BiCNU^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Emcure Pharmaceuticals, Ltd. (India)

ATC Code

L01AD01 (Carmustine)

Active Substance

Carmustine (Rec.INN registered by WHO)

Dosage Form

BiCNU®

Lyophilizate for preparation of solution for infusion 100 mg: fl. 1 pc. incl. with solvent

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for infusion in the form of small separate flakes or a lyophilized mass of light yellow color; solvent – a transparent colorless volatile liquid.

* after reconstitution, each vial with 1 ml of solution contains 3.3 mg of carmustine.

Solvent: ethanol – 3 ml (vials).

Dark glass vials (1) in a set with solvent (fl. of colorless glass type I 1 pc.) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, alkylating compound

Pharmacological Action

Antineoplastic agent of alkylating action from the group of nitrosourea derivatives. It acts on the bases and phosphate groups of DNA, leading to breaks and cross-links of its molecule. It is a cycle-nonspecific compound. The action of carmustine may also be associated with the modification of proteins.

Pharmacokinetics

It is rapidly metabolized in the liver with the formation of active metabolites. Metabolites can persist in blood plasma for several days.

It penetrates the blood-brain barrier.

It is excreted mainly by the kidneys in the form of metabolites – 60-70%, with feces – 1%, through the respiratory tract – 10%.

Indications

For palliative treatment as monotherapy or in combination with other chemotherapeutic drugs for the following diseases: malignant brain tumors (glioblastoma, brainstem glioma, medulloblastoma, astrocytoma, ependymoma) and metastases to the brain from tumors of various locations; multiple myeloma (in combination with prednisolone); Hodgkin’s disease (as part of second-line combination therapy in patients with disease relapse after primary therapy or in case of its ineffectiveness); non-Hodgkin’s lymphomas (as part of second-line combination therapy in patients with disease relapse after primary therapy or in case of its ineffectiveness); malignant melanoma.

ICD codes

Dosage Regimen

Administer as a slow intravenous infusion over a minimum of two hours.

Infuse faster rates may cause intense pain and burning at the injection site.

Determine the dosage individually based on the specific indication, disease stage, and patient’s hematological status.

Calculate the dose based on body surface area (BSA).

For monotherapy in previously untreated patients, the initial single dose is 200 mg/m² administered once every 6 weeks.

Divide this dose into daily injections of 100 mg/m² on two successive days.

Alternatively, administer a single dose of 200 mg/m² every 6 to 8 weeks.

Do not repeat doses until circulating blood elements have returned to acceptable levels (platelets > 100,000/mm³, leukocytes > 4,000/mm³).

Adjust subsequent doses downward by 20-50% based on the nadir blood counts from the prior cycle.

For combination therapy with other myelosuppressