CARMUSTINE: 3,376 Adverse Event Reports & Safety Profile

The active ingredient in Carmustine for injection, USP is a nitrosourea with the chemical name 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.06. The drug product is supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine for Injection, USP is administered by intravenous infusion after reconstitution, as recommended. The structural formula of carmustine is: Carmustine for Injection, USP is available in 100-mg single dose vials of lyophilized material. Sterile diluent for constitution of Carmustine for Injection, USP is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 mL of Dehydrated Alcohol Injection, USP.

Structural Formula

The active ingredient in Carmustine for injection, USP is a nitrosourea with the chemical name 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.06. The drug product is supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in alcohol and lipids, and poorly soluble in water. Carmustine for Injection, USP is administered by intravenous infusion after reconstitution, as recommended. The structural formula of carmustine is: Carmustine for Injection, USP is available in 100-mg single dose vials of lyophilized material. Sterile diluent for constitution of Carmustine for Injection, USP is co-packaged with the active drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 mL of Dehydrated Alcohol Injection, USP.

Structural

Formula

AND USAGE Carmustine for Injection is a nitrosourea indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in the following: Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors (1) Multiple myeloma-in combination with prednisone (1) Relapsed or refractory Hodgkin's lymphoma in combination with other approved drugs (1) Relapsed or refractory Non-Hodgkin's lymphomas in combination with other approved drugs (1) Carmustine for injection is indicated as palliative therapy as a single agent or in established combination therapy in the following: Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. Multiple myeloma 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.

Carmustine for injection is indicated as palliative therapy as a single agent or in established combination therapy in the following: Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors. Multiple myeloma 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.

AND ADMINISTRATION Recommended Dosage: As a single agent, 150 to 200 mg/m 2 Carmustine for Injection intravenously every 6 weeks as a single dose or divided into daily injections such as 75 to 100 mg/m 2 on 2 successive days. Adjust dose for combination therapy or in patients with reduced bone marrow reserve (2.1) Administer reconstituted solution only as a slow intravenous infusion over at least 2 hours. (2.2)

2.1 Dosage The recommended dose of Carmustine for Injection as a single agent in previously untreated patients is 150 to 200 mg/m 2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m 2 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: Nadir After Prior Dose Percentage of Prior Dose to be Given Leukocytes/mm 3 Platelets/mm 3 >4000 >100,000 100% 3000-3999 75,000-99,999 100% 2000-2999 25,000-74,999 70% <2000 <25,000 50% The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of Carmustine for Injection 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. 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. [see Adverse Reactions (6) ].

2.2 Preparation and Administration of Intravenous Solution Dissolve carmustine for injection with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of carmustine in 10% ethanol. Such solutions should be protected from light. The reconstituted solution is a clear, colorless to yellowish solution. Once reconstituted, the solution must be further diluted with Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be re-dissolved by warming the vial to room temperature with agitation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution as recommended, carmustine for injection is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F) in glass container. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation. Vials reconstituted as directed and further diluted with 500 mL Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, in glass or polypropylene containers to a concentration of 0.2 mg/mL, should be stored at room temperature, protected from light and utilized within 8 hours. These solutions are also stable 24 hours under refrigeration (2°-8°C, 36°-46°F) and an additional 6 hours at room temperature protected from light. Administer reconstituted solution by slow intravenous infusion over at least two hours. Administration of carmustine for injection over a period of less than two hours can lead to pain and burning at the site of injection. Monitor the injected area during the administration. The rate of administration of the intravenous infusion should not be more than 1.66 mg/m 2 /min.

See Section

16.2 for important instructions on the storage and handling of the injection. carmustine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial. Accidental contact of reconstituted carmustine for injection with the skin has caused transient hyperpigmentation of the affected areas. Wear impervious gloves to minimize the risk of dermal exposure impervious gloves when handling vials containing carmustine for injection. Immediately wash the skin or mucosa thoroughly with soap and water if carmustine for injection lyophilized material or solution contacts the skin or mucosa 1 .

