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简介：   卡莫司汀（BiCNU®） 卡莫司汀是一种用于治疗淋巴瘤，骨髓瘤和脑肿瘤化疗药物。 适应症和用法BiCNU BiCNU（卡莫司汀用于注射）被表示为姑息疗法作为单一药剂或在既定组合疗法在以下其他批准的化学治疗剂： •脑肿瘤 - 胶质母细胞瘤，脑干胶质瘤，髓母细胞瘤，星形细胞瘤，室管膜瘤，转移性脑肿瘤。 •强的松多发性骨髓瘤的组合。 •霍奇金病 - 在谁，同时与主要治疗药物，或谁不为主要疗法治疗反应的患者复发与其他批准的药物联合治疗继发。 •非霍奇金淋巴瘤，至于是谁，同时与主要疗法，或谁不为主要疗法治疗反应的患者复发与其他批准的药物联合治疗继发。 禁忌 BiCNU不应该给谁已经证明以前的过敏它的个体。 --------------------------------------------------------- BiCNU® Class: Chemotherapy Generic Name: Carmustine (kar-MUS-teen), BCNU Trade Name: BiCNU® For which conditions is this drug approved? Carmustine is FDA approved for the treatment of the following conditions: several types of brain tumors (including glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma and metastatic brain tumors); multiple myeloma in combination with prednisone; recurrent Hodgkin’s lymphoma in combination with other agents; recurrent non-Hodgkin’s lymphoma in combination with other agents. It is important for patients to remember that physicians have the ability to prescribe medication for conditions other than those for which the drug has been approved by the FDA. Patients who have received a prescription of this drug for a condition other than which it is approved may wish to discuss this issue with their physician. What is the mechanism of action? Carmustine belongs to a group of drugs referred to as nitrosoureas. Carmustine produces its anti-cancer effects by causing chemical reactions that result in damage to both DNA and amino acids in a cell. The DNA and amino acid damage caused by carmustine ultimately result in cell death. How is carmustine typically given (administered)? Carmustine is given intravenously (into a vein), and the dose depends on several factors, including the condition being treated, the size of the patient, the particular regimen being used and the overall health of the patient. Carmustine is also produce in a wafer form that can be directly implanted into the brain (see Gliadel® wafer). Carmustine is unique from several chemotherapy agents in that it is able to pass through the blood-brain barrier (a protective barrier surrounding the brain and spinal cord). How are patients typically monitored? Patients will usually have scheduled meetings with their healthcare provider while they are being treated with carmustine. Typically, blood will be drawn to check levels of blood cells and to monitor functions of some organ systems such as the liver and kidneys. Patients may also undergo physical examinations, scans or other measures to assess side effects and response to therapy. Although uncommon, treatment with carmustine may cause serious damage to the lungs. Therefore, pulmonary function tests may also be performed prior to treatment and during treatment with carmustine. Blood pressure is typically monitored during administration. What are the common (occur in 30% or more of patients) side effects of treatment with carmustine? • Low white blood cell levels – increases risk of infection • Low platelet levels – increases risk of bleeding • Nausea and vomiting • Pain or burning at administration site, usually associated with rapid infusion rate • Redness of face, skin flushing, usually associated with rapid infusion rate What are the less common (occur in 10% to 29% of patients) side effects of treatment with carmustine? • Abnormalities in liver function levels as determined by blood tests; hepatic disease with high dose therapy • Low red blood cell levels  – increases risk of anemia and transfusions • Dizziness • Loss of balance or coordination • Abnormalities of the eye  (redness, visual changes) • Reduced blood pressure This is not a complete list of side effects. Some patients may experience other side effects that are not listed here. Patients may wish to discuss with their physician the other less common side effects of this drug, some of which may be serious. Some side effects may require medical attention. Other side effects do not require medical attention and may go away during treatment. Patients should check with their physician about any side effects that continue or are bothersome. What are the possible late side effects of treatment with carmustine? With the use of this drug, there is risk of developing side effects months or years after treatment has been completed.  In some instances a secondary malignancy may occur as a result of receiving carmustine.  