Oral: readily and completely absorbed. Highly lipid soluble, present in breast milk. Volume of distribution % within 96 hours

Transcription

1 Drug Monograph Drug Name Mechanism of Action and Pharmacokinetics Indications and Status Adverse ffects Dosing Administration Guidelines Special Precautions Interactions Recommended Clinical Monitoring References A Drug Name carmustine SYNONYM(S): 3 bis(2 chloroethyl) 1 nitrosourea; BCNU COMMON TRAD NAM(S): BiCNU (Bristol Myers Squibb) B Mechanism of Action and Pharmacokinetics Carmustine is a highly lipophilic nitrosourea compound which undergoes hydrolysis in vivo to form reactive metabolites. These metabolites cause alkylation and cross linking of DNA and RNA. Other biologic effects include inhibition of DNA repair and de novo purine synthesis. Nitrosoureas generally lack cross resistance with other alkylating agents. Absorption Distribution Metabolism limination Oral: readily and completely absorbed Highly lipid soluble, present in breast milk Cross blood brain barrier? Volume of distribution PPB Yes, CSF equilibrates within 1 hour to 30 97% of plasma levels 3.3L/kg 80% (in vitro) Rapid (within 15 minutes) degradation and metabolism via hepatic microsomal enzyme oxidation system; enterohepatic circulation of metabolites occurs. Active metabolites Inactive metabolites Yes Yes Predominantly by kidneys, 10% by respiratory excretion, 1% in feces Urine 60 70% within 96 hours Page 1 of 8

2 Half life Clearance (terminal) 22 minutes 56 ml/min/kg C Indications and Status Health Canada Approvals: Primary brain tumours Gastrointestinal cancer, advanced disease, when other treatment has failed Hodgkin s lymphoma Malignant melanoma (metastatic) Multiple myeloma Non Hodgkin s lymphomas D Adverse ffects metogenic potential: High (>250 mg/m2) Moderate ( 250 mg/m2) xtravasation Potential: Vesicant ORGAN SIT SID FFCT* (%) ONST** Cardiovascular Cardiac ischemia (high doses) I Flushing (lasting for about 4 hours) Hypotension Tachycardia Venous Thromboembolism (rare) Dermatological Rash I Gastrointestinal Anorexia Diarrhea Dysphagia sophagitis Nausea Vomiting I General Pain (chest pain) I I I I I Page 2 of 8

3 Hematological Myelosuppression (nadir 4 6 weeks, recovery 6 8 weeks; D L may be cumulative) Hepatobiliary LFTs (26%) (usually with high dose) L Hypersensitivity Hypersensitivity (rare) I Injection site Injection site reaction (burning, pain on injection common) I Phlebitis (chemical) Vein discolouration I Musculoskeletal Myalgia Neoplastic Leukemia (secondary) (acute leukemia, marrow dyscrasias) Nervous System Ataxia (including loss of balance) Dizziness ncephalopathy (acute rare) Headache Ophthalmic ye disorders (neuroretinitis with high dose or intracarotid) Other (conjunctival injection lasting for about 4 hours) I Renal Acute kidney injury (or glomerular and tubular lesions) D Reproductive and breast Gynecomastia (rare) disorders Infertility (rare) L Respiratory Lung infiltrate (up to 30%) L Pulmonary fibrosis (up to 30%) carmustine I L L * "Incidence" may refer to an absolute value or the higher value from a reported range. "Rare" may refer to events with < 1% incidence, reported in post marketing, phase 1 studies, isolated data or anecdotal reports. Dose limiting side effects are underlined. ** I = immediate (onset in hours to days) = early (days to weeks) D = delayed (weeks to months) L = late (months to years) Myelosuppression is common, dose related and cumulative. Since delayed bone marrow toxicity (nadir 4 6 weeks) is the major toxicity, blood counts should be monitored for at least 6 weeks after the dose. The tissue necrosis that happens with extravasation may occur weeks to months after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected. Carmustine induced pulmonary toxicity is dose related (cumulative doses 1200 to 1500 mg/m 2 ) and occurs in 20 30% of patients with mortality of 24 80%. The onset is usually within 3 years of treatment but can have an onset as late as 17 years after completion of treatment. Steroids are seldom of benefit. Risk factors include pre existing lung disease, smoking, treatment with other agents which cause pulmonary toxicity and recent thoracic radiation. There is a high Page 3 of 8

4 incidence in patients treated for pediatric malignancies which does not appear to be related to cumulative dose. Patients with baseline forced vital capacity (FVC) and/or pulmonary diffusion capacity for carbon monoxide (DL CO ) that are less than 70% of the predicted value are at high risk. Carmustine should be discontinued in patients with respiratory syndromes, and patients should be investigated for pulmonary toxicity. Nausea and vomiting are dose related but may be severe, with an onset of a few minutes to 2 hours after administration and lasting 4 6 hours. Local burning occurs at the injection site and along the course of the vein. Rapid IV infusion may produce facial flushing and conjunctival injection. These effects are thought to be secondary to the alcohol diluent. When used in high doses ( mg/m 2 ) prior to bone marrow transplantation, toxicities include severe nausea and vomiting, encephalopathy, hepatotoxicity and pulmonary toxicity. Hepatotoxicity and pulmonary toxicity may be dose limiting. The pulmonary toxicity of high dose carmustine may manifest as severe interstitial pneumonitis, which occurs most frequently in patients who have had recent radiation to the mediastinum. Renal toxicity is seen in patients who have received high cumulative doses of carmustine. carmustine Dosing Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Dosage may need adjustment when given concomitantly with other myelotoxic drugs. Guidelines for dosing also include consideration of white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy. Due to carmustine s late nadir (at 4 6 weeks), it should be given no more frequently than every 6 weeks. Lifetime dosage should not exceed 1400mg/m 2. Page 4 of 8

5 Adults: Intravenous: mg/m² very 6 weeks Bone marrow transplant: Much higher doses are used for ablation prior to marrow transplantation Dosage with Toxicity: Dosage with myelosuppression: A repeat course should not start until hematological recovery (i.e. platelets 100 x 10 9 /L and WBC 4 x 10 9 /L). WBC (x 10 9 /L) Platelets (x 10 9 /L) % usual dose or % or % <2 or <25 50% Dosage with pulmonary toxicity: Discontinue pending investigation. Dosage with Hepatic Impairment: Dosage adjustment may be necessary; no specific recommendations found. Dosage with Renal Impairment: xcreted via the kidney. Use with caution. Suggested dose modifications: Creatinine clearance (ml/min) Dosage No recommendations found <10 Discontinue Page 5 of 8

6 Dosage in the elderly: Risk of adverse effects may be greater due to decreased renal function. Use q8w: 50 75% of usual dose Children: Use with extreme caution in children due to the high risk of pulmonary toxicity. F Administration Guidelines Before reconstitution, if the drug liquefies and appears as an oil film on the bottom of the vial, this is a sign of degradation and the vial should be discarded. Reconstitute with the supplied diluent (absolute alcohol) and sterile water for injection (SWI) as directed. Solution in the supplied diluent must be complete before SWI is added. Mix in mL polyolefin bag/glass bottle (5% Dextrose, Normal Saline). Use non PVC tubing. Rapidly degraded in aqueous solutions at ph greater than 6; drug should not be admixed with nor given through the same tubing or site with sodium bicarbonate containing solutions. Infuse IV over 60 minutes or longer (faster infusion, if tolerated). xtra IV fluid (up to 750mL) may be run at the same time by piggyback, to reduce vein irritation. May be mixed in 500mL Normal Saline and infused through main IV line, with an additional 250mL Normal Saline co infused through a piggyback line (more IV fluid if ordered by physician). Should be protected from light and must be refrigerated (2 8 o C). G Special Precautions Other: Carmustine is contraindicated in patients who are hypersensitive to the drug or any component of its formulation. Carmustine has been shown to be teratogenic, clastogenic, mutagenic, embryotoxic and carcinogenic in experimental models and should not be used in pregnancy. ffective contraception should be used by both sexes during carmustine treatment and for at least 6 months after the last dose. Present in breast milk; therefore, breast feeding is not recommended. Page 6 of 8

7 Carmustine is classified as dangerous goods (a flammable substance) under the Transportation of Dangerous Goods Act, and must be declared as such for the purpose of transportation. H Interactions AGNT FFCT MCHANISM MANAGMNT Cimetidine potentiates marrow toxicity of carmustine possible metabolism of carmustine do not use cimetidine; choose a different H2 blocker Digoxin may serum digoxin levels possibly due to alterations of the GI mucosa caused by carmustine and/or other chemotherapy observe for decreased effect of digoxin; adjust digoxiin dose if necessary Phenytoin may serum phenytoin levels possibly due to phenytoin absorption or metabolism of phenytoin monitor serum phenytoin levels; adjust phenytoin dose if necessary Mitomycin corneal and conjunctival damage abnormal tearing Caution; monitor closely I Recommended Clinical Monitoring Recommended Clinical Monitoring CBC; baseline and regular Pulmonary function tests especially in patients at risk (lung disease, thoracic radiation, smokers, DLco <70%, FVC <70%); baseline and regular Renal and liver function tests; baseline and regular Clinical toxicity assessment for pulmonary toxicity, fever, infection, nausea and vomiting. Grade toxicity using the current NCI CTCA (Common Terminology Criteria for Adverse vents) version Suggested Clinical Monitoring Page 7 of 8

8 Local Site Toxicity ratings J References Aronoff GR, Bennett WM, Berns JS, editors. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults. 4th ed. The American College of Physicians; Cancer Drug Manual (the Manual), 1994, British Columbia Cancer Agency (BCCA). Carmustine: e Drugdex. Micromedex Healthcare Series. Carmustine: e Cancer Chemotherapy Manual. Mcvoy GK, editor. AHFS Drug Information Bethesda: American Society of Health System Pharmacists, p Revised January 2010 Page 8 of 8