Page 8 - 2020 Catalog

FULL PRESCRIBING INFORMATION potential risk to the fetus [see Use in Specific Populations (8.1, 8.3)]. Advise females of The mechanism of action of carmustine is not fully understood. While carmustine alkylates DNA
reproductive potential to use highly effective contraception during and after treatment with and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also
carmustine for injection, USP for at least 6 months after therapy. Advise males of reproductive inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The
WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY potential to use effective contraception during and after treatment with carmustine for injection, metabolites may contribute to antitumor activity and toxicities of carmustine.
Myelosuppression USP for at least 3 months after therapy [see Use in Specific Populations (8.1, 8.3)]. 12.2 Pharmacodynamics
Carmustine for injection, USP causes suppression of marrow function 6 ADVERSE REACTIONS The exposure-response relationship for efficacy or safety is unknown.
(including thrombocytopenia and leukopenia), which may contribute to The following serious adverse reactions are described elsewhere in the labeling: 12.3 Pharmacokinetics
bleeding and overwhelming infections . [see Warnings and Precautions (5.1) • Myelosuppression [see Warnings and Precautions (5.1)] Distribution
and Adverse Reactions (6)]. Monitor blood counts weekly for at leas t 6 weeks • Pulmonary toxicity [see Warnings and Precautions (5.2)] Carmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or
after each dos e. Adjust dosage based on nadir blood counts from the prior dos • Administration Reactions [see Warnings and Precautions (5.3)] equal to 50% of those measured concurrently in plasma.
e [see Dosage and Administration (2.1)]. Do not administer a repeat course of • Carcinogenicity [see Warnings and Precautions (5.4)] Elimination
carmustine for injection, USP until blood counts recover. • Ocular Toxicity [see Warnings and Precautions (5.5)] Following a short intravenous infusion, the reported elimination half-life ranges from 15 minutes
Pulmonary Toxicity The following adverse reactions associated with the use of carmustine for injection, USP were to 75 minutes.
Carmustine for injection, USP causes dose-related pulmonary toxicity. Patients identified in clinical studies or postmarketing reports. Because some of these reactions were Metabolism
receiving greater than 1400 mg/m cumulative dose are at significantly higher reported voluntarily from a population of uncertain size, it is not always possible to reliably Carmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and
risk than those receiving less. Delayed pulmonary toxicity can occur years after estimate their frequency or establish a causal relationship to drug exposure. microsomal enzymes, including NADPH and glutathione-S-transferase.
treatment, and can result in death, particularly in patients treated in childhood Cardiac Disorders Excretion
[see Adverse Reactions (6) and Use in Specific Populations (8.4)]. Tachycardia and chest pain. Approximately 60% to 70% of a total dose is excreted in the urine within 96 hours.
Eye Disorders Approximately 10% is eliminated as respiratory CO2.
1 INDICATIONS AND USAGE Conjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perception 13 NONCLINICAL TOXICOLOGY
Carmustine for injection, USP is indicated as palliative therapy as a single agent or in Gastrointestinal Toxicity 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
established combination therapy in the following: Nausea, vomiting, anorexia, and diarrhea Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in
- Brain tumors glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma, Hepatotoxicity doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic
and metastatic brain tumors. Increased transaminase, increased alkaline phosphatase, increased bilirubin levels potential in humans [see Adverse Reactions (6.1)].
- Multiple myeloma in combination with prednisone. Infections and Infestations Carmustine was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology
- Relapsed or refractory Hodgkin's lymphoma in combination with other approved drugs. Opportunistic infection (including with fatal outcome). studies.
- Relapsed or refractory Non-Hodgkin's lymphomas in combination with other approved drugs. Neoplasms Benign, Malignant and Unspecified (including cysts and polyps) Male rats treated with carmustine at cumulative doses _ 36 mg/kg (216 mg/ m2), approximately
2 DOSAGE AND ADMINISTRATION Acute leukemia, bone marrow dysplasias. 0.15 times the maximum cumulative human dose on a mg/ m2 basis, showed decreases in
2.1 Dosage Nephrotoxicity reproductive potential when mated with untreated female rats (e.g., decreased implantations,
The recommended dose of carmustine for injection, USP as a single agent in previously Progressive azotemia, decrease in kidney size, renal failure increased resorption rate, and a decrease in viable
untreated patients is 150 to 200 mg/m2 intravenously every 6 weeks. Administer as a single Nervous System Disorders fetuses).
dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days. Lower the Headaches, encephalopathy, and seizures 15 REFERENCES
dose when carmustine for injection, USP is used with other myelosuppressive drugs or in Pulmonary Toxicity 1. “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
patients in whom bone marrow reserve is depleted. Administer carmustine for injection, USP for Pneumonitis, interstitial lung disease 16 HOW SUPPLIED/STORAGE AND HANDLING
the duration according to the established regimen. Premedicate each dose with anti-emetics. Reproductive System and Breast Disorders 16.1 How Supplied
Adjust doses subsequent to the initial dose according to the hematologic response of the patient Gynecomastia Carmustine for injection, USP. Each package includes a vial containing 100 mg carmustine and
to the preceding dose. The following schedule is suggested as a guide to dosage adjustment: Skin and Subcutaneous Tissue Disorders a vial containing 3 mL sterile diluent.
Burning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic NDC 70710-1525-9
reaction 16.2 Storage and Handling
Vascular Disorders Store product and diluent in a refrigerator (2°-8°C, 36°-46°F).
Veno-occlusive disease. Stability
7 DRUG INTERACTIONS Store the unopened vial of the dry drug in a refrigerator (2°-8°C, 36°-46°F). Store the diluent
7.1 Effects of Other Drugs on carmustine for injection, USP vials in a refrigerator (2°-8°C, 36°-46°F). The recommended storage of unopened carmustine for
Cimetidine: Greater myelosuppression (e.g., leukopenia and neutropenia) has been reported injection, USP vials provides a stable product for up to 2 years.
The hematologic toxicity can be delayed and cumulative. Monitor blood counts weekly. Do not when oral cimetidine has been coadministered with carmustine. Consider alternative drugs to Compatibility/ Incompatibility with Containers
administer a repeat course of carmustine for injection, USP until circulating blood elements have cimetidine. The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC
returned to acceptable levels (platelets above 100 Gi/L, leukocytes above 4 Gi/L and absolute Phenobarbital: Phenobarbital induces the metabolism of carmustine and may compromise Containers. Administer carmustine for injection, USP solution from the glass bottles or
neutrophil count above 1 Gi/L). The usual interval between courses is 6 weeks. antitumor activity polypropylene container only. Ensure the polypropylene containers used are PVC free
Evaluate renal function prior to administration and periodically during treatment. For patients with of carmustine for injection, USP. Consider alternative drugs to phenobarbital. and DEHP free.
compromised renal function, monitor for toxicity more frequently. Discontinue carmustine for 7.2 Effects of carmustine for injection, USP on Other Drugs Important Note
injection, USP if the creatinine clearance is less than 10 mL/min. Do not administer carmustine Phenytoin: Carmustine for injection, USP when coadministered with phenytoin may reduce Carmustine for injection, USP has a low melting point (30.5°-32.0°C or 86.9°-89.6°F). Exposure
for injection, USP to patients with compromised renal function. Monitor transaminases and phenytoin serum concentrations. Consider alternative drugs to phenytoin. of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film
bilirubin periodically during treatment. [see Adverse Reactions (6)]. 8 USE IN SPECIFIC POPULATIONS on the vials. This is a sign of decomposition and vials should be discarded. If there is a question
2.2 Preparation and Administration of Intravenous Solution 8.1 Pregnancy of adequate refrigeration upon receipt of this product, immediately inspect the vial in each
• Dissolve carmustine for injection, USP with 3 mL of the supplied sterile diluent (Dehydrated Risk Summary individual carton. Hold the vial to a bright light for inspection. The carmustine for injection, USP
Alcohol Injection, USP). Carmustine for injection, USP can cause fetal harm when administered to a pregnant woman will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the
• Aseptically add 27 mL Sterile Water for Injection, USP. based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals carmustine for injection, USP is suitable for use and should be refrigerated immediately.
• Each mL of resulting solution contains 3.3 mg of carmustine for injection, USP in 10% ethanol. [see Data]. Limited available data with carmustine for injection, USP use in pregnant women are 17 PATIENT COUNSELING INFORMATION
Such solutions should be protected from light. insufficient to inform a drug-associated risk of major birth defects and miscarriage. Carmustine Myelosuppression [see Warnings and Precautions (5.1)].
