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.

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).

Storage And Handling

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

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

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.

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.

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.

REFERENCES

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

Manufactured by: Emcure Pharmaceuticals Ltd.,Hinjawadi, Pune, India. Revised: March 2017.

Black Box Warnings

The drug should be administered under the supervision of an experienced cancer chemotherapy physician

Bone marrow suppression (notably thrombocytopenia and leukopenia) is the most common and severe of the toxic effects that may result from carmustine administration. It may contribute to bleeding and infections. Monitor blood counts for at least 6 weeks after a dose. Do not give recommended dosage more frequently than every 6 weeks. Adjust dose based on nadir blood counts from prior dose. Do not administer a repeat course of BiCNU until blood counts recover.

Pulmonary toxicity is dose related. Risk increases with cumulative doses > 1400 mg/m², history of lung disease and duration of therapy. Delayed cases of pulmonary fibrosis that can result in death have been reported 15 years after administration in children

Contraindications

Hypersensitivity

Cautions

Do not give more frequently than q6-8wk due to delayed myelosuppression; complete blood count should be monitored weekly for at least six weeks after each dose

Risk of irreversible pulmonary fibrosis on long-term treatment

Injection site reactions may occur during administration; rapid infusion may cause burning along the vein and flushing of skin

Extravasation risk, monitor closely during infusion

Ocular toxicity associated with intracarotid route (investigational); safety and efficacy not established

Associated with moderate to high emetic potential; administer antiemetics to prevent nausea and vomiting

Monitor liver function tests periodically during therapy; reversible increases (rare) in bilirubin, alkaline phosphatase levels, and transaminases reported

Wafer implant associated with intracranial hypertension; brain edema reported in patients with newly diagnosed glioma; monitor closely for intracranial hypertension related to brain edema, inflammation, or necrosis of brain tissues surrounding resection; in refractory cases, removing the wafer may be necessary

Meningitis reported in patients with recurrent glioma receiving wafer implants; monitor postoperatively for signs/symptoms of meningitis and CNS infection

Renal failure, decreased kidney size, and progressive azotemia reported in patients receiving low or large cumulative doses or prolonged treatment; monitor renal function periodically

Long-term use associated with development of secondary malignancies (acute leukemia and bone marrow dysplasias)

Wafer implants associated with seizures; treatment-emergent seizures reported within 5 days of surgery; initiate optimal anti-seizure therapy prior to surgery

Impaired neurosurgical wound healing, including wound dehiscence, delayed healing, and subdural, subgleal or wound effusions associated with wafer implant treatment; cerebrospinal fluid leaks also reported; monitor for impaired neurosurgical wound healing following surgery

Avoid pregnancy

Contraception

• Advise female patients to avoid pregnancy during therapy because of risk of fetal harm
• 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 therapy and for at least three months after final dose of carmustine

Fertility

• Based on nonclinical findings, male fertility may be compromised by therapy

IV Incompatibilities

Solution: D5W (may be used in shorter time periods)

Additive: sodium bicarbonate

Y-site: allopurinol

IV Compatibilities

Solution: NS

Y-site: amifostine, aztreonam, cefepime, etoposide PO4, filgrastim, fludarabine, gemcitabine, granisetron, melphalan, ondansetron, piperacillin/tazobactam, sargramostim, teniposide, thiotepa, vinorelbine

IV Preparation

Initially dilute with 3 mL of supplied diluent (dehydrated alcohol); further dilute aseptically with 27 mL SWI to result in a concentration of 3.3 mg/mL in 10% alcohol

Standard dilution: dose/150-500 mL D5W or NS

IV Administration

Significant absorption to PVC containers; should be administered in either glass or Excel container

Infuse over 1-2 hr

High dose carmustine: maximum rate of infusion <3 mg/sq.meter/min to avoid excessive flushing, agitation, & hypotension; infusions should run over at least 2 hr

Extravasation Management

Elevate extremity

Inject long-acting dexamethasone or by hyaluronidase throughout tissue with a 25- to 37-gauge needle

Apply warm, moist compresses

Storage

Store intact vials under refrigeration

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if carmustine is excreted in human breast milk or if it will harm your nursing baby. It is generally recommended that women receiving carmustine treatments should not breastfeed.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with carmustine, especially:

• cimetidine.

This list is not complete. Other drugs may interact with carmustine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Medicines used to treat cancer are very strong and can have many side effects. Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

A nurse or other trained health professional will give you this medicine in a hospital. This medicine is given through a needle placed in one of your veins.

This medicine is usually given every 6 weeks. This maybe given as a single dose or divided into daily injections on 2 consecutive days.

Carmustine is sometimes given together with certain other medicines. If you are using a combination of medicines, it is important that you receive each one at the proper time. If you are taking some of these medicines by mouth, ask your doctor to help you plan a way to take them at the right times.

This medicine often causes nausea and vomiting, which usually last no longer than 4 to 6 hours. It is very important that you continue to receive the medicine, even if you begin to feel ill. Ask your doctor for ways to lessen these effects.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. Females need to use an effective form of birth control during treatment and for at least 6 months while you are using this medicine to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away. Males need to use an effective form of contraceptive during treatment and for at least 3 months after your last dose to prevent your partner from becoming pregnant.

This medicine may increase your risk of developing cancer and lung problems (such as pulmonary fibrosis or toxicity). This is more likely if you receive high doses of this medicine or use it for a long time.

While you are being treated with carmustine injection, and after you stop treatment with it, do not have any immunizations (vaccines) without your doctor's approval. Carmustine may lower your body's resistance and the vaccine may not work as well for you or you might get the infection the vaccine is meant to prevent. In addition, you should not be around other persons living in your household who receive live vaccines because there is a chance they could pass the virus on to you. Some examples of live vaccines include measles, mumps, influenza (nasal flu vaccine), poliovirus (oral form), rotavirus, and rubella. Do not get close to them and do not stay in the same room with them for very long. If you have questions about this, talk to your doctor.

Carmustine can temporarily lower the number of white blood cells in your blood, increasing the chance of getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

• If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
• Check with your doctor immediately if you notice any unusual bleeding or bruising, black, tarry stools, blood in the urine or stools, or pinpoint red spots on your skin.
• Be careful when using a regular toothbrush, dental floss, or toothpick. Your medical doctor, dentist, or nurse may recommend other ways to clean your teeth and gums. Check with your medical doctor before having any dental work done.
• Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
• Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
• Avoid contact sports or other situations where bruising or injury could occur.

If carmustine accidentally seeps out of the vein into which it is injected, it may damage some tissues and cause scarring. Tell the doctor or nurse right away if you notice redness, pain, or swelling at the injection site.

This medicine may increase risk of lung problems while smoking.

If you plan to have children, talk with your doctor before using this medicine. Some men using this medicine have become infertile (unable to have children).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you have an allergy to carmustine or any other part of BiCNU.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take BiCNU with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.
• Other drugs may be given before BiCNU to help avoid side effects.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Chest pain.
• Very bad headache.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Signs of lung or breathing problems like shortness of breath or other trouble breathing, cough, or fever.
• Feeling very tired or weak.
• A fast heartbeat.
• Very bad dizziness or passing out.
• Change in eyesight.
• Feeling confused.
• Seizures.
• Enlarged breasts.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Upset stomach or throwing up.
• Not hungry.
• Loose stools (diarrhea).
• Hair loss.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

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

How 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.

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

• Breast Cancer
• Cancer