NDC 54879-036 Carmustine

Carmustine

NDC Product Code 54879-036

NDC 54879-036-64

Package Description: 1 KIT in 1 CARTON * 30 mL in 1 VIAL, SINGLE-DOSE (54879-023-51) * 3 mL in 1 VIAL (54879-024-13)

NDC Product Information

Carmustine with NDC 54879-036 is a a human prescription drug product labeled by Sti Pharma Llc. The generic name of Carmustine is carmustine. The product's dosage form is kit and is administered via form.

Labeler Name: Sti Pharma Llc

Dosage Form: Kit - A packaged collection of related material.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • ALCOHOL (UNII: 3K9958V90M)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Sti Pharma Llc
Labeler Code: 54879
FDA Application Number: ANDA209278 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-16-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Carmustine Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Myelosuppression And Pulmonary Toxicity

MyelosuppressionCarmustine for Injection 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 for Injection until blood counts recover.





Pulmonary ToxicityCarmustine for Injection causes dose-related pulmonary toxicity. Patients receiving greater than 1400 mg/m





2cumulative 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)]





.

Other

  • 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.

For injection: 100 mg of carmustine as a lyophilized powder in a single-dose vial for reconstitution and a vial containing 3 mL sterile diluent (Dehydrated Alcohol Injection, USP).

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

The main result of overdose is myeloablation. No proven antidotes have been established for Carmustine for Injection overdosage.

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.

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 DosePercentage of Prior Dose to





be Given





Leukocytes/mm





3Platelets/mm





3>4000>100,000100%3000-399975,000-99,999100%2000-299925,000-74,99970%<2000<25,00050%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.
  • 1The lyophilized dosage formulation contains no preservatives and is not intended for use as a multiple dose via.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.

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 [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 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


[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: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 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 DisordersTachycardia and chest pain.Eye DisordersConjunctival edema, conjunctival hemorrhage, blurred vision and loss of depth perceptionGastrointestinal ToxicityNausea, vomiting, anorexia, and diarrheaHepatotoxicityIncreased transaminase, increased alkaline phosphatase, increased bilirubin levelsInfections and InfestationsOpportunistic infection (including with fatal outcome).Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)Acute leukemia, bone marrow dysplasias.NephrotoxicityProgressive azotemia, decrease in kidney size, renal failureNervous System DisordersHeadaches, encephalopathy, and seizuresPulmonary ToxicityPneumonitis, interstitial lung diseaseReproductive System and Breast DisordersGynecomastiaSkin and Subcutaneous Tissue DisordersBurning sensation, hyperpigmentation, swelling, pain, erythema, skin necrosis, alopecia, allergic reactionVascular DisordersVeno-occlusive disease.

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.

8.1 Pregnancy

Risk SummaryCarmustine 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 2-4% and 15-20%, respectively.DataAnimal DataIntraperitoneal (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/ m





2), approximately 0.1 times the maximum cumulative human dose of 1400 mg/m





2, 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/m





2), approximately 0.02 times the maximum cumulative human dose based on a mg/m





2 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/m





2), approximately 0.03 times the maximum cumulative human dose on a mg/ m





2 basis. Intravenous (IV) administration of carmustine to rats at a cumulative dose of 50 mg/kg (300 mg/ m





2), approximately 0.2 times the maximum cumulative human dose on a mg/m





2 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/ m





2), approximately 0.1 times the maximum cumulative human dose on a mg/ m





2 basis.

8.2 Lactation

Risk SummaryThere is no information regarding the presence of carmustine in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse events (e.g., carcinogenicity and myelosuppression) in nursing infants, nursing should be discontinued while taking Carmustine for Injection.

8.3 Females And Males Of Reproductive Potential

ContraceptionAdvise female patients to avoid pregnancy during treatment with carmustine for injection because of the risk of fetal harm


[see Use in Specific Populations


(8.1)]


.


Advise female patients of reproductive potential to use highly effective contraception during and for up to six months after completion of treatment.Advise males with female sexual partners of reproductive potential to use effective contraception during carmustine for injection treatment and for at least three months after the final dose of carmustine for injection [


see Nonclinical Toxicology


(13.1)].


InfertilityBased on nonclinical findings, male fertility may be compromised by treatment with carmustine for injection 


[see Nonclinical Toxicology


(13.1)].

8.4 Pediatric Use

Safety and effectiveness in children have not been established. Delayed onset pulmonary fibrosis occurring up to 17 years after treatment has been reported in a long-term study of patients who received carmustine for injection in childhood and early adolescence (1-16 years). Eight out of the 17 patients (47%) who survived childhood brain tumors, including all the 5 patients initially treated at less than 5 years of age, died of pulmonary fibrosis.