• The reconstituted solution is a clear, colorless to yellowish solution. was embryotoxic in rats and rabbits and teratogenic in rats (thoracoabdominal closure, neural A serious and frequent toxicity of carmustine for injection, USP is delayed myelosuppression and
• Once reconstituted, the solution must be further diluted with Sodium Chloride Injection, USP or tube, and eye defects and malformations of the skeletal system of the fetus) when given in usually occurs 4 to 6 weeks after drug administration. Hence, patients should be advised to get
5% Dextrose Injection, USP. doses lower than the maximum cumulative human dose based on body surface area. Consider blood counts monitored weekly for at least 6 weeks. The bone marrow toxicity of carmustine for
• Examine reconstituted vials for crystal formation prior to use. If crystals are observed, they may the benefits and risks of carmustine for injection, USP for the mother and possible risks to the injection, USP is cumulative.
be re-dissolved by warming the vial to room temperature with agitation. fetus when prescribing carmustine for injection, USP to a pregnant woman. Pulmonary Toxicity [see Warnings and Precautions (5.2)].
• Parenteral drug products should be inspected visually for particulate matter and discoloration Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of Advise patients to contact a health care professional immediately for any of the following:
prior to administration, whenever solution and container permit. medications. The estimated background risk of major birth defects and miscarriage for the shortness of breath, particularly during exercise, dry, hacking cough, fast, shallow breathing,
• After reconstitution as recommended, carmustine for injection, USP is stable for 24 hours indicated population is unknown. In the U.S. general population, the estimated background risk gradual unintended weight loss, tiredness, aching joints and muscles, clubbing (widening and
under refrigeration (2°-8°C, 36°-46°F) in glass container. Examine reconstituted vials for crystal of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, rounding) of the tips of the fingers or toes.
formation prior to use. If crystals are observed, they may be redissolved by warming the vial to respectively. Seizures [see Adverse Reactions (6)] Inform the patient that they may suffer from fits and advise
room temperature with agitation. Data them to get medical attention immediately in such cases.
• Vials reconstituted as directed and further diluted with 500 mL Sodium Chloride Injection, USP Animal Data Pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1 and 8.3)]
or 5% Dextrose Injection, USP, in glass or polypropylene containers to a concentration of 0.2 Intraperitoneal (IP) administration of carmustine to pregnant rats 14 days prior to mating and Advise pregnant women and females of reproductive potential that carmustine for injection, USP
mg/mL, should be stored at room temperature, protected from light and utilized within 8 hours. during the period of organogenesis at cumulative doses _ 26 mg/kg (158 mg/ m2), approximately exposure during pregnancy can result in fetal harm. Advise female patients to contact their
These solutions are also stable 24 hours under refrigeration (2°-8°C, 36°-46°F) and an additional 0.1 times the maximum cumulative human dose of 1400 mg/m2, resulted in pre-implantation healthcare provider with a known or suspected pregnancy. Advise women of reproductive
6 hours at temperature protected from light. loss, increased resorptions (including completely resorbed litters), and reduced the number of potential to avoid becoming pregnant. Advise
• Administer reconstituted solution by slow intravenous infusion over at least two hours. live births in the presence of maternal toxicity. Carmustine administered IP to pregnant rats females of reproductive potential to use effective contraception during treatment.
Administration of carmustine for injection, USP over a period of less than two hours can lead to during the period of organogenesis at cumulative doses _ 4 mg/kg (24 mg/m2), approximately Lactation [see Use in Specific Populations (8.2)]
pain and burning at the site of injection. Monitor the injected area during the administration. The 0.02 times the maximum cumulative human dose based on a mg/m2 basis, resulted in reduced Advise the female patient to discontinue nursing while taking carmustine for injection, USP.
rate of administration of the intravenous infusion should not be more than 1.66 mg/m2/min fetal weight and various malformations, which included thoracoabdominal closure defects, neural
• See Section 16.2 for important instructions on the storage and handling of the injection. tube defects, and eye defects, including microphthalmia/anophthalmia, and skeletal anomalies in INSTRUCTIONS FOR USE OF PRODUCT KIT GUARD FOR
Carmustine for injection, USP is a cytotoxic drug. Follow applicable special handling and the skull, sternebra, vertebrae and ribs, and reduced skeletal ossification) in the presence of CARMUSTINE FOR INJECTION, USP, 100 MG/VIAL
disposal procedures.1 maternal toxicity. Embryo-fetal death was observed at cumulative doses _ 8 mg/kg (48 mg/m2), About Product Kit Guard
• The lyophilized dosage formulation contains no preservatives and is not intended for use as a approximately 0.03 times the maximum cumulative human dose on a mg/ m2 basis. Intravenous − This Product Kit Guard is specially designed for your safety.
