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: Intravenous Carmustine is highly emetogenic. Antiemetics should be advised prior to administration of the drug.

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

• 150 to 200 mg/m2 Intravenous 6-weekly or 75 to 100 mg/m2 /day for 2 days 6-weekly as a single agent in previously untreated patients).
• Lower doses should be used when used in a combinaiton with other chemotherapeutic agents.

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Newly diagnosed high-grade Glioma or recurrent Glioblastoma:

• Wafer  Implantation:
  • 8 wafers (7.7 mg each) implanted intracranially into in the resection cavity.
  • The maximum possible should be implanted if the recommended number of wafers could not be placed.

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Off label use in the treatment of primary Brain tumor:

• 80 mg/m² /day Intravenous for 3 days 8-weekly for 6 cycles or
• 200 mg/m² 8-weekly to a maximum cumulative dose of 1,500 mg/m²

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

• Mini-BEAM regimen: 60 mg/m2 Intravenous on day 1 every 4 to 6 weeks in combination with etoposide, cytarabine, and melphalan.

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

• VBMCP regimen: 20 mg/m2 Intravenous on day 1 every 35 days in combination with vincristine, melphalan, cyclophosphamide, and prednisone.

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

• Topical:
  • Ointment (10 mg/100 grams petrolatum):
    • Apply once a day to the affected areas.
  • Solution (10 mg/60 mL water):
    • Apply once a day to the affected areas.

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

• BEAM regimen: 300 mg/m2 Intravenous as a single dose 6 days prior to the transplant in combination with etoposide, cytarabine, and melphalan.
• CBV regimen: 600 mg/m2 as a single dose 3 days prior to the transplant in combination with cyclophosphamide and etoposide.

Carmustine Dose in Childrens

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

• Infants, Children, and Adolescents:
  • 100 mg/m2 /dose Intravenous twice daily for 3 days (total: 600 mg/m2 ) as part of a high dose combination chemotherapy regimen.

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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)

• BEAM regimen:
  • Adolescents 15 years of age or older:
    • 300 mg/m2 /dose Intravenous for 1 dose followed by etoposide, cytarabine, and melphalan.
• CBV regimen:
  • Children and Adolescents:
    • 100 mg/m2 /dose Intravenous once a day for 3 days (total dose: 300 mg/m2 ) on days -8 through -6 in combination with cyclophosphamide and etoposide.

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Carmustine dose adjustment for toxicity:

• Hematologic toxicity:

  • Intravenous:
    • If leukocytes 3,000/mm³ or more and platelets 75,000/mm³ or more: Administer the full recommended dose.
    • If leukocytes 2,000 - 2,999/mm³ or platelets 25,000 - 74,999/mm³: Administer 70% of the recommended dose.
    • If leukocytes less than 2,000/mm³ or platelets less than 25,000/mm³: Administer half the recommended dose.

Pregnancy Risk Category D

• A baselin pregnancy test should be done for females at their reproductive age.
• It is important that women are advised to use effective contraception throughout and for at most six months after treatment. Carmustine can have serious consequences for fetuses.
• High-quality contraceptives should be used by males during and for at most 3 months after therapy.
• It can also negatively affect male fertility, so male patients should be aware of these potential risks.

Carmustine can be used duringBreastfeeding:

• It is unknown whether the drug can be absorbed into breastmilk. 
• Patients receiving injectable therapy should avoid it and wait at least seven days before using the wafers.

Carmustine Dose in Renal Disease:

According to the Manufacturer’s labeling, Patients with a CrCl of less than 10 mL/minute should discontinue treatment. Carmustine dose may be adjusted in patients with renal impairment as follows:

• CrCl 46 - 60 mL/minute:
  • Reduce the dose to 80% of the usual dose
• CrCl 31 - 45 mL/minute:
  • Reduce the dose to 75% of the usual dose
• CrCl of less than 30 mL/minute:
  • Consider the use of an alternative drug.

Wafer implant: Adjustment in dose has not been provided in the manufacturer’s labeling.

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:

