carmustine

BOXED WARNING WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY Myelosuppression Carmustine causes suppression of marrow function (including thrombocytopenia and leukopenia), which may contribute to bleeding and overwhelming infections. [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6 )]. Monitor blood counts weekly for at least 6 weeks after each dose. Adjust dosage based on nadir blood counts from the prior dose [see Dosage and Administration ( 2.1 )]. Do not administer a repeat course of carmustine until blood counts recover. Pulmonary Toxicity Carmustine causes dose-related pulmonary toxicity. Patients receiving greater than 1,400 mg/m 2 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 [see Adverse Reactions ( 6 ) and Use in Specific Populations ( 8.4 )] . WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY See full prescribing information for complete boxed warning • Suppression of marrow function, notably thrombocytopenia and leukopenia, is the most common and severe of the toxic effects of carmustine. Monitor blood counts. ( 5 , 6 ). • Pulmonary toxicity from carmustine appears to be dose related. Patients receiving greater than 1,400 mg/m 2 cumulative dose are at significantly higher risk than those receiving less ( 5 , 6 ).

5 WARNINGS AND PRECAUTIONS • Administration Reactions: Extravasation may occur; monitor infusion site closely during administration ( 5.3 ) • Carcinogenicity: Potentially carcinogenic to humans. Monitor patient periodically for such signs and apprise the patient of the symptoms for which they need to seek medical help. ( 5.4 ) • Ocular Toxicity: Has occurred when administered via unapproved intraarterial intracarotid route. ( 5.5 ) • Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy. ( 5.6 ) 5.1 Myelosuppression Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine occurring 4 to 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 [see Adverse Reactions ( 6 )] . Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine [see Drug Interactions ( 7 )]. 5.2 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 1,400 mg/m 2 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 1,800 mg/m 2 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. 5.3 Administration Reactions Injection site reactions may occur during the administration of carmustine. 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. 5.4 Carcinogenicity Long-term use of nitrosoureas, such as carmustine, has been reported to be associated with the development of secondary malignancies. Carmustine was carcinogenic when administered to laboratory animals [see Nonclinical Toxicity ( 13.1 )] . Nitrosourea therapy, such as carmustine, has carcinogenic potential in humans. Patients treated with carmustine should be monitored long-term for development of second malignancies. 5.5 Ocular Toxicity Carmustine has been administered through an intraarterial intracarotid route; this procedure is investigational and has been associated with ocular toxicity. Safety and effectiveness of the intra­ arterial route have not been established. 5.6 Embryo-Fetal Toxicity Carmustine was embryotoxic in rats and rabbits and teratogenic in rats when given in doses lower than the maximum cumulative human dose based on body surface area. There are no adequate and well- controlled studies in pregnant women. Advise pregnant women of the potential risk to the fetus [see Use in Specific Populations ( 8.1 , 8.3 )]. Advise females of reproductive potential to use highly effective contraception during and after treatment with carmustine for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with carmustine for at least 3 months after therapy [see Use in Specific Populations ( 8.1 , 8.3 )].

5.1 Myelosuppression Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine occurring 4 to 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 [see Adverse Reactions ( 6 )] . Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine [see Drug Interactions ( 7 )].

5.2 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 1,400 mg/m 2 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 1,800 mg/m 2 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.

5.3 Administration Reactions Injection site reactions may occur during the administration of carmustine. 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: · Myelosuppression [see Warnings and Precautions ( 5.1 )] · Pulmonary toxicity [see Warnings and Precautions ( 5.2 )] · Administration Reactions [see Warnings and Precautions ( 5.3 )] · Carcinogenicity [see Warnings and Precautions ( 5.4 )] · Ocular Toxicity [see Warnings and Precautions ( 5.5 )] The following adverse reactions associated with the use of carmustine were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders Tachycardia and chest pain. Eye Disorders Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perception Gastrointestinal Toxicity Nausea, vomiting, anorexia, and diarrhea Hepatotoxicity Increased transaminase, increased alkaline phosphatase, increased bilirubin levels Infections and Infestations Opportunistic infection (including with fatal outcome). Neoplasms Benign, Malignant and Unspecified (including cysts and polyps) Acute leukemia, bone marrow dysplasias. Nephrotoxicity Progressive azotemia, decrease in kidney size, renal failure Nervous System Disorders Headaches, encephalopathy, and seizures Pulmonary Toxicity Pneumonitis, interstitial lung disease Reproductive System and Breast Disorders Gynecomastia Skin and Subcutaneous Tissue Disorders Burning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic reaction Vascular Disorders Veno-occlusive disease. Most common adverse reactions (>1%) are nausea, vomiting, renal toxicity, pneumonitis, pulmonary toxicity, myelosuppression ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr.Reddy's Laboratories Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.