Carmustine, also known as BCNU (bis-chloroethylnitrosourea), is an alkylating agent chemotherapy drug. It is primarily used in the treatment of various types of cancer, including brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphoma.

Carmustine works by interfering with the DNA replication process of cancer cells, ultimately leading to their destruction. It is classified as a nitrosourea, a type of alkylating agent that forms chemical bonds with DNA, preventing the cancer cells from dividing and growing.

Carmustine is a chemotherapeutic drug that impairs the functions of DNA, RNA, and enzymatic proteins in the tumor cells. It is indicated for the following conditions:

• As an intravenous drug for the palliative treatment of Brain tumors including:
  • Glioblastoma
  • Brainstem glioma
  • Medulloblastoma
  • Astrocytoma
  • Ependymoma, and
  • Metastatic brain tumors
• As a Wafer implant (biodegradable discs) for the treatment of:
  • Newly-diagnosed high-grade glioma as an adjunct to surgery and radiation.
  • Treatment of recurrent glioblastoma as an adjunct to surgery.

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• As an intravenous drug for the palliative treatment of Relapsed or refractory Hodgkin lymphoma in combination with other antineoplastics.

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• As an intravenous drug for the palliative treatment of Multiple myeloma in combination with prednisone.

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• As an intravenous drug for the palliative treatment of relapsed or refractory Non-Hodgkin lymphomas.

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• As a topical agent for the Off-Label therapy of Mycosis fungoides.

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• Off-llabel use in autologous stem cell or bone marrow transplant.

Carmustine Dose in Adults

Note: Carmustine, when given through an intravenous (IV) infusion, can make you feel nauseous and cause vomiting. The likelihood of experiencing these side effects depends on the dose of carmustine you receive.

Carmustine Dose in Brain tumors, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma:

The recommended dosage of carmustine for the treatment of brain tumors, Hodgkin lymphoma, multiple myeloma, and non-Hodgkin lymphoma can vary depending on the specific situation and the combination with other chemotherapy agents.

The following dosing information is based on the manufacturer's labeling:

• Brain tumors:
  • The typical recommended dosage is 150 to 200 mg/m² given through intravenous infusion every 6 weeks.
  • This may be used as a single agent in previously untreated patients.
• Hodgkin lymphoma and non-Hodgkin lymphoma:
  • The usual dosage is 150 to 200 mg/m² given through intravenous infusion every 6 weeks.
  • This is often used in combination with other chemotherapy agents.
• Multiple myeloma:
  • In the treatment of multiple myeloma, carmustine is typically administered at a lower dosage of 75 to 100 mg/m² per day for 2 consecutive days every 6 weeks.
  • It is often used in combination with other chemotherapy agents.

Carmustine dose in Newly diagnosed high-grade Glioma or recurrent Glioblastoma:

In the treatment of recurrent glioblastoma or newly-diagnosed high-grade glioma, carmustine can be administered through implantation of wafers directly into the resection cavity in the brain.

The following information is based on the manufacturer's labeling:

• Implantation:
  • In this method, carmustine is available in the form of small wafers.
  • Typically, eight wafers are implanted intracranially into the resection cavity.
  • Each wafer contains 7.7 mg of carmustine.
  • The total dose of carmustine with eight wafers would be 61.6 mg.
• Adjustments:
  • If the size or shape of the resection cavity does not allow for the placement of eight wafers, the maximum number of wafers that can fit (up to eight) should be used.

Carmustine Off label use in the treatment of primary Brain tumor:

In the treatment of primary brain tumors, carmustine can be used in off-label doses.

• Intravenous (IV) administration: Carmustine can be given through an IV infusion.
• Dose for 6 cycles: One recommended off-label dose is 80 mg/m² per day for 3 consecutive days. This treatment is repeated every 8 weeks for a total of 6 cycles. (Brandes, 2004)
• Dose every 8 weeks: Another off-label dose is 200 mg/m² given every 8 weeks. However, the maximum cumulative dose of carmustine should not exceed 1,500 mg/m². (Selker, 2002)

Carmustine Off label use in the treatment of relapsed or refractory of Hodgkin lymphoma:

In the treatment of relapsed or refractory Hodgkin lymphoma, carmustine can be used in an off-label dose as part of the Mini-BEAM regimen.