multiple dose via. Accidental contact of reconstituted carmustine for injection, USP with the skin (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/ m2), − Please do not remove the vials from the Product Kit Guard.
has caused transient hyperpigmentation of the affected areas. Wear impervious gloves to approximately 0.2 times the maximum cumulative human dose on a mg/m2 basis, during the last − Keep the Product Kit Guard in a carton till the time of use.
minimize the risk of dermal quarter of pregnancy resulted in the death of offspring within 4 months. Carmustine administered How to use this Product Kit Guard
exposure impervious gloves when handling vials containing carmustine for injection, USP. IV to rabbits during the period of organogenesis resulted in spontaneous abortions in mothers The instructions below explain how to use this Product Kit Guard Product Kit Guard has two
Immediately wash the skin or mucosa thoroughly with soap and water if carmustine for injection, and growth defects in the fetus, mainly at cumulative doses _ 13 mg/kg (156 mg/ m2), compartments. One holds 100 mg carmustine vial and other holds the 3 mL sterile diluent
USP lyophilized material or solution contacts the skin or mucosa1. approximately 0.1 times the maximum cumulative human dose on a mg/ m2 basis. (Dehydrated Alcohol Injection, USP) vial.
3 DOSAGE FORMS AND STRENGTHS 8.2 Lactation List of items required: gloves, alcohol swabs, sterile syringe.
For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for Risk Summary Wear gloves at all times when handling Product Kit Guard.
reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP). There is no information regarding the presence of carmustine in human milk, the effects on the Discard the Product Kit Guard after use.
4 CONTRAINDICATIONS breastfed infant, or the effects on milk production. Because many drugs are excreted in human
Carmustine for injection, USP is contraindicated in patients with previous hypersensitivity to milk and because of the potential for serious adverse events (e.g., carcinogenicity and
carmustine for injection, USP or its components. myelosuppression) in nursing infants, nursing should be discontinued while taking carmustine for
5 WARNINGS AND PRECAUTIONS injection, USP.
5.1 Myelosuppression 8.3 Females and Males of Reproductive Potential
Bone marrow toxicity is a dose-limiting, common and severe toxic effect of carmustine for Contraception
injection, USP occurring 4-6 weeks after drug administration (thrombocytopenia occurs at about Advise female patients to avoid pregnancy during treatment with carmustine for injection, USP
4 weeks post-administration persisting for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks after because of the risk of fetal harm [see Use in Specific Populations (8.1)].
a dose of carmustine for injection, USP persisting for 1 to 2 weeks; thrombocytopenia is Advise female patients of reproductive potential to use highly effective contraception during and
generally more severe than leukopenia; anemia is less frequent and less severe compared to for up to six months after completion of treatment.
thrombocytopenia and/or leukopenia) Complete blood count should therefore be monitored Advise males with female sexual partners of reproductive potential to use effective contraception
weekly for at least six weeks after a dose. Repeat doses of carmustine for injection, USP should during carmustine for injection, USP treatment and for at least three months after the final dose
not be given more frequently than every six weeks. The bone marrow toxicity of carmustine for of carmustine for injection, USP [see Nonclinical Toxicology (13.1)].
injection, USP is cumulative and therefore the dosage adjustment must be considered on the Infertility
basis of nadir blood counts from prior dose [see Adverse Reactions (6)]. Greater myelotoxicity Based on nonclinical findings, male fertility may be compromised by treatment with carmustine
(e.g., leukopenia and neutropenia) has been reported when carmustine was combined with for injection, USP [see Nonclinical Toxicology (13.1)].
cimetidine [see Drug Interactions (7)]. 8.4 Pediatric Use
5 . 2 Pulmonary Toxicity Safety and effectiveness in children have not been established. Delayed onset pulmonary
Cases of fatal pulmonary toxicity with carmustine for injection, USP have been reported. fibrosis occurring up to 17 years after treatment has been reported in long-term study of patients
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to who received carmustine for injection, USP in childhood and early adolescence (1-16 years).