2.1 Dosage The recommended dose of Carmustine for Injection as a single agent in previously untreated patients is 150 to 200 mg/m 2 intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m 2 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: Nadir After Prior Dose Percentage of Prior Dose to be Given Leukocytes/mm 3 Platelets/mm 3 >4000 >100,000 100% 3000-3999 75,000-99,999 100% 2000-2999 25,000-74,999 70% <2000 <25,000 50% The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not administer a repeat course of Carmustine for Injection 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. 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. [see Adverse Reactions (6) ].

2.2 Preparation and Administration of Intravenous Solution Dissolve carmustine for injection with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Aseptically add 27 mL Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of carmustine in 10% ethanol. Such solutions should be protected from light. The reconstituted solution is a clear, colorless to yellowish solution. Once reconstituted, the solution must be further diluted with Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be re-dissolved by warming the vial to room temperature with agitation. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. After reconstitution as recommended, carmustine for injection is stable for 24 hours under refrigeration (2°-8°C, 36°-46°F) in glass container. Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may be redissolved by warming the vial to room temperature with agitation. Vials reconstituted as directed and further diluted with 500 mL Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, in glass or polypropylene containers to a concentration of 0.2 mg/mL, should be stored at room temperature, protected from light and utilized within 8 hours. These solutions are also stable 24 hours under refrigeration (2°-8°C, 36°-46°F) and an additional 6 hours at room temperature protected from light. Administer reconstituted solution by slow intravenous infusion over at least two hours. Administration of carmustine for injection over a period of less than two hours can lead to pain and burning at the site of injection. Monitor the injected area during the administration. The rate of administration of the intravenous infusion should not be more than 1.66 mg/m 2 /min.

See Section

16.2 for important instructions on the storage and handling of the injection. carmustine for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures. 1 The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose vial. Accidental contact of reconstituted carmustine for injection with the skin has caused transient hyperpigmentation of the affected areas. Wear impervious gloves to minimize the risk of dermal exposure impervious gloves when handling vials containing carmustine for injection. Immediately wash the skin or mucosa thoroughly with soap and water if carmustine for injection lyophilized material or solution contacts the skin or mucosa 1 .

Hypersensitivity (4) Carmustine for Injection is contraindicated in patients with previous hypersensitivity to carmustine or its components.

Carmustine for Injection is contraindicated in patients with previous hypersensitivity to carmustine or its components.

REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Seizures [ see Warnings and Precautions (5.1) ]

Intracranial

Hypertension [ see Warnings and Precautions (5.2) ]

Impaired Neurosurgical Wound

Healing [ see Warnings and Precautions (5.3) ] Meningitis [ see Warnings and Precautions (5.4) ] Newly-Diagnosed High-Grade Glioma: Most common adverse reactions (incidence >10% and between arm difference ≥4%) are cerebral edema, asthenia, nausea, vomiting, constipation, wound healing abnormalities and depression ( 6.1 ).

Recurrent

High-Grade Glioma: Most common adverse reactions (incidence >10% and between arm difference ≥4%) are urinary tract infection, wound healing abnormalities and fever ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly-Diagnosed High-Grade Glioma The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1). The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving GLIADEL Wafers compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1). The incidence of common adverse reactions in GLIADEL Wafer-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2.

Table

1. Per-Patient Incidence of Adverse Reactions Occurring in Gliadel Wafer-Treated Patients with Newly-Diagnosed High-Grade Glioma (Study 1) (Between Arm Difference of ≥ 4%)

Adverse

Reaction GLIADEL Wafer N=120 Placebo N=120 % % GASTROINTESTINAL Nausea 22 17 Vomiting 21 16 Constipation 19 12 Abdominal pain 8 2 GENERAL AND ADMINISTRATION SITE CONDITION Asthenia 22 15 Chest pain 5 0 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound healing abnormalities Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision) 16 12 MUSCULOSKELETAL AND CONNECTIVE TISSUE Back pain 7 3 PSYCHIATRIC Depression 16 10 Table 2. Incidence of Local Adverse Reactions, Study 1 Not seen at baseline or worsened if present at baseline.