• Intravenous (IV) administration: Carmustine is given through an IV infusion.
• Mini-BEAM regimen: Carmustine is used as part of the Mini-BEAM regimen, which also includes other chemotherapy drugs such as etoposide, cytarabine, and melphalan.
• Dose: The off-label dose of carmustine in the Mini-BEAM regimen is 60 mg/m² given on day 1 of each treatment cycle.
• Treatment schedule: The Mini-BEAM regimen is typically repeated every 4 to 6 weeks.

Carmustine Off label use in treatment of relapsed or refractory of Multiple myeloma:

In the treatment of relapsed or refractory multiple myeloma, carmustine can be used in an off-label dose as part of the VBMCP regimen.

• Intravenous (IV) administration: Carmustine is given through an IV infusion.
• VBMCP regimen: Carmustine is used as part of the VBMCP regimen, which also includes other chemotherapy drugs such as vincristine, melphalan, cyclophosphamide, and prednisone.
• Dose: The off-label dose of carmustine in the VBMCP regimen is 20 mg/m² given on day 1 of each treatment cycle.
• Treatment schedule: The VBMCP regimen is typically repeated every 35 days.

Carmustine Off label use in the treatment of early-stage Mycosis fungoides:

In the off-label use of carmustine for early-stage mycosis fungoides, a type of cutaneous T-cell lymphoma, it can be used topically in two different forms: ointment and solution.

Ointment form:

• Concentration: The ointment contains carmustine at a concentration of 10 mg per 100 grams of petrolatum.
• Application: Apply the ointment once daily to the affected areas of the skin.

Solution form:

• Concentration: The solution contains carmustine at a concentration of 10 mg per 60 mL of water.
• Application: Apply the solution once daily to the affected areas of the skin.

Carmustine Off label use in the treatment of autologous Stem cell or bone marrow transplant conditioning regimen:

In the off-label use of carmustine as part of a conditioning regimen for stem cell or bone marrow transplant (autologous), two different regimens are mentioned: BEAM and CBV.

BEAM regimen:

• Administration: Carmustine is given through an intravenous (IV) infusion.
• Dose: The off-label dose of carmustine in the BEAM regimen is 300 mg/m² as a single dose. This is given 6 days prior to the transplant.
• Combination: Carmustine is used in combination with other chemotherapy drugs, including etoposide, cytarabine, and melphalan.

CBV regimen:

• Administration: Carmustine is given through an intravenous (IV) infusion.
• Dose: The off-label dose of carmustine in the CBV regimen is 600 mg/m² as a single dose. This is given 3 days prior to the transplant.
• Combination: Carmustine is used in combination with other chemotherapy drugs, including cyclophosphamide and etoposide.

Carmustine Dose in Children

Note: It is important to consider the risks and benefits before using carmustine in children, as they are at higher risk for pulmonary (lung) toxicity. The specific dosing and frequency of carmustine may vary depending on the individual treatment protocol being followed.

Carmustine Use in treatment of Brain tumors and myeloablative therapy prior to autologous stem cell rescue: (based on very limited data)

When it comes to using carmustine as part of myeloablative therapy before autologous stem cell rescue in the treatment of brain tumors, the available data is very limited.

• Patients: The available data primarily focuses on infants, children, and adolescents.
• Administration: Carmustine is given through an intravenous (IV) infusion.
• Dose: The reported doses vary depending on the trials and their outcomes.
  • High Dose Combination Regimen: The most commonly reported dose is 100 mg/m² per dose, given twice daily for 3 days, resulting in a total dose of 600 mg/m². However, the results from trials using this regimen have been mixed.
  • Lower Dose Combination Regimen: A phase I trial identified a lower dose of 100 mg/m² per dose, given once daily for 3 days, resulting in a total dose of 300 mg/m². This lower dose was used in combination with thiotepa. It was found to be the maximum tolerated regimen, but it also showed a high degree of pulmonary toxicity.

Carmustine Use in treatment of relapsed or resistant to Non-Hodgkin lymphoma and as high-dose chemotherapy prior to autologous bone marrow transplant: (based on limited data)

In the treatment of relapsed or resistant non-Hodgkin lymphoma, high-dose chemotherapy may be used prior to autologous bone marrow transplant. The available data for the specific regimens in this context is limited.