A secondary malignancy is a new cancer that is unrelated to the cancer that was initially treated. Secondary malignancies occur as a result of previous treatment with radiation or chemotherapy. Sterility may also occur as a result of treatment with carmustine. In addition, damage to the lungs can occur years following treatment. Patients should discuss these late side effects with their physician. What can patients do to help alleviate or prevent discomfort and side effects? • Pay careful attention to the physician’s instructions and inform the physician of any side effects. • Maintain adequate rest and nutrition. • Wear sunscreen and protective clothing and try to minimize sun exposure. • Drink plenty of fluids. (Patients should ask their physician about the amount of liquid to consume during a day.) • If possible, avoid large crowds or people who are sick or not feeling well, as this drug may leave some patients susceptible to infection. • Wash hands often to reduce the risk of infection. • Avoid activities that may cause injury or bruising. • Use a soft toothbrush and an electric razor to prevent cuts on the mouth or skin. • Eat small meals frequently to help alleviate nausea. Are there any special precautions patients should be aware of before starting treatment? • Patients should inform their physician if they are pregnant, breastfeeding or planning a family in the near future. This drug may cause birth defects. It is important to use some kind of birth control while undergoing treatment. Also, patients may want to talk to their physician if they are considering having children in the future, since some drugs may cause fertility problems. • It is important that patients inform their physician of any pre-existing conditions (chicken pox, heart disease, kidney disease, liver disease, lung disease, etc.) as they may worsen with this drug. • Patients should inform their physician of any other medication they are taking (whether prescription or over-the-counter, including vitamins, herbs, etc.) as they may interfere with treatment. • Patients should check with their physician before starting any new drug or nutritional supplement. • Patients should inform their physician of any known drug or food allergies or any reactions to medications they have experienced in the past. • Since this drug can cause dizziness or loss of coordination, patients should refrain from driving or operating heavy machinery until their response to therapy with carmustine has been established. When should patients notify their physician? • Fever • Chills • Flu or cold-like symptoms • Signs of infection – redness, pus, swelling, tenderness • Sore throat • Severe, prolonged fatigue • Unexplained bleeding (nosebleeds, blood in urine, black tarry stools, bruising, etc.) • Visual changes • Hearing changes • Dizziness, loss of balance • Yellowing of skin or eyes • Change in color or urine or stool • Swelling of ankles, feet or face • Persistent nausea and vomiting • Difficulty breathing What is a package insert? A package insert is required by the FDA and contains a summary of the essential scientific information needed for the safe and effective use of the drug for healthcare providers and consumers.  A package insert typically includes information regarding specific indications, administration schedules, dosing, side effects, contraindications, results from some clinical trials, chemical structure, pharmacokinetics and metabolism of the specific drug. By carefully reviewing the package insert, you will get the most complete and current information about how to safely use this drug. If you do not have the package insert for the drug you are using, your pharmacist or physician may be able to provide you with a copy. Copyright © 2010 CancerConnect Last updated 07/10. Important Limitations of Use The information provided above on the drug you have selected is provided for your information only and is not a substitute for consultation with an appropriate medical doctor. We are providing this information solely as a courtesy and, as such, it is in no way a recommendation as to the safety, efficacy or appropriateness of any particular drug, regimen, dosing schedule for any particular cancer, condition or patient nor is it in any way to be considered medical advice. Patients should discuss the appropriateness of a particular drug or chemotherapy regimen with their physician. As with any printed reference, the use of particular drugs, regimens and drug dosages may become out-of-date over time, since new information may have been published and become generally accepted after the latest update to this printed information. Please keep in mind that health care professionals are fully responsible for practicing within current standards, avoiding use of outdated regimens, employing good clinical judgment in selecting drugs and/or regimens, in calculating doses for individual patients, and verifying all dosage calculations. DISCLAIMER OF WARRANTIES CANCERCONSULTANTS.COM SPECIFICALLY DISCLAIMS AND EXCLUDES ALL EXPRESSED OR IMPLIED WARRANTIES, INCLUDING ANY IMPLIED WARRANTIES AS TO QUALITY, ACCURACY (INCLUDING TYPOGRAPHICAL ERRORS), MERCHANTABILITY, OR FITNESS FOR ANY PARTICULAR PURPOSE OF THE INFORMATION CONTAINED HEREIN.  CANCERCONSULTANTS.COM DISCLAIMS ALL LIABILITY OR DAMAGES ARISING FROM ANY USE OF THE INFORMATION. The prescribing physician is solely responsible for making all decisions relating to appropriate patient care including, but not limited to, drugs, regimens, dose, schedule, and any supportive care. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6cbb63c-e0b1-43ee-ad6f-408da0772079