• Allergy to carmustine and any other component of the formulation

Warnings and Precautions

• Suppression of bone marrow [US Boxed Warning]
  • Intravenous Carmustine can cause bone marrow suppression.
  • This may manifest in bleeding due to thrombocytopenia or recurrent infections caused by leukopenia.
  • Each dose should be followed up with a blood count check every week for at least six weeks.
  • The hematological parameters should guide the adjustment of the Carmustine dose prior to infusion. Patients with severe cytopenias should be avoided.
  • After administration, myelosuppression can take up to 6 weeks.
  • Before repeating the course, platelet counts must be greater than 100,000/mm3, ANC (absolute neuophils count), should be higher than 1,000/mm3, leukocytes more than 4,000/mm3.
• Gastrointestinal toxicities:
  • It is extremely emetogenic. It should be administered prior to its administration.
• Hepatic:
  • It is important to monitor liver functions as it has been linked with a reversible rise in transaminases and bilirubin.
• Reactions at the infusion site:
  • It can cause local reactions, especially if extravasation occurs in the subcutaneous space.
  • Rapid infusions lasting less than two hours can also cause skin flushing or suffusion of conjunctiva
• Intracranial hypertension
  • It may cause brain edema, which may be resistant to corticosteroids therapy.
  • Monitor patients for signs of elevated intracranial hypertension.
  • Refractory cases might require the wafers to be removed.
• Meningitis
  • Post-operatively, monitor the patient for signs of meningitis and CNS infection.
• Toxicity in the lungs: [US Boxed Warning]
  • Dose-related pulmonary toxicities are associated with intravenous Carmustine (although interstitial Fibrosis can occur at lower doses).
  • The development of pulmonary fibrosis can occur many years after the treatment, which could be fatal in particular for children.
  • It is characterised by pulmonary fibrosis, infiltrates, and a combination of the two. 
  • Patients who have a history of lung disease or have a baseline abnormal pulmonary function (FVC/DLCO less than 70%) are at greater risk for developing pulmonary toxicity.
  • Patients should be assessed periodically and at baseline for their pulmonary function.
• Secondary malignancies
  • Long-term therapy patients should be closely monitored for secondary malignancies such as bone marrow dysplasias or acute leukemias.
• Seizures
  • Seizures can occur in patients who have carmustine wafer implanted.
  • Seizure monitoring should be done on patients. Anti-seizure medication should also be adjusted.
• Inability to heal wounds
  • You should monitor the patient for any signs of impaired neurosurgical wound healing.
  • This could include wound dehiscence, delayed wound healing, and possible wound effusions from carmustine wafer implants.
  • Leakage of cerebrospinal fluid can also happen.
• Renal impairment
  • Adjustment of dose may be necessary for patients with severe renal impairment. Therapy should be stopped in severe renal impairment.

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

Monitoring parameters:

 Prior to carmustine therapy, pregnancy should be excluded in women of reproductive ages.

With intravenous carmustine, Monitor:

• CBC with differential and platelet count once a week for at least 6 weeks after a dose
• Pulmonary function tests at baseline and frequently during the treatment
• Liver function tests periodically
• Renal function tests periodically
• Blood pressure and vital signs during the infusion
• Infusion site for possible infiltration
• Clinical features of pulmonary toxicity
• Monitor for development of secondary malignancies.

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Wafer:

• Monitor postoperatively for seizures
• Impaired neurosurgical wound healing
• Features of meningitis or CNS infection
• Obstructive hydrocephalus & intracranial hypertension related to brain edema, inflammation, or necrosis of brain tissue surrounding the area of resection.

How to administer Carmustine?

• Carmustine can be highly emetogenic. Before administering the drug, it is recommended to use antiemetic drugs .

Carmustine Injection Administration:

• To minimize pain and irritation, infuse the drug slowly for at least 2 hours using a free-flowing dextrose or saline infusion. Infusion rate should not exceed 1.66 mg/m2 per minute. 

Extravasation into local tissues should be avoided, as it can cause irritation and local damage. To avoid excessive flushing, agitation and hypotension when administering high-dose carmustine to transplant patients off-label, it is important that you infuse for at least 2 hours. Attention: Stem cell rescue is not recommended for high-dose carmustine users.

The patient should be in a Trendelenburg position or supine during the infusion. They may also require fluid support and vasopressor therapy. During the infusion, it is important to monitor your vital signs. Placement of the Implant Before handling, wear a second glove. The outer gloves should be thrown away after handling wafers. 

The pouch's exterior is not sterilizable. To prevent it from breaking, the pouch should be opened gently. Wafers that have been broken into two pieces can be used. However, wafers that have been broken into more pieces than 2 should be thrown away in a biohazard container. Before closing the cavity, water it. 

Mechanism of action of Carmustine:

• Carmustine crosseslinks DNA and RNA strands, interfering with their normal functions. 
• Carmustine can also have possible effects on protein modification. It inhibits enzymes by carbamylation, which is the process of converting amino acids into DNA.

AbsorptionWafer): Systemic Absorption can be measured within a day of insertion It is highly lipid-soluble and easily absorbableCrosses the blood-brain barrierCSF levels can go up to50%Plasma levels of at least 80%. It is growing rapidlyMetabolizedThe liver converts active metabolites to a substance and it has an effect on the liver.

Eliminating half-lifeAfter intravenous administration, it takes approximately 15 to 75 minutes. Time to get therePeak plasma concentrationThe wafer should be inserted within 3 hours. 60% - 70% of drug isExcretedWithin 96 hours of intravenous administration.  

International brands of Carmustine:

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

Carmustine Brands in pakistan:

No brands available in Pakistan