BEAM regimen:

• Adolescents ≥15 years:
  • Administration: Carmustine is given through an intravenous (IV) infusion.
  • Dose: The limited available data suggests a dose of 300 mg/m² for a single dose. This is typically followed by the administration of other chemotherapy drugs, such as etoposide, cytarabine, and melphalan.

CBV regimen:

• Children and Adolescents:
  • Administration: Carmustine is given through an intravenous (IV) infusion.
  • Dose: The limited available data suggests a dose of 100 mg/m² once daily for 3 consecutive days. This results in a total dose of 300 mg/m². The administration of carmustine is typically done on days -8 through -6 in combination with cyclophosphamide and etoposide.

Carmustine dose adjustment for toxicity:  

When it comes to dosing adjustment for toxicity in adult patients receiving carmustine, the adjustments are typically based on nadir counts (the lowest point) of white blood cells and platelets from the previous dose.

• Hematologic toxicity (related to blood cell counts):
  • Leukocytes (white blood cells) and platelets are monitored.
  • If the leukocyte count is ≥3,000/mm³ and the platelet count is ≥75,000/mm³, the full 100% dose is administered.
  • If the leukocyte count is between 2,000 and 2,999/mm³ or the platelet count is between 25,000 and 74,999/mm³, 70% of the dose is administered.
  • If the leukocyte count is <2,000/mm³ or the platelet count is <25,000/mm³, 50% of the dose is administered.

Pregnancy Risk Category D

• Based on the way carmustine works and studies done on animals, there is a risk of harm to a developing fetus if carmustine is given to a pregnant woman.
• There is limited information available about the use of carmustine during pregnancy.
• It is important to assess whether a woman is pregnant before starting carmustine treatment.
• Women who can become pregnant should use effective birth control methods during treatment with carmustine and for at least 6 months afterward.
• Men who can father children should also use effective birth control methods during treatment and for at least 3 months afterward.
• Carmustine may also affect male fertility, so men should be aware of the potential risk of infertility.

Carmustine can be used duringBreastfeeding:

• It is uncertain whether carmustine is present in breast milk.
• Since there is a possibility of serious side effects in breastfed infants, the manufacturer advises against breastfeeding while undergoing treatment with carmustine injection and for at least 7 days after the implantation of the wafer.

Carmustine Dose in Renal Disease:

In patients with impaired kidney function, the use of carmustine requires caution and appropriate dosage adjustments. Here are the dosage adjustment recommendations based on creatinine clearance (CrCl) levels:

• CrCl <10 mL/minute: Treatment should be discontinued. Carmustine should not be given to patients with compromised renal function.
• CrCl 46 to 60 mL/minute: The dose should be reduced to 80% of the usual dose.
• CrCl 31 to 45 mL/minute: The dose should be reduced to 75% of the usual dose.
• CrCl ≤30 mL/minute: Consider using an alternative drug instead of carmustine.

These dosage adjustments are based on the reported recommendations in the study conducted by Kintzel in 1995. It's important to note that there are no specific dosage adjustments provided in the manufacturer's labeling for wafer implantation.

Carmustine Dose in Liver Disease:

The manufacturer has not provided any dose adjustment in patients with hepatic impairment.

Common Side Effects Of Carmustine Include:

• Central nervous system:
  • Seizure
  • Cerebral edema
  • Depression
• Dermatologic:
  • Skin rash
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Constipation
• Genitourinary:
  • Urinary tract infection
• Neuromuscular & skeletal:
  • Weakness
• Miscellaneous:
  • Wound healing impairment
  • Fever

Less Common Side Effects Of Carmustine Include:

• Cardiovascular:
  • Chest pain
• Central nervous system:
  • Intracranial hypertension
  • Cerebral hemorrhage
  • Meningitis
• Gastrointestinal:
  • Abdominal pain
• Infection:
  • Abscess
• Neuromuscular & skeletal:
  • Back pain

Side effects with Intravenous therapy: (Frequency not defined)

