carmustine

CARMUSTINE

Complete information including dosage, side effects, interactions and pregnancy & breast feeding warnings for patient and professional use.

Overview and uses

Carmustine is an alkylating agent belonging to Nitrosoureas used for the treatment of cancer. Nitrosoureas are highly lipid soluble compounds with a wide range of anti-tumor activity.

Indication (uses)

  • Injection
    • Carmustine (for injection) is indicated as palliative therapy as a single agent or in established combination therapy in the following:
      • Glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and
      • Metastatic brain tumors.
      • Multiple myelomas in combination with prednisone.
      • Relapsed or refractory Hodgkin’s lymphoma in combination with other approved drugs.
      • Relapsed or refractory Non-Hodgkin’s lymphomas in combination with other approved drugs. Hodgkin’s Lymphoma
    • Carmustine (for implant)
      • Newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and
      • Recurrent glioblastoma multiforme as an adjunct to surgery.

Pharmacological classification

Alkylating agent (Nitrosoureas) used for the treatment of cancer.

Brand names

GLIADEL (implant), BiCNU (for injection)

Dosage form

  • GLIADEL Wafer is off-white to pale yellow round wafer. Each GLIADEL Wafer contains 7.7 mg of Carmustine.
  • For injection: 100 mg of Carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).

Mechanism of action

The mechanism of action of Carmustine is not fully understood. Carmustine alkylates DNA and RNA. It may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The metabolites may contribute to antitumor activity and toxicities of carmustine.

Dosage

  • Carmustine (for injection)
    • The recommended dose of Carmustine (for injection) as a single agent in previously untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks.
    • Administer as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days.
    • Lower the dose when Carmustine (for injection) is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted.
    • Administer Carmustine (for injection) for the duration according to the established regimen.
    • Premedicate each dose with anti-emetics.
    • Adjust doses subsequent to the initial dose according to the hematologic response of the patient to the preceding dose.
    • The following schedule is suggested as a guide to dosage adjustment:
      • Leukocytes (/mm3) > 4000 & Platelets (/mm3) > 100,000
        • 100% of prior dose should be given.
      • Leukocytes (/mm3) 3000 – 3999 & Platelets (/mm3) 75,000 – 99,999
        • 100% of prior dose should be given.
      • Leukocytes (/mm3) 2000 – 2999 & Platelets (/mm3) 25,000 – 74,999
        • 70% of prior dose should be given.
      • Leukocytes (/mm3) < 2000 & Platelets (/mm3) < 25,000
        • 50% of prior dose should be given.
      • The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly.
      • Do not administer a repeat course of BiCNU until circulating blood elements have returned to acceptable levels (platelets above 100 Gi/L, leukocytes above 4 Gi/L and absolute neutrophil count above 1 Gi/L).
      • The usual interval between courses is 6 weeks.
  • Carmustine (implant)
    • The recommended dose of Carmustine (implant) Wafer is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially.
    • The safety and effectiveness of repeat administration have not been studied.
    • Read the package insert for insertion instructions.

Renal dose adjustments

  • Carmustine (for injection)
    • Evaluate renal function prior to administration and periodically during treatment.
    • For patients with compromised renal function, monitor for toxicity more frequently.
    • Discontinue Carmustine (for injection) if the creatinine clearance is less than 10 mL/min.
    • Do not administer Carmustine (for injection) to patients with compromised renal function.
    • Monitor transaminases and bilirubin periodically during treatment.

Hepatic dose adjustments

  • Data not available. Dose adjustments may be required.

Geriatric dose adjustments

  • Data not available. Dose adjustments may be required.

Pediatric Use

  • Data not available. Dose adjustments may be required.

Overdosage

  • No specific antidote is known.
  • Symptoms of Overdosage includes
    • Myeloablation
    • Treatment of overdosage involves
    • General supportive measures.

Side effects or adverse effects

Side effects specific to Carmustine for injection

  • Myelosuppression
    • Bone marrow toxicity is a dose-limiting, common and severe toxic effect of Carmustine occurring 4-6 weeks after drug administration.
    • Thrombocytopenia occurs at about 4 weeks post-administration persisting for 1 to 2 weeks.
    • Leukopenia occurs at 5 to 6 weeks after a dose of Carmustine persisting for 1 to 2 weeks.
    • Thrombocytopenia is generally more severe than leukopenia.
    • Anemia is less frequent and less severe compared to thrombocytopenia and/or leukopenia.
    • Complete blood count should, therefore, be monitored weekly for at least six weeks after a dose.
    • Repeat doses of Carmustine should not be given more frequently than every six weeks.
    • The bone marrow toxicity of Carmustine is cumulative and therefore the dosage adjustment must be considered on the basis of nadir blood counts from prior dose.
    • Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when Carmustine was combined with cimetidine.
  • Pulmonary toxicity
    • Cases of fatal pulmonary toxicity with Carmustine have been reported.
    • 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.
    • Pulmonary toxicity from Carmustine is dose-related.
    • Patients receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those receiving less.
    • However, there have been reports of pulmonary fibrosis in patients receiving lower total doses.
    • Interstitial fibrosis (with lower doses) occurred rarely.
    • Additionally, delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients who received Carmustine (in cumulative doses ranging from 770 to 1800 mg/m2 combined with cranial radiotherapy for intracranial tumors) in childhood and early adolescence.
    • Other risk factors include past history of lung disease and duration of treatment.
    • 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.
  • Administration reaction
    • 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.
    • 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.
  • Carcinogenicities
    • Secondary malignancies may develop.
  • Ocular toxicity
    • Ocular toxicity may develop.
  • Embryo fetal toxicities
    • Carmustine can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Side effects specific to Carmustine implant

  • Seizures
    • Development of new seizures or worsening of the pre-existing seizures within the first five post-operative days.
    • Median time to onset of seizures was 4 days.
    • Optimize anti-seizure therapy prior to surgery.
    • Monitor patients for seizures postoperatively.
  • Intracranial hypertension
    • Brain edema may occur.
    • Intracranial mass effect unresponsive to corticosteroids leading to brain herniation may occur.
    • Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection.
    • In refractory cases, consider re-operation and removal of Carmustine implant or imlant remnants.
  • Impaired neurosurgical wound healing
    • Wound dehiscence, delayed wound healing and subdural, sublegal, or wound effusions may occur.
  • Meningitis
    • Meningitis may occur.
    • Monitor postoperatively for signs of meningitis and central nervous system infection.
  • Wafer (implant) migration
    • Wafer migration may occur.
    • To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation.
    • Monitor patients for signs of obstructive hydrocephalus.
  • Embryo fetal toxicities
    • Carmustine can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Other side effects

  • Bone marrow depression
    • Bone marrow depression is the most serious side effect/toxicity. It is also a limiting factor for the dose. Infections and bleeding are the common complications.
    • Bone marrow depression results in granulocytopenia, agranulocytosis, thrombocytopenia and aplastic anemia.
    • Consult your doctor as soon as possible if you observe any of the below-mentioned symptoms:
      • Sore throat
      • Chills
      • Sudden fever
      • Weakness in limbs
      • Mouth ulcers
      • Bleeding gums
      • Sore mouth
      • Fast heart rate
      • Low blood pressure
      • Sore gums
      • Skin abscesses
      • Rapid breathing
      • Rapid progression of infection of any organ
      • Rapid progression of Septicemia
    • Gastrointestinal side effects
      • Nausea and vomiting are commonly observed with anticancer medicines.
      • Mucositis – painful inflammation and ulceration of mucus membrane lining the digestive tract.
      • Diarrhea, shredding of mucosa and hemorrhage due to decreased rate of renewal of gastrointestinal mucosa lining.
    • Skin
      • Alopecia or hair loss.
      • Dermatitis
    • Oral side effects
      • Breaches during chewing.
      • Depression of immunity due to a reduction in the number of WBCs largely increases the risk of oral infections.
      • Bleeding gums
      • Rapid progression of dental caries.
    • Gonadal side effects
      • Infertility due to Oligozoospermia in males.
      • Impotence in males.
      • Loss or reduces sex drive.
      • Inhibition of ovulation in females
      • Amenorrhea in females.
      • Damage to germinal cells may lead to mutagenesis.
    • Lymphoreticular tissue
      • Lymphocytopenia (reduced number of lymphocytes)
      • Inhibition of lymphocyte function.
      • Suppression of immunity due to bone marrow depression and reduced lymphocyte function highly increases the risk of opportunistic infections like:
        • Candida and other infections causing deep mycosis.
        • Cytomegalo virus
        • Herpes zoster
        • Pneumocystis jiroveci
        • Toxoplasma
      • Fetal side effects
        • Use of anti-cancer medicines in pregnant women may cause fetal damage leading to:
          • Fetal death
          • Abortion
          • Teratogenesis
        • Renal side effects
          • Renal failure, Gout, and Urate stones may develop in the urinary tract.
        • Hyperuricemia
          • An elevated level of uric acid is common in leukemia and bulky lymphomas.
        • Please note: The side effects mentioned above are from the reported cases. However, side effects are not limited to above-mentioned conditions and symptoms. Consult your doctor as soon as possible if you feel or observe any symptoms that you relate to your treatment.

Warnings & Precautions

  • Carmustine can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment and for 2 weeks after the final dose.

Contraindications

  • Contraindicated in patients with previous hypersensitivity to Carmustine.

Pregnancy & breast feeding warnings

  • Pregnancy
    • Category D, which means there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
  • Nursing
    • It is not known whether Carmustine is excreted in human breast milk or not.
    • Since many drugs are excreted in milk and because of the potential for side effects in nursing infants, a decision should be made whether to discontinue drug or to discontinue nursing.

Interactions

Drug – drug interactions

  • Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported when oral cimetidine has been coadministered with Carmustine. Consider alternative drugs to cimetidine.
  • Phenobarbital induces the metabolism of Carmustine and may compromise the antitumor activity of Carmustine. Consider alternative drugs to phenobarbital.
  • Carmustine, when coadministered with phenytoin, may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.
  • Concomitant use of Carmustine with following drugs/medicines should be strictly avoided.
    • Leflunomide as it increases the risk of infections.
    • Adalimumab as it increases the risk of infections.
    • Teriflunomide as it increases the risk of infections.
    • Certolizumab as it increases the risk of infections.
    • Clozapine as it may lower the WBC count.
    • Cimetidine may increase the suppressive effect of Carmustine on bone marrow function.
    • Tofacitinib as it increases the risk of infections.
    • Deferiprone as it may lower the WBC count.
    • Etanercept as it increases the risk of infections.
    • Fingolimod as it increases the risk of infections.
    • Golimumab as it increases the risk of infections.
    • Infliximab as it increases the risk of infections.
    • Thalidomide may increase the risk of dangerous blood clots.
    • Lomitapide may cause liver problems and concomitant use with Carmustine may increase that risk.
    • Mipomersen may cause liver problems and concomitant use with Carmustine may increase that risk.
    • Nalidixic acid as the combination may cause unusual bruising or bleeding, nausea, stomach pain, unusual weakness, low fever and loss of appetite.
    • Natalizumab as it increases the risk of infections.
    • Thiotepa may increase the blood levels of Carmustine.
    • Brentuximab may cause liver problems and concomitant use with Carmustine may increase that risk.
    • Doxorubicin may increase the side effects of Carmustine, especially on bone marrow function.
    • Aldesleukin may increase the side effects of Carmustine, especially on bone marrow function.
    • Alefacept as it increases the risk of infections.
    • Alemtuzumab as it increases the risk of infections.
    • Azathioprine as it increases the risk of infections.
    • Bedaquiline may cause liver problems and concomitant use with Carmustine may increase that risk.
    • Bendamustine may increase the side effects of Carmustine, especially on bone marrow function.
    • Carmustine may increase the side effects of Lomustine, especially on bone marrow function.
    • Busulfan may increase the side effects of Carmustine, especially on bone marrow function.
    • Naltrexone may cause liver problems and concomitant use with Carmustine may increase that risk.
    • Bleomycin may increase the side effects of Carmustine, especially on bone marrow function.
    • Canakinumab as it increases the risk of infections.
    • Cisplatin may increase the side effects of Carmustine, especially on bone marrow function.
    • Cladribine as it increases the risk of infections.
    • Capecitabine may increase the side effects of Carmustine, especially on bone marrow function.
    • Carboplatin may increase the side effects of Carmustine, especially on bone marrow function.
    • Daunorubicin may increase the side effects of Carmustine, especially on bone marrow function.
    • Cyclophosphamide may increase the side effects of Carmustine, especially on bone marrow function.
    • Ganciclovir may increase the side effects of Carmustine, especially on bone marrow function.
    • Dacarbazine may increase the side effects of Carmustine, especially on bone marrow function.
    • Decitabine may increase the side effects of Carmustine, especially on bone marrow function.
    • Dactinomycin may increase the side effects of Carmustine, especially on bone marrow function.
    • Roflumilast as it increases the risk of infections.

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Reference

  • Highlights of prescribing information: 1, 2
By |2017-12-20T13:14:01+00:00August 10th, 2017|medicines|0 Comments

About the Author:

B. Pharm (K.L.E. society's S.V.V. Patil College of Pharmacy, Bengaluru) M. Pharm (Maharishi Arvind Institute of Pharmacy, Jaipur)

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