Carmustine
100mg Injection

What Carmustine Is And Usage

Carmustine for injection is one of the nitrosoureas used in the treatment of certain neoplastic diseases.

Carmustine for injection 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, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors.
• Multiple myeloma—in combination with 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 for patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

This medication is given by injection into a vein by a health care professional. Dosage is based on your medical condition, body size, and response to treatment. This medication is usually given every 6 weeks or as directed by your doctor.

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 2 successive days. When Carmustine is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.

First, dissolve Carmustine with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of Carmustine in 10% ethanol. Such solutions should be protected from light.

Reconstitution as recommended results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

More than 10 in every 100 people have one or more of the side effects listed below.

A temporary drop in the number of blood cells made by the bone marrow, causing

An increased risk of getting an infection from a drop in white blood cells – it is harder to fight infections and you can become very ill. You may have headaches, aching muscles, a cough, sore throat, pain passing urine or feel cold and shivery

Tiredness and breathlessness due to a drop in red blood cells (anaemia) – you may need a blood transfusion

Bruising more easily due to a drop in platelets – you may have nosebleeds, bleeding gums after brushing your teeth, or lots of tiny red spots or bruises on your arms or legs (known as petechia)

Some of these side effects can be life threatening, particularly infections. Contact your treatment centre straight away if you have any of these effects. Your doctor will check your blood counts regularly to see how well your bone marrow is working.

Other common side effects include

• Tiredness and weakness (fatigue) during and after treatment – most people find their energy levels are back to normal within 6 months to a year
• Feeling and being sick – this usually starts within 2 hours of having the drug and can last for up to 6 hours. You should have anti sickness medicines before the chemotherapy and will have them to take regularly at home. Tell your doctor or nurse if your anti sickness medicines are not working
• Loss of appetite
• Women may stop having periods (amenorrhoea) but this may only be temporary
• Loss of fertility – you may not be able to get pregnant or father a child after treatment with this drug. It is important to talk to your doctor about your fertility before starting treatment.

Side effects of carmustine wafers in the brain

If you have carmustine wafers implanted in your brain, you might also have these side effects

• Swelling of the brain (oedema)
• Convulsions (fits)
• Problems with wound healing
• Infection of the brain tissue

Occasional side effects

Between 1 and 10 in every 100 people have one or more of these.

• Lung problems – you may have a cough or breathlessness due to inflammation of the lungs. Tell your doctor if you have this side effect. This can happen in up to 1 in 3 people treated, but usually only affects people who have had high doses of BCNU
• Skin flushing, especially of the face – this can last for about 4 hours
• Headaches
• Diarrhoea – drink plenty of fluids. If diarrhoea becomes severe or continues you could get dehydrated, so tell your doctor or nurse
• Inflammation around the drip site – if you notice any signs of redness, swelling or leaking at your drip site, tell your chemotherapy nurse straight away
• Kidney changes that are mild and unlikely to cause symptoms – they will usually go back to normal when treatment finishes, but you will have regular blood tests to check how well your kidneys are working
• An increased risk of leukaemia or blood disorders some years after treatment

Fewer than 1 in 100 people have liver changes that are very mild and unlikely to cause symptoms. The liver will almost certainly go back to normal when treatment is finished, but you will have regular blood tests to check how well your liver is working.

Overdose:
If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

Missed dose:
For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor immediately to establish a new dosing schedule.

Drug interactions:
Tell your doctor about all other medications you use, especially cimetidine.

There may be other drugs that can interact with carmustine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug include: digoxin, drugs that may decrease bone marrow function (e.g., azathioprine, cimetidine), nalidixic acid, phenytoin.

Pregnancy and contraception
This drug may have a harmful effect on a developing baby. It is important not to become pregnant or father a child while having treatment. Talk to your doctor or nurse about contraception before having treatment if there is any chance that you or your partner could become pregnant.

Breastfeeding
Breastfeeding is not advisable during this treatment because the drug may come through in the breast milk.

How to Supplied

Carmustine for Injection. Each package includes a vial containing 100 mg carmustine and an ampule containing 3 mL sterile diluent.

Carmustine is available in 100-mg single dose vials of lyophilized material. Sterile diluent for constitution of Carmustine is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in an ampule containing 3 mL of Dehydrated Alcohol Injection, USP.

Store in a refrigerator (2°-8°C, 36°-46°F).
Store diluent at controlled room temperature (15°-30°C, 59°-86°F) or in a refrigerator (2°-8°C, 36°-46°F).

Your doctor or pharmacist can provide more information about carmustine

Carmustine
100mg Injection

WARNINGS

Carmustine for injection should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to bleeding and overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of Carmustine.

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of Carmustine should not be given more frequently than every 6 weeks.

The bone marrow toxicity of Carmustine is cumulative and therefore dosage adjustment must be considered on the basis of nadir blood counts from prior dose.

Pulmonary toxicity from Carmustine appears to be dose related. Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less.

Delayed pulmonary toxicity can occur years after treatment, and can result in death, particularly in patients treated in childhood.

DESCRIPTION

Carmustine for injection is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It is 1,3-bis(2-chloroethyl)-1-nitrosourea. It is sterile lyophilized pale yellow flakes or congealed mass with a molecular weight of 214.06. It is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine is administered by intravenous infusion after reconstitution as recommended.

The structural formula is:

Carmustine is available in 100-mg single dose vials of lyophilized material. Sterile diluent for constitution of Carmustine is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in an ampule containing 3 mL of Dehydrated Alcohol Injection, USP.

CLINICAL PHARMACOLOGY

Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.

Intravenously administered carmustine is rapidly degraded, with no intact drug detectable after 15 minutes. However, in studies with 14C-labeled drug, prolonged levels of the isotope were detected in the plasma and tissue, probably representing radioactive fragments of the parent compound.

It is thought that the antineoplastic and toxic activities of carmustine may be due to metabolites. Approximately 60% to 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.

Because of the high lipid solubility and the relative lack of ionization at physiological pH, carmustine crosses the blood-brain barrier quite effectively. Levels of radioactivity in the CSF are ≥50% of those measured concurrently in plasma.

INDICATIONS AND USAGE

Carmustine for injection 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, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors.
• Multiple myeloma— in combination with 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 for patients who relapse while being treated with primary therapy, or who fail to respond to primary therapy.

CONTRAINDICATIONS

Carmustine should not be given to individuals who have demonstrated a previous hypersensitivity to it.

WARNINGS

Since the major toxicity is delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose. At the recommended dosage, courses of Carmustine should not be given more frequently than every 6 weeks.

The bone marrow toxicity of Carmustine is cumulative; therefore, dosage adjustment must be considered on the basis of nadir blood counts from prior dose.

Pulmonary toxicity from Carmustine appears to be dose related. Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less. Additionally delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received Carmustine in childhood and early adolescence.

Long-term use of nitrosoureas has been reported to be associated with the development of secondary malignancies.

Liver and renal function tests should be monitored periodically.

Carmustine for injection may cause fetal harm when administered to a pregnant woman. Carmustine has been shown to be embryotoxic in rats and rabbits and teratogenic in rats when given in doses equivalent to the human dose. There are no adequate and well-controlled studies in pregnant women. 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.

Carmustine has been administered through an intraarterial intracarotid route; this procedure is investigational and has been associated with ocular toxicity.

Injection site reactions may occur during the administration of Carmustine. Given the possibility of extravasation, close monitoring of the infusion site for possible infiltration during drug administration is recommended. A specific treatment for extravasation reactions is unknown at this time.

PRECAUTIONS

In all instances where the use of Carmustine is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Carmustine therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to possible recurrence of toxicity.

Due to delayed bone marrow suppression, blood counts should be monitored weekly for at least 6 weeks after a dose.

Baseline pulmonary function studies 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.

Since Carmustine may cause liver dysfunction, it is recommended that liver function tests be monitored.

Renal function tests should also be monitored periodically.

Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine.

Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans. Carmustine also affects fertility in male rats at doses somewhat higher than the human dose.

Pregnancy Category D
See WARNINGS.

It is not known whether this drug is excreted in human milk. Because of the potential for serious adverse events in nursing infants, nursing should be discontinued while taking Carmustine.

Safety and effectiveness in children have not been established. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study of patients who received Carmustine in childhood and early adolescence (1–16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5 patients initially treated at less than 5 years of age, died of pulmonary fibrosis. Therefore, the risks and benefits of Carmustine therapy must be carefully considered, due to the extremely high risk of pulmonary toxicity.

No data from clinical studies of Carmustine are available for patients 65 years of age and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger 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 other drug therapy.

Carmustine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

ADVERSE REACTIONS

Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to occur from 9 days to 43 months after treatment with Carmustine and related nitrosoureas. Most of these patients were receiving prolonged therapy with total doses of Carmustine greater than 1400 mg/m2. However, there have been reports of pulmonary fibrosis in patients receiving lower total doses. Other risk factors include past history of lung disease and duration of treatment. Cases of fatal pulmonary toxicity with Carmustine have been reported.

Additionally, delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study with 17 patients who received Carmustine in childhood and early adolescence (1–16 years) in cumulative doses ranging from 770 to 1800 mg/m2 combined with cranial radiotherapy for intracranial tumors. Chest x-rays demonstrated pulmonary hypoplasia with upper zone contraction. Gallium scans were normal in all cases. Thoracic CT scans have demonstrated an unusual pattern of upper zone fibrosis. There was some late reduction of pulmonary function in all long-term survivors. This form of lung fibrosis may be slowly progressive and has resulted in death in some cases. In this long-term study, 8 of 17 died of delayed pulmonary lung fibrosis, including all those initially treated (5 of 17) at less than 5 years of age.