• Cardiovascular:
  • Chest pain
  • Flushing with rapid infusion
  • Occlusive arterial disease
  • Tachycardia
• Central nervous system:
  • Brain disease
  • Headache
  • Seizure
• Dermatologic:
  • Alopecia
  • Burning sensation of skin
  • Hyperpigmentation
• Gastrointestinal:
  • Anorexia
  • Diarrhea
  • Nausea
  • Vomiting
• Genitourinary:
  • Gynecomastia
• Hematologic & oncologic:
  • Acute leukemia
  • Anemia
  • Bone marrow
  • Dysplasia
  • Leukemia
  • Leukopenia
  • Thrombocytopenia
• Hepatic:
  • Increased serum alkaline phosphatase
  • Increased serum bilirubin
  • Increased serum transaminases
• Hypersensitivity:
  • Hypersensitivity reaction
• Infection:
  • Opportunistic infection
• Local:
  • Burning sensation
  • Erythema
  • Pain
  • Swelling, and
  • Tissue necrosis at the injection site
• Ophthalmic:
  • Blurred vision
  • Conjunctival edema
  • Conjunctival hemorrhage
  • Ophthalmic signs and symptoms manifested by loss of depth perception
  • A suffusion of the conjunctiva with rapid infusion of the drug
• Renal:
  • Azotemia (progressive)
  • Nephron atrophy
  • Renal failure
• Respiratory:
  • Interstitial pulmonary disease
  • Pneumonitis
  • Pulmonary fibrosis (occurring up to 17 years after treatment),
  • Pulmonary Infiltrates

Contraindication to Carmustine include:

For the intravenous (IV) administration of carmustine, it is contraindicated in individuals who have a hypersensitivity (allergic) reaction to carmustine or any component of the formulation. If someone has experienced an allergic reaction to carmustine in the past or has known allergies to any of its ingredients, IV administration of carmustine should be avoided.

Regarding the implantation of carmustine wafers, there are no contraindications specified in the manufacturer's labeling. This means that there are no specific conditions or situations where the use of carmustine wafers is prohibited according to the manufacturer's recommendations.

Warnings and Precautions

Suppression of bone marrow [US Boxed Warning]

• Bone marrow suppression is a serious side effect of carmustine IV treatment.
• It can cause a decrease in the production of blood cells, specifically platelets (which are important for blood clotting) and white blood cells (which help fight infections).
• To monitor this side effect, blood counts should be checked weekly for at least 6 weeks after each dose.
• The dosage of carmustine should be adjusted based on the lowest blood cell counts observed from the previous dose.
• It is important not to administer another course of treatment until blood counts have recovered.
• Bone marrow suppression usually occurs about 4 to 6 weeks after treatment, with thrombocytopenia (low platelet count) being more severe and occurring around 4 weeks, while leukopenia (low white blood cell count) occurs around 5 to 6 weeks.
• Anemia (low red blood cell count) may also occur but is less common and less severe than thrombocytopenia or leukopenia.
• Before starting another course of treatment, platelet counts should be above 100,000/mm³, absolute neutrophil count (ANC) should be above 1,000/mm³, and total leukocyte count should be above 4,000/mm³.
• Repeat courses of carmustine should not be given more frequently than every 6 weeks.

Gastrointestinal toxicities:

• Carmustine IV treatment can cause gastrointestinal (GI) toxicity, particularly nausea and vomiting.
• The potential for these side effects is moderate to high and is related to the dose of carmustine received.
• To prevent or reduce nausea and vomiting, it is recommended to use antiemetic medications.
• These medications can help manage and alleviate these GI side effects associated with carmustine treatment.

Hepatic:

• In rare cases, the intravenous (IV) formulation of carmustine may cause reversible increases in certain liver function tests, such as transaminases, bilirubin, and alkaline phosphatase.
• These abnormalities in liver function are usually temporary and can be monitored through periodic liver function tests during the course of treatment.
• If any significant changes in liver function tests are observed, further evaluation and potential adjustments to the treatment plan may be necessary.
• Regular monitoring allows for early detection of any potential hepatic toxicity and helps ensure the safe use of carmustine.

