Carmustine (Page 2 of 5)

5.1 Myelosuppression

Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine for injection 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 for injection 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 for injection should not be given more frequently than every six weeks. The bone marrow toxicity of carmustine for injection 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 for injection 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 for injection and related nitrosoureas. Pulmonary toxicity from carmustine for injection is dose-related. Patients receiving greater than 1,400 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 for injection (in cumulative doses ranging from 770 mg/m2 to 1,800 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.

5.3 Administration Reactions

Injection site reactions may occur during the administration of carmustine for injection. Rapid intravenous infusion of carmustine for injection 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 for injection, 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 for injection, has carcinogenic potential in humans. Patients treated with carmustine for injection should be monitored long-term for development of second malignancies.

5.5 Ocular Toxicity

Carmustine for injection 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 injection, for at least 6 months after therapy. Advise males of reproductive potential to use effective contraception during and after treatment with carmustine for injection, for at least 3 months after therapy [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

The following adverse reactions associated with the use of carmustine for injection 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

7 DRUG INTERACTIONS

7.1 Effects of Other Drugs on Carmustine for Injection

Cimetidine

Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported when oral cimetidine has been co-administered with carmustine. Consider alternative drugs to cimetidine.

Phenobarbital

Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine for injection. Consider alternative drugs to phenobarbital.

7.2 Effects of Carmustine for Injection on Other Drugs

Phenytoin

Carmustine for injection when co-administered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Carmustine for injection can cause fetal harm when administered to a pregnant woman based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals [see Data]. Limited available data with carmustine for injection use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage. Carmustine was embryotoxic in rats and rabbits and teratogenic in rats (thoracoabdominal closure, neural tube, and eye defects and malformations of the skeletal system of the fetus) when given in doses lower than the maximum cumulative human dose based on body surface area. Consider the benefits and risks of carmustine for injection, for the mother and possible risks to the fetus when prescribing carmustine for injection to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Intraperitoneal (IP) administration of carmustine to pregnant rats 14 days prior to mating and during the period of organogenesis at cumulative doses ≥ 26 mg/kg (158 mg/m2), approximately 0.1 times the maximum cumulative human dose of 1,400 mg/m2 , resulted in pre-implantation loss, increased resorptions (including completely resorbed litters), and reduced the number of live births in the presence of maternal toxicity.

Carmustine administered IP to pregnant rats during the period of organogenesis at cumulative doses ≥ 4 mg/kg (24 mg/m2), approximately 0.02 times the maximum cumulative human dose based on a mg/m2 basis, resulted in reduced fetal weight and various malformations, which included thoracoabdominal closure defects, neural tube defects, and eye defects, including microphthalmia/anophthalmia, and skeletal anomalies in the skull, sternebra, vertebrae and ribs, and reduced skeletal ossification) in the presence of maternal toxicity. Embryo-fetal death was observed at cumulative doses ≥ 8 mg/kg (48 mg/m2), approximately 0.03 times the maximum cumulative human dose on a mg/m2 basis. Intravenous (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/m2), approximately 0.2 times the maximum cumulative human dose on a mg/m2 basis, during the last quarter of pregnancy resulted in the death of offspring within 4 months. Carmustine administered IV to rabbits during the period of organogenesis resulted in spontaneous abortions in mothers and growth defects in the fetus, mainly at cumulative doses ≥ 13 mg/kg (156 mg/m2), approximately 0.1 times the maximum cumulative human dose on a mg/m2 basis.

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