 BiCNU

Generic Name: carmustine
       Dosage Form: injection

 

WARNING: MYELOSUPPRESSION and PULMONARY TOXICITY

Myelosuppression

BiCNU 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 BiCNU until blood counts recover.

Pulmonary Toxicity

BiCNU causes dose-related pulmonary toxicity. Patients receiving greater than 1400 mg/m2cumulative 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)].

Indications and Usage for BiCNU

BiCNU®(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.

BiCNU Dosage and AdministrationDosage

The recommended dose of BiCNU as a single agent in previously untreated patients is 150 to 200 mg/m2intravenously every 6 weeks. Administer as a single dose or divided into daily injections such as 75 to 100 mg/m2 on two successive days. Lower the dose when BiCNU is used with other myelosuppressive drugs or in patients in whom bone marrow reserve is depleted. Administer BiCNU 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/mm3	Platelets/mm3
>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 BiCNU 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 BiCNU if the creatinine clearance is less than 10 mL/min. Do not administer BiCNU to patients with compromised renal function. Monitor transaminases and bilirubin periodically during treatment. [see Adverse Reactions (6)].

Preparation and Administration of Intravenous Solution

·         Dissolve BiCNU with 3 mL of the supplied sterile diluent (Dehydrated Alcohol Injection, USP).

·         Aseptically add 27 mL Sterile Water for Injection, USP.

o    Each mL of resulting solution contains 3.3 mg of BiCNU in 10% ethanol. Such solutions should be protected from light.

o    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.

o    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.

o    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

o    After reconstitution as recommended, BiCNU 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.

o    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 BiCNU 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/m2/min.

·         See Section 16.2 for important instructions on the storage and handling of the injection. BiCNU 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 via.

Accidental contact of reconstituted BiCNU 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 BiCNU. Immediately wash the skin or mucosa thoroughly with soap and water if BiCNU lyophilized material or solution contacts the skin or mucosa1.

Dosage Forms and Strengths

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).

Contraindications

BiCNU is contraindicated in patients with previous hypersensitivity to BiCNU or its components.

Warnings and PrecautionsMyelosuppression

Bone marrow toxicity is a dose-limiting, common and severe toxic effect of BiCNU 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 BiCNU 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 BiCNU should not be given more frequently than every six weeks. The bone marrow toxicity of BiCNU 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)].

Pulmonary Toxicity

Cases of fatal pulmonary toxicity with BiCNU 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 BiCNU and related nitrosoureas. Pulmonary toxicity from BiCNU is dose-related. Patients receiving greater than 1400 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 BiCNU (in cumulative doses ranging from 770 to 1800 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.

Administration Reactions

Injection site reactions may occur during the administration of BiCNU. Rapid intravenous infusion of BiCNU 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.

Carcinogenicity

Long-term use of nitrosoureas, such as BiCNU, 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 BiCNU, has carcinogenic potential in humans. Patients treated with BiCNU should be monitored long-term for development of second malignancies.

Ocular Toxicity

BiCNU 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.

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

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 BiCNU 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.

Drug InteractionsEffects of Other Drugs on BiCNU

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 BiCNU. Consider alternative drugs to phenobarbital.

Effects of BiCNU on Other Drugs

Phenytoin: BiCNU when coadministered with phenytoin may reduce phenytoin serum concentrations. Consider alternative drugs to phenytoin.

USE IN SPECIFIC POPULATIONSPregnancy

Risk Summary

BiCNU (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 BiCNU 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 BiCNU for the mother and possible risks to the fetus when prescribing BiCNU 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.

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 1400 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/m2basis, 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.

Lactation

Risk Summary

There 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 BiCNU.

Females and Males of Reproductive Potential

Contraception

Advise female patients to avoid pregnancy during treatment with BiCNU 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 BiCNU treatment and for at least three months after the final dose of BiCNU [see Nonclinical Toxicology (13.1)].

Infertility

Based on nonclinical findings, male fertility may be compromised by treatment with BiCNU [see Nonclinical Toxicology (13.1)].

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 BiCNU 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)].

Geriatric Use

Clinical studies of BiCNU 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.

BiCNU 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.

Overdosage

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

BiCNU Description

The active ingredient in BiCNU® (carmustine for injection) 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. BiCNU is administered by intravenous infusion after reconstitution, as recommended.

The structural formula of carmustine is:

BiCNU is available in 100-mg single dose vials of lyophilized material. Sterile diluent for constitution of BiCNU 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.

BiCNU - Clinical Pharmacology

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.

Pharmacodynamics

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

Pharmacokinetics

Distribution

Carmustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are greater than or equal to 50% of those measured concurrently in plasma.

Elimination

Following a short intravenous infusion, the reported elimination half-life ranges from 15 minutes to 75 minutes.

Metabolism

Carmustine may be inactivated through denitrosation reactions catalyzed by both cytosolic and microsomal enzymes, including NADPH and glutathione-S-transferase.

Excretion

Approximately 60% to 70% of a total dose is excreted in the urine within 96 hours. Approximately 10% is eliminated as respiratory CO2.

Nonclinical ToxicologyCarcinogenesis, 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/ m2), approximately 0.15 times the maximum cumulative human dose on a mg/ m2 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).

REFERENCES

1. "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

How Supplied/Storage and HandlingHow Supplied

BiCNU® (carmustine for injection). Each package includes a vial containing 100 mg carmustine and a vial containing 3 mL sterile diluent.

NDC 23155-261-41

Storage and Handling

Store product and diluent in a refrigerator (2°-8°C, 36°-46°F).

Stability

Store 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 BiCNU vials provides a stable product for up to 3 years.

Compatibility/ Incompatibility with Containers

The intravenous solution is unstable in polyvinyl chloride container. DO NOT USE PVC Containers.

Administer BiCNU solution from the glass bottles or polypropylene container only. Ensure the polypropylene containers used are PVC free and DEHP free.

Important Note

BiCNU 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 BiCNU will appear as a very small amount of dry flakes or dry congealed mass. If this is evident, the BiCNU is suitable for use and should be refrigerated immediately.

Patient Counseling Information

Myelosuppression [see Warnings and Precautions (5.1)].

A serious and frequent toxicity of BiCNU 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 BiCNU 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 BiCNU 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 BiCNU.

Manufactured by:

Emcure Pharmaceuticals Ltd.,

Hinjawadi, Pune, India.

Manufactured for:

Heritage Pharmaceuticals Inc.

Eatontown, NJ 07724,

1.866.901.DRUG (3784)

Rev: 03/17

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - diluent label

NDC 23155-262-31

Rx only

Dehydrated Alcohol Injection, USP

3 mL

Sterile Diluent for BiCNU®

(carmustine for injection)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - vial label

NDC 23155-589-31

BiCNU®

(carmustine for injection)

100 mg per vial

For intravenous infusion after reconstitution

REFRIGERATE IMMEDIATELY

Single Dose Vial - Discard Unused Portion

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - carton

NDC 23155-261-41

Rx only

BiCNU®

(carmustine for injection)

100 mg per vial

Each carton contains: 1 vial BiCNU (carmustine) for injection 100 mg, 1 vial Sterile Diluent for BiCNU 3 mL

For intravenous infusion after reconstitution

REFRIGERATE IMMEDIATELY

Single Dose Vial – Discard Unused Portion

BiCNU  carmustine kit

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:23155-261

Packaging # Item Code Package Description 1 NDC:23155-261-41 1 KIT in 1 CARTON

Quantity of Parts Part # Package Quantity Total Product Quantity Part 1 1 VIAL 3 mL Part 2 1 VIAL, SINGLE-DOSE 30 mL

Part 1 of 2 DEHYDRATED ALCOHOL  alcohol injection

Product Information Item Code (Source) NDC:23155-262 Route of Administration INTRAVENOUS DEA Schedule

Inactive Ingredients Ingredient Name Strength ALCOHOL

Packaging # Item Code Package Description 1 NDC:23155-262-31 3 mL in 1 VIAL

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017422 04/04/2013

Part 2 of 2 BiCNU  carmustine injection, powder, lyophilized, for solution

Product Information Item Code (Source) NDC:23155-589 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CARMUSTINE (CARMUSTINE) CARMUSTINE 100 mg  in 30 mL

Packaging # Item Code Package Description 1 NDC:23155-589-31 30 mL in 1 VIAL, SINGLE-DOSE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017422 04/04/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA017422 04/04/2013

Labeler - Heritage Pharmaceuticals Inc. (780779901)

Registrant - Emcure Pharmaceuticals Limited (916921919)
Establishment
Name	Address	ID/FEI	Operations
Emcure Pharmaceuticals Limited		862602830	analysis(23155-261, 23155-262, 23155-589), label(23155-261, 23155-262, 23155-589), manufacture(23155-261, 23155-262, 23155-589), pack(23155-261, 23155-262, 23155-589)

Revised: 03/2017

Heritage Pharmaceuticals Inc.