occur from 9 days to 43 months after treatment with carmustine for injection, USP and related Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5
nitrosoureas. Pulmonary toxicity from carmustine for injection, USP is dose-related. Patients patients initially treated at less than 5 years of age, died of pulmonary fibrosis. [see Adverse
receiving greater than 1400 mg/m2 cumulative dose are at significantly higher risk than those Reactions (6.1)].
receiving less. However, there have been reports of pulmonary fibrosis in patients receiving 8.5 Geriatric Use
lower total doses. Interstitial fibrosis (with lower doses) occurred rarely. Additionally, delayed Clinical studies of carmustine for injection, USP did not include sufficient numbers of subjects
onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in patients aged 65 and over to determine whether they respond differently from younger subjects. Other
who received carmustine for injection, USP (in cumulative doses ranging from 770 to 1800 reported clinical experience has not identified differences in responses between the elderly and
mg/m2 combined with cranial radiotherapy for intracranial tumors) in childhood and early younger patients. In general, dose selection for an elderly patient should be cautious, usually
adolescence. Other risk factors include past history of lung disease and duration of treatment. starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic,
Baseline pulmonary function studies should be conducted along with frequent pulmonary renal, or cardiac function, and of concomitant disease or other drug therapy.
function tests during treatment. Patients with a baseline below 70% of the predicted forced vital Carmustine for injection, USP and its metabolites are known to be substantially excreted by the
capacity (FVC) or carbon monoxide diffusing capacity (DLCO) are particularly at risk. kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal
5.3 Administration Reactions function. Because elderly patients are more likely to have decreased renal function, care should
Injection site reactions may occur during the administration of carmustine for injection, USP. be taken in dose selection, and renal function should be monitored.
Rapid intravenous infusion of carmustine for injection, USP may produce intensive flushing of 10 OVERDOSAGE
the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. It is also The main result of overdose is myeloablation. No proven antidotes have been established for
associated with burning at the site of injection although true thrombosis is rare. Given the carmustine for injection, USP overdosage.
possibility of extravasation, close monitoring of the infusion site for possible infiltration during 11 DESCRIPTION
drug administration is recommended. A specific treatment for extravasation reactions is unknown The active ingredient in carmustine for injection, USP is a nitrosourea with the chemical name
at this time. 1,3-bis(2-chloroethyl)-1-nitrosourea and a molecular weight of 214.06. The drug product is
5.4 Carcinogenicity supplied as sterile lyophilized pale yellow flakes or a congealed mass, and it is highly soluble in
Long-term use of nitrosoureas, such as carmustine for injection, USP, has been reported to be alcohol and lipids, and poorly soluble in water. Carmustine for injection, USP is administered by
associated with the development of secondary malignancies. Carmustine was carcinogenic intravenous infusion after reconstitution, as recommended.
when administered to laboratory animals [see Nonclinical Toxicity (13.1)]. Nitrosourea therapy, The structural formula of carmustine is:
such as carmustine for injection, USP, has carcinogenic potential in humans. Patients treated
with carmustine for injection, USP should be monitored long-term for development of second
malignancies.
5.5 Ocular Toxicity

Carmustine for injection, USP has been administered through an intraarterial intracarotid route; Carmustine for injection, USP is available in 100-mg single-dose vials of lyophilized material. Please refer the product information leaflet before administration.
this procedure is investigational and has been associated with ocular toxicity. Safety and Sterile diluent for constitution of carmustine for injection, USP is co-packaged with the active For more information call Zydus Pharmaceuticals USA Inc. at +1-877-993-8779.
effectiveness of the intraarterial route have not been established. drug product for use in constitution of the lyophile. The diluent is supplied in a vial containing 3 Distributed by:
5.6 Embryo-Fetal Toxicity mL of Dehydrated Alcohol Injection, USP. Zydus Pharmaceuticals USA Inc.
Carmustine was embryotoxic in rats and rabbits and teratogenic in rats when given in doses 12 CLINICAL PHARMACOLOGY Pennington, NJ 08534
lower than the maximum cumulative human dose based on body surface area. There are no 12.1 Mechanism of Action Revised 10/2018
adequate and well-controlled studies in pregnant women. Advise pregnant women of the 30140518 R6