Reactions at the infusion site:

• When carmustine is administered rapidly through infusion, it can cause certain reactions at the site of infusion.
• These reactions include skin flushing (reddening of the skin) and suffusion of the conjunctiva (reddening of the eye).
• These reactions typically occur within two hours of the infusion and last for about four hours.
• Additionally, carmustine may cause injection-site burning and local tissue reactions, such as swelling, pain, redness, and even tissue death (necrosis).
• It is important to closely monitor the infusion site for any signs of infiltration or injection-site reactions.
• It is crucial to avoid the extravasation (leakage of the drug outside the intended vein) of carmustine during administration.

Intracranial hypertension

• Intracranial hypertension is a potential side effect associated with the use of carmustine wafer implants in patients with newly diagnosed glioma.
• This condition involves an increase in pressure within the skull due to brain swelling.
• It is important to closely monitor patients who have received wafer implants for signs of intracranial hypertension, which may result from brain edema (swelling), inflammation, or necrosis of the brain tissue surrounding the surgical resection.
• In rare cases, intracranial mass effect, which refers to the compression of brain structures, may occur and may not respond to corticosteroid treatment.
• This can lead to a dangerous condition called brain herniation.
• If refractory intracranial hypertension is observed, re-operation may be necessary to remove the wafer implants or any remnants left behind.
• Timely identification and management of intracranial hypertension are crucial to prevent further complications and ensure patient safety.

Meningitis

• In rare cases, patients with recurrent glioma who have received wafer implants of carmustine have developed meningitis.
• Among these cases, two were caused by bacterial infection, resulting in the removal of the implants in one patient shortly after implantation.
• Another case was identified as chemical meningitis, which resolved with the use of corticosteroids.
• It is important to closely monitor patients after the implantation procedure for any signs or symptoms of meningitis or central nervous system (CNS) infection.
• These can include fever, headache, neck stiffness, and changes in mental status.
• Prompt recognition and appropriate management are essential for the early treatment of meningitis and prevention of potential complications.

Ocular toxicity:

• The investigational administration of carmustine through the intraarterial intracarotid route (which is not an approved route of administration) has been associated with ocular toxicity.
• This means that when carmustine is delivered directly into the arteries supplying the brain, there have been reports of adverse effects specifically related to the eyes.

Toxicity in the lungs: [US Boxed Warning]

• Carmustine administered intravenously (IV) carries a significant risk of pulmonary toxicity, which is a serious and potentially life-threatening adverse effect.
• The risk is higher in patients who receive cumulative doses exceeding 1,400 mg/m².
• Pulmonary toxicity can manifest as pulmonary fibrosis, characterized by the scarring and thickening of lung tissue, and can occur years after treatment, even in children.
• Reports have shown cases of pulmonary toxicity occurring in children and adolescents up to 17 years after carmustine treatment for intracranial tumors, with cumulative doses ranging from 770 to 1,800 mg/m² when combined with cranial radiotherapy.
• Pulmonary toxicity may present as pulmonary infiltrates and/or fibrosis and can occur anywhere from 9 days to 43 months after treatment with carmustine or other nitrosoureas.
• It's important to note that pulmonary fibrosis has been reported even with cumulative doses below 1,400 mg/m², although it is rare.
• Certain factors increase the risk of pulmonary toxicity, including a history of lung disease and baseline lung function measurements such as forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) below 70%.
• It is recommended to assess lung function before starting carmustine treatment and periodically thereafter.
• In high-dose treatments such as transplantation (off-label use), acute lung injury may occur approximately 1 to 3 months after the transplant.
• Patients should be advised to promptly report any symptoms such as shortness of breath, cough, or fever to their transplant physician, as interstitial pneumonia (inflammation of the lung tissue) may be managed with a course of corticosteroids.
• Close monitoring and timely intervention are crucial to detect and manage pulmonary toxicity associated with carmustine treatment.

Renal:

• Carmustine treatment has been associated with renal complications, including renal failure, progressive azotemia (increased levels of nitrogen waste products in the blood), and decreased kidney size.
• It is important to monitor renal function regularly during carmustine treatment.
• This involves performing renal function tests to assess the overall health and functioning of the kidneys.

Secondary malignancies

• Long-term use of carmustine administered intravenously (IV) has been linked to an increased risk of developing secondary malignancies, specifically acute leukemias (cancers affecting the blood and bone marrow) and bone marrow dysplasias (abnormalities in the bone marrow).
• This risk is particularly relevant in patients who have received prolonged and repeated courses of carmustine treatment.