A frequent and serious toxicity of Carmustine is delayed myelosuppression. It usually occurs 4 to 6 weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a dose of Carmustine and persists for 1 to 2 weeks. Thrombocytopenia is generally more severe than leukopenia. However, both may be dose-limiting toxicities.

Carmustine may produce cumulative myelosuppression, manifested by more depressed indices or longer duration of suppression after repeated doses.

The occurrence of acute leukemia and bone marrow dysplasias has been reported in patients following long-term nitrosourea therapy.

Anemia also occurs, but is less frequent and less severe than thrombocytopenia or leukopenia.

Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine.

Nausea and vomiting after intravenous administration of Carmustine are noted frequently. This toxicity appears within 2 hours of dosing, usually lasting 4 to 6 hours, and is dose related. Prior administration of antiemetics is effective in diminishing and sometimes preventing this side effect.

A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline phosphatase and bilirubin levels, has been reported in a small percentage of patients receiving Carmustine.

Renal abnormalities consisting of progressive azotemia, decrease in kidney size, and renal failure have been reported in patients who received large cumulative doses after prolonged therapy with Carmustine and related nitrosoureas. Kidney damage has also been reported occasionally in patients receiving lower total doses.

Accidental contact of reconstituted Carmustine with skin has caused burning and hyperpigmentation of the affected areas.

Rapid intravenous infusion of Carmustine may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. It is also associated with burning at the site of injection although true thrombosis is rare.

Local soft tissue toxicity has been reported following extravasation of Carmustine. Infiltration of Carmustine may result in swelling, pain, erythema, burning sensation, and skin necrosis.

Neuroretinitis, chest pain, headache, allergic reaction, hypotension, and tachycardia have been reported as part of ongoing surveillance.

OVERDOSAGE

No proven antidotes have been established for Carmustine overdosage.

DOSAGE AND 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 daily injections such as 75 to 100 mg/m2 on 2 successive days. When Carmustine is used in combination with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted, the doses should be adjusted accordingly.

Doses subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the preceding dose. The following schedule is suggested as a guide to dosage adjustment:

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 6 weeks. Adequate number of neutrophils should be present on a peripheral blood smear. Blood counts should be monitored weekly and repeat courses should not be given before 6 weeks because the hematologic toxicity is delayed and cumulative.

As with other potentially toxic compounds, caution should be exercised in handling Carmustine and preparing the solution of Carmustine. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1–4 Accidental contact of reconstituted Carmustine with the skin has caused transient hyperpigmentation of the affected areas. To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Carmustine. If Carmustine lyophilized material or solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. More information is available in the references listed below.

Reconstituted solution should only be administered by slow intravenous infusion. Administration of Carmustine over a period of less than 2 hours can lead to pain and burning at the site of injection.

First, dissolve Carmustine with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of Carmustine in 10% ethanol. Such solutions should be protected from light.

Reconstitution as recommended results in a clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, USP. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial.

The unopened vial of the dry drug must be stored in a refrigerator (2°-8°C, 36°-46°F). The diluent ampules may be stored at controlled room temperature (15°-30°C, 59°-86°F) or in a refrigerator (2°-8°C, 36°-46°F). The recommended storage of unopened Carmustine vials provides a stable product for up to 3 years. After reconstitution as recommended, Carmustine is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F). Reconstituted vials 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.

Vials reconstituted as directed and further diluted to a concentration of 0.2 mg/mL in 5% Dextrose Injection, USP, should be stored at room temperature, protected from light and utilized within 8 hours.

Glass containers were used for the stability data provided in this section. Only use glass containers for Carmustine administration.

Carmustine has a low melting point (30.5°-32.0°C or 86.9°-89.6°F). Exposure of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This is a sign of decomposition and vials should be discarded. If there is a question of adequate refrigeration upon receipt of this product, immediately inspect the vial in each individual carton. Hold the vial to a bright light for inspection. The Carmustine will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the Carmustine is suitable for use and should be refrigerated immediately.

HOW SUPPLIED

Carmustine for injection. Each package includes a vial containing 100 mg carmustine and an ampule containing 3 mL sterile diluent.

Store in a refrigerator (2°-8°C, 36°-46°F).
Store diluent at controlled room temperature (15°-30°C, 59°-86°F) or in a refrigerator (2°-8°C, 36°-46°F).

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling occupational exposure to hazardous drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.
3. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.
4. Polovich M, White JM, Kelleher LO, eds. 2005. Chemotherapy and biotherapy guidelines and recommendations for practice. 2nd ed. Pittsburgh, PA: Oncology Nursing Society.