[see Adverse Reactions


(6.1)].

8.5 Geriatric Use

Clinical studies of carmustine for injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dose range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Carmustine for injection and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and renal function should be monitored.

12.1 Mechanism Of Action

The mechanism of action of carmustine is not fully understood. While carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. The metabolites may contribute to antitumor activity and toxicities of carmustine.

12.2 Pharmacodynamics

The exposure-response relationship for efficacy or safety is unknown.

12.3 Pharmacokinetics

DistributionCarmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or equal to 50% of those measured concurrently in plasma.EliminationFollowing a short intravenous infusion, the reported elimination half-life ranges from 15 minutes to 75 minutes.MetabolismCarmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes, including NADPH and glutathione-S-transferase.ExcretionApproximately 60% to 70% of a total dose is excreted in the urine within 96 hours. Approximately 10% is eliminated as respiratory CO





2.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carmustine is carcinogenic in rats and mice, producing a marked increase in tumor incidence in doses approximating those employed clinically. Nitrosourea therapy does have carcinogenic potential in humans





[see Adverse Reactions





(6.1)]





.





Carmustine was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies. Male rats treated with carmustine at cumulative doses ≥ 36 mg/kg (216 mg/ m





2), approximately 0.15 times the maximum cumulative human dose on a mg/ m





2 basis, showed decreases in reproductive potential when mated with untreated female rats (e.g., decreased implantations, increased resorption rate, and a decrease in viable fetuses).

15 References

1. "OSHA Hazardous Drugs."





OSHA.





http://www.osha.gov/SLTC/hazardousdrugs/index.html

16.1 How Supplied

Carmustine for injection, USP. Each package includes a vial containing 100 mg carmustine and a vial containing 3 mL sterile diluent.NDC 54879-023-64

16.2 Storage And Handling

Store product and diluent in a refrigerator (2°-8°C, 36°-46°F).StabilityStore the unopened vial of the dry drug in a refrigerator (2°-8°C, 36°-46°F). Store the diluent vials in a refrigerator (2°-8°C, 36°-46°F). The recommended storage of unopened Carmustine for Injection, USP vials provides a stable product for up to 2 years.Compatibility/ Incompatibility with ContainersThe intravenous solution is unstable in polyvinyl chloride container.





DO NOT USE PVC Containers.





Administer Carmustine for Injection, USP solution from the





glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free.Important NoteCarmustine for Injection, USP has a low melting point (30.5°-32.0°C or 86.9°-89.6°F). Exposure of the drug to this temperature or above will cause the drug to liquefy and appear as an oil film on the vials. This is a sign of decomposition and vials should be discarded. If there is a question of adequate refrigeration upon receipt of this product, immediately inspect the vial in each individual carton. Hold the vial to a bright light for inspection. The Carmustine for Injection, USP will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the Carmustine for Injection, USP is suitable for use and should be refrigerated immediately.

17 Patient Counseling Information

Myelosuppression [see Warnings and Precautions





(5.1)].





A serious and frequent toxicity of Carmustine for Injection is delayed myelosuppression and usually occurs 4 to 6 weeks after drug administration. Hence, patients should be advised to get blood counts monitored weekly for at least 6 weeks. The bone marrow toxicity of Carmustine for Injection is cumulative.Pulmonary Toxicity [see Warnings and Precautions





(5.2)].





Advise patients to contact a health care professional immediately for any of the following: shortness of breath, particularly during exercise, dry, hacking cough, fast, shallow breathing, gradual unintended weight loss, tiredness, aching joints and muscles, clubbing (widening and rounding) of the tips of the fingers or toes.Seizures [see Adverse Reactions





(6)]





Inform the patient that they may suffer from fits and advise them to get medical attention immediately in such cases.Pregnancy [see Warnings and Precautions





(5.6) and Use in Specific Populations (





8.1 and





8.3)]





Advise pregnant women and females of reproductive potential that Carmustine for Injection exposure during pregnancy can result in fetal harm. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Advise women of reproductive potential to avoid becoming pregnant. Advise females of reproductive potential to use effective contraception during treatment.Lactation [see Use in Specific Populations





(8.2)]





Advise the female patient to discontinue nursing while taking Carmustine for Injection.Manufactured in Germany For:STI Pharma LLC





Newtown, PA 18940,





1.888.301.9680





Rev: 12/18

* Please review the disclaimer below.

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