Seizures

• Patients who have undergone carmustine wafer implants may be at risk of experiencing seizures, including new-onset or worsening seizures following the treatment.
• Studies have shown that more than half of the treatment-emergent seizures occurred within 5 days of the surgery, with a median onset of 4 days for the first new or worsened postoperative seizure.
• To minimize the risk of seizures, it is recommended to initiate appropriate anti-seizure therapy before the surgery.
• Close monitoring for the occurrence of seizures should be conducted in the postoperative period to promptly identify and manage any seizure activity.

Inability to heal wounds

• Patients undergoing carmustine wafer implant treatment for neurosurgical purposes may experience impaired wound healing in the surgical area.
• This can manifest as complications such as wound dehiscence (separation of wound edges), delayed healing, and the formation of subdural, subgaleal, or wound effusions.
• Additionally, there have been reports of cerebrospinal fluid leaks associated with this treatment.
• It is important to closely monitor patients in the post-operative period to identify any signs or symptoms of impaired neurosurgical wound healing.

Renal impairment

• In patients with renal impairment, the use of carmustine may necessitate dosage adjustment or even discontinuation.
• It is important to note that carmustine should not be administered intravenously to patients with compromised renal function.
• This caution is taken to ensure the safety and effectiveness of the medication in individuals with impaired kidney function.

Carmustine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Risk Factor C (Monitor therapy).
Chloramphenicol Ophthalmic	May increase the toxic/adverse effects of Myelosuppressive Agents.
CloZAPine	CloZAPine's toxic/adverse effects may be exacerbated by myelosuppressive agents. Particularly, there may be an increase in the risk of neutropenia.
Coccidioides immitis skin test	Coccidioides immitis Skin Test may be affected by immunosuppressants.
Denosumab	Might increase the toxic/adverse effects of Immunosuppressants. In particular, there may be an increase in the risk of serious infections.
Melphalan	Can increase the toxic/adverse effects of Carmustine. Melphalan can be used to increase the risk of carmustine lung toxicities.
Ocrelizumab	May increase the immunosuppressive effects of Immunosuppressants.
Pidotimod	Pidotimod's therapeutic effects may be diminished by immunosuppressants.
Promazine	May increase the myelosuppressive effects of Myelosuppressive Drugs.
Siponimod	Siponimod's immunosuppressive effects may be enhanced by taking immunosuppressants.
Sipuleucel - T	Sipuleucel T's therapeutic effects may be diminished by immunosuppressants
Tertomotide	Tertomotide's therapeutic effects may be diminished by immunosuppressants.
Trastuzumab	May increase the neutropenic effects of Immunosuppressants.
Risk Factor D (Regard therapy modification)
Baricitinib	Baricitinib's immunosuppressive effects may be enhanced by immunosuppressants. Baricitinib should not be used in combination with immunosuppressants like azathioprine and cyclosporine. It is permissible to use methotrexate antirheumatically or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently.
Cimetidine	Carmustine may increase myelosuppressive effects. Treatment: Patients receiving Carmustine should consider alternatives to Cimetidine. Monitor for increased carmustine myelotoxicity if the combination is not possible.
Echinacea	Might decrease the therapeutic effects of Immunosuppressants.
Fingolimod	Fingolimod may be immunosuppressed by immunosuppressants. When possible, avoid the use of fingolimod with other immunosuppressants. Patients should be closely monitored for any additive immunosuppressant effects, such as infections, if they are used together.
Leflunomide	Leflunomide's toxic/adverse effects may be exacerbated by immunosuppressants. The risk of hematologic toxicities such as pancytopenia and agranulocytosis may increase. Patients on immunosuppressants should not be given a leflunomide loading dosage. Patients who are receiving leflunomide or another immunosuppressant must be checked for bone marrow suppression at minimum monthly.
Lenograstim	Antineoplastic Agents can reduce the therapeutic effects of Lenograstim. Management: Lenograstim should be avoided 24 hours prior to and 24 hours following the completion of myelosuppressive, cytotoxic chemotherapy.
Lipegfilgrastim	Antineoplastic agents may reduce the therapeutic effects of Lipegfilgrastim. Management: It is important to avoid the simultaneous use of lipegfilgrastim with myelosuppressive, cytotoxic chemotherapy. After myelosuppressive chemotherapy has been completed, lipegfilgrastim must be given at least 24 hours.
Nivolumab	Nivolumab's therapeutic effects may be diminished by immunosuppressants.
Palifermin	Can increase the toxic/adverse effects of Antineoplastic Agents. In particular, oral mucositis can be more severe and prolonged. Management: Avoid palifermin administration within the first 24 hours of infusion or 24 hours following myelotoxic chemotherapy.
Roflumilast	May increase the immunosuppressive effects of Immunosuppressants.
Tofacitinib	Tofacitinib's immunosuppressive effects may be enhanced by immunosuppressants. Management: It is permissible to use methotrexate (or nonbiologic disease-modifying antirheumatic drug (DMARDs), concurrently with antirheumatic doses. This warning appears to be particularly targeted at more potent immunosuppressants.
Vaccines (Inactivated).	Immunosuppressants can reduce the therapeutic effects of Vaccines (Inactivated). Management: The effectiveness of vaccines may be decreased. All age-appropriate vaccines must be completed at least two weeks before you start an immunosuppressant. Re-vaccinate anyone who was vaccinated while on immunosuppressant therapy.
Risk Factor X (Avoid Combination)
BCG (Intravesical).	The therapeutic effects of BCG (Intravesical) may be diminished by immunosuppressants
BCG (Intravesical).	Myelosuppressive agents may reduce the therapeutic effects of BCG (Intravesical).
Cladribine	May increase the immunosuppressive effects of Immunosuppressants.
Cladribine	May increase the myelosuppressive effects of Myelosuppressive Drugs.
Deferiprone	Deferiprone may have a neutropenic effect that myelosuppressive agents can increase.
Dipyrone	May increase the toxic/adverse effects of Myelosuppressive Agents. In particular, there may be an increase in the risk of pancytopenia and agranulocytosis.
Natalizumab	Natalizumab's toxic/adverse effects may be exacerbated by immunosuppressants. Particularly, concurrent infections may increase.
Pimecrolimus	May increase the toxic/adverse effects of Immunosuppressants
Tacrolimus - Topical	May increase the toxic/adverse effects of Immunosuppressants
Vaccines (Live).	Immunosuppressants can increase the toxic/adverse effects of Vaccines (Live). Immunosuppressants can decrease the therapeutic effects of Vaccines. Management: Live-attenuated vaccines should be avoided for at least three months following immunosuppressants.

Monitoring parameters:

Pregnancy Evaluation:

• Prior to initiating carmustine therapy, evaluate the pregnancy status of the patient.

Injection:

• Complete Blood Count (CBC) with differential and platelet count:
  • Weekly monitoring is recommended for at least 6 weeks after each dose of carmustine.
• Pulmonary Function Tests (Forced Vital Capacity, Diffusing Capacity):
  • Perform baseline tests before starting treatment and monitor them frequently during therapy.
• Liver Function Tests:
  • Periodically assess liver function during carmustine treatment.
• Renal Function Tests:
  • Regularly monitor renal function in patients receiving carmustine.
• Blood Pressure and Vital Signs:
  • Monitor blood pressure and vital signs closely during carmustine administration.
• Infusion Site:
  • Monitor the infusion site for any signs of infiltration or injection-site reactions.
• Pulmonary Toxicity:
  • Watch for signs and symptoms of pulmonary toxicity, such as breathing difficulties or coughing.
• Development of Secondary Malignancies:
  • Be vigilant for the development of secondary malignancies during long-term carmustine therapy.

Wafer:

• Seizure Monitoring:
  • After carmustine wafer implantation, closely monitor patients for the occurrence of seizures.
• Impaired Neurosurgical Wound Healing:
  • Postoperatively, carefully observe patients for impaired healing of neurosurgical wounds, including wound dehiscence, delayed healing, and subdural, subgleal, or wound effusions.
• Meningitis and CNS Infection:
  • Be vigilant for signs and symptoms of meningitis and central nervous system (CNS) infection in patients who have received carmustine wafer implants.
• Intracranial Hypertension:
  • Monitor patients closely for signs of intracranial hypertension, which may be related to brain edema, inflammation, or necrosis of brain tissue surrounding the resection site.
• Obstructive Hydrocephalus:
  • Observe patients for symptoms suggestive of obstructive hydrocephalus, such as headache, nausea, vomiting, or altered mental status.

How to administer Carmustine?

Adult Administration:

• Intravenous (IV) Infusion:
  • Administer carmustine IV slowly over a minimum of 2 hours.
  • Use a free-flowing saline or dextrose infusion, or administer through a central catheter to minimize venous pain or irritation.
  • Do not exceed a rate of 1.66 mg/m²/minute.
  • Monitor the infusion site closely for any signs of infiltration or injection-site reactions.
  • Avoid extravasation of the medication.

High-dose Carmustine (Transplant Dose; Off-label use):

• Infuse over at least 2 hours to prevent excessive flushing, agitation, and hypotension.
• In some cases, it may be infused over 1 hour in clinical trials.
• Vital signs should be frequently monitored during the infusion.
• Patients should be in a supine position during the infusion and may require additional support such as Trendelenburg position, fluid support, and vasopressor therapy.
• High-dose carmustine may be fatal if not followed by stem cell rescue.

Implant Administration:

• Double glove before handling carmustine wafers.
• Discard the outer gloves used for handling wafers as chemotherapy waste.
• Any removed wafers or remnants during repeat surgery should also be disposed of as chemotherapy waste.
• The outer surface of the external foil pouch is not sterile.
• Open the pouch gently, avoiding pressure on the wafers to prevent breakage.
• Slight overlapping of wafers during placement is acceptable.
• Oxidized regenerated cellulose (Surgicel) may be used to secure the wafers, and cavity irrigation is recommended prior to closure.

Topical Administration (Off-label use):

• Wear gloves during the application of carmustine solution.
• Apply the solution using a brush or gauze pads.
• Only apply the ointment or solution to the affected areas and avoid contact with eyes or orifices.

Children Administration:

• Parenteral Administration:
  • Administer carmustine IV over 2 hours to prevent injection site pain or burning.
  • Use glass or polyolefin containers for preparation, as significant absorption can occur in PVC containers.

High-dose Carmustine (Transplant Dose):

• Follow the same guidelines as for adults, infusing over at least 2 hours to avoid adverse effects.
• Vital signs should be frequently monitored during the infusion, and additional support may be required.

Mechanism of action of Carmustine:

• Carmustine works by interfering with the normal functioning of DNA and RNA in the body.
• It does this through a process called alkylation, where it attaches alkyl groups to the DNA and RNA strands.
• This leads to the cross-linking of these strands, which disrupts their structure and prevents them from functioning properly.
• Additionally, carmustine can modify proteins and inhibit enzyme processes by carbamylation, which involves the attachment of carbamyl groups to amino acids in proteins.
• These actions of carmustine ultimately disrupt the essential processes of DNA, RNA, and proteins in the body.

Absorption:

• Wafer: After insertion, there is measurable systemic absorption for about 24 hours.

Distribution:

• IV: Carmustine distributes throughout the body with a volume of distribution of 3.3 L/kg.
• It easily crosses the blood-brain barrier, reaching cerebrospinal fluid levels that are at least 50% of blood plasma levels.
• Carmustine is highly lipid soluble, allowing it to move through fatty tissues.

Metabolism:

• Carmustine undergoes rapid metabolism in the liver.
• It forms active metabolites during this process.

Elimination:

• IV: The elimination half-life of carmustine ranges from 15 to 75 minutes.

Time to Peak:

• Wafer: Systemic levels of carmustine reach their peak approximately 3 hours after insertion.

Excretion:

• IV: The primary route of excretion for carmustine is through urine, accounting for approximately 60% to 70% of the dose within 96 hours.
• A small portion (~10%) is excreted through the lungs as carbon monoxide (CO).

International brands of Carmustine:

• Bcnu
• Becenun
• BiCNU
• Bicnu
• Carmubris
• Gliadel
• Gliadel Implant
• Nitrumon

Carmustine Brands in pakistan:

No brands available in Pakistan