Local Adverse

Reactions GLIADEL Wafer N=120 Placebo N=120 % % Cerebral edema 23 19 Intracranial hypertension 9 2 Cerebral hemorrhage 6 4 Brain abscess 6 4 Brain cyst 2 3 Recurrent High-Grade Glioma The safety of GLIADEL Wafers was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 222 patients with recurrent high-grade glioma who received up to eight GLIADEL Wafers or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 2). Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery. The population in Study 2 was 64% male, 92% White, and the median age was 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers. Sixty-four severe adverse reactions were reported in 43(39%) patients receiving GLIADEL Wafers. Adverse reactions in GLIADEL Wafer-treated patients are shown in Table 3. Meningitis occurred in four patients receiving GLIADEL Wafers and in no patients receiving placebo. Bacterial meningitis was confirmed in two patients: the first with onset four days following GLIADEL Wafer implantation; the second following resection for tumor recurrence 155 days following GLIADEL Wafer implantation. One case, attributed to chemical meningitis resolved following steroid treatment. The cause of the fourth case was undetermined but resolved following antibiotic treatment.

Table

3. Per-Patient Incidence of Adverse Reactions in Gliadel Wafer-Treated Patients with Recurrent High-Grade Glioma (Study 2) (Between Arm Difference of ≥ 4%)

Adverse

Reaction GLIADEL Wafer N=110 Placebo N=112 % % GENERAL Fever 12 8 INFECTIOUS Urinary tract infections 21 17 INJURY, POISONING AND PROCEDURAL COMPLICATIONS Wound healing abnormalities Included (1) fluid, CDS, or subdural fluid collection; (2) CSF leak; (3) wound dehiscence, breakdown, or poor healing; and (4) subgaleal or wound effusions (including yellow discharge at the incision) 14 5 The incidence of seizures is shown in Table 4. The incidence of hydrocephalus, cerebral edema and intracranial hypertension is shown in Table 5.

Table

4. Incidence of Seizures, Study 2 Adverse Reaction GLIADEL Wafer N=110 Placebo N=112 Patients with seizures (%) Any seizures after wafer implantation 37 29 New or worsening seizures 20 20 Time to new or worsening seizures (days) Days from implantation to onset of first new or worsening seizure. Mean (SD) 26.09 (0.75) 62.36 (48.66)

Median

3.5

61.0 Table 5. Hydrocephalus and Cerebral Edema, Study 2 Not seen at baseline or worsened if present at baseline.

Adverse

Reaction GLIADEL Wafer N=110 Placebo N=112 % % Hydrocephalus 5 2 Cerebral edema 4 1

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 for injection 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 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

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 1400 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 for injection (in cumulative doses ranging from 770 to 1800 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 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicity (13.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

5.1 Myelosuppression Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine for injection 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 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . Greater myelotoxicity (e.g., leukopenia and neutropenia) has been reported when carmustine was combined with cimetidine <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

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 1400 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 for injection (in cumulative doses ranging from 770 to 1800 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 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicity (13.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

INTERACTIONS Cimetidine: Increased myelosuppression with concomitant use. (7.1) Phenobarbital: Induces carmustine metabolism, reducing exposure. May lead to reduced efficacy. (7.1) Phenytoin: Carmustine for Injection may reduce the efficacy of phenytoin. (7.2)

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 coadministered with carmustine. Consider alternative drugs to cimetidine. Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine. Consider alternative drugs to phenobarbital.

7.2 Effects of Carmustine for Injection on Other Drugs Phenytoin: Carmustine when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

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 coadministered with carmustine. Consider alternative drugs to cimetidine. Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise antitumor activity of carmustine. Consider alternative drugs to phenobarbital.

7.2 Effects of Carmustine for Injection on Other Drugs Phenytoin: Carmustine when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.