose of carmustine should be reduced depending on the glomerular filtration rate.

 

Elderly patients

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 therapy with other medicinal products.

Because 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.

 

In elderly patients the incidence of stomatitis (oral mucositis) is higher when high dose of carmustine is administered.

 

Method of administration

Stenar is for intravenous use after reconstitution and further dilution.

 

Stenar is given as a slow intravenous infusion. Stenar should not be administered as a rapid intravenous injection.

 

For instructions on handling and reconstitution of the medicinal product prior to use, see section 6.6.

 

Stenar should be administered immediately 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.

 

There is no general limit to the duration of use of Stenar therapy. In case the tumour remains uncurable or some serious or untolerable side effects appear, the Stenar therapy must be terminated.

• Hypersensitivity to the active substance (carmustine), 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. • Pregnancy and breast-feeding. • Children and adolescents.

Stenar should be used only by physicians with specific experience in the field of chemotherapy.

 

Bone marrow toxicity

Delayed and cumulative bone marrow toxicity is a common and severe toxic adverse reaction of Stenar. 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 Stenar therapy (see section 4.8). Repeat doses of Stenar should not be given more frequently than every six weeks.

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

 

Monitoring organ functions

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

 

Ethanol

Health risk for patients suffering from alcoholism. Should be considered in pregnant or lactating women and in children and patients at increased risk due to liver disease or epilepsy. The amount of alcohol in this medicine may affect the effectiveness of other medicines. The amount of alcohol in this medicine may impair the ability to drive and operate machinery.

 

Stenar contains ethanol absolute. 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.

 

Pulmonary toxicity

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.

 

Renal toxicity

Renal changes with decrease in renal size, progressive azotemia, and renal failure have been observed after high-cumulative doses and after long-term treatment with carmustine and related nitrosoureas.

 

Liver toxicity

Hepatic necrosis may occur after administration of doses higher than those recommended in the dosing instructions.

 

Comorbidities and poor disease status

Patients with comorbidities and poorer disease status are at higher risk for adverse events. This is especially important for elderly patients.

 

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 Stenar to the carotid artery has been associated with ocular toxicity.

During administration of Stenar, 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.

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) or increased myelotoxicity (e.g., leukopenia and neutropenia).

Digoxin

Concomitant use 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.

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. Stenar 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 effects 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 effects
		Clinically important side effects are in italics
Infections and Infestations	not known	Opportunistic infections (including fatal outcome)
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
Metabolism and nutrition disorders	Not known	Electrolyte disorders (hypokalaemia, hypomagnesaemia, and hypophosphataemia)
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
		Nausea and vomiting, severe; begins within 2-4 h of administration and lasts for 4-6 h.
	common	Anorexia, constipation, diarrhoea, stomatitis.
	Not known	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.
Metabolism and nutrition disorders	not known	Electrolyte abnormalities (hypokalemia, hypomagnesemia and hypophosphatemia)
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.

 

To reports any side effect(s):

Saudi Arabia:

·       The National Pharmacovigilance Centre (NPC):

-       SFDA Call Center: 19999

-       E-mail: npc.drug@sfda.gov.sa

-       Website: https://ade.sfda.gov.sa/

Other GCC States:

-        Please contact the relevant competent authority

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 medicine, alkylating agent, nitrosourea.

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.

 

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 CO_2. 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 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 absolute,

-  Tertiary butanol,

-  Nitrogen,

-  Water

Compatibility/incompatibility with containers

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.

Unopened vial: 2 years. After reconstitution and dilution: After reconstitution as recommended, Stenar is stable for 24 hours at refrigerator (2°C-8°C) and protected from light. The reconstituted solution should be further diluted with 500 ml of sodium chloride (0.9%) solution or 500 ml dextrose (5%) solution. These solutions 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 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.

Keep this medicine out of the sight and reach of children.

 

Unopened vials: Store in a refrigerator (2-8°C).

 

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:

USP type-I amber moulded glass vial (30 ml) with 20 mm rubber stopper and sealed with 20 mm aluminium seal having polypropylene disc.

 

Solvent:

Type-I clear tubular glass vial (5 ml) with 20 mm rubber stopper and sealed with 20 mm aluminium seal having polypropylene disc.

 

Pack size: 2 Vials (one pack contains one vial with 100 mg of powder for concentrate for solution for infusion and one vial with 3 ml of solvent).

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

 

The medicinal product is for single use only.

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 of the powder for concentrate for solution for infusion

Dissolve the 100 mg lyophilized Stenar powder with 3 ml of the supplied sterile refrigerated ethanol solvent provided in the carton. Stenar must be completely dissolved in ethanol 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 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, Stenar is stable for 24 hours under refrigeration (2-8°C), stored in a glass container and protected from light.

 

The reconstituted solution must be further diluted with either 500 ml sodium chloride solution (0.9%) or 500 ml dextrose (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 8 hours. These solutions are also stable for 24 hours at (2-8°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. 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 (30.5-32.0°C). 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 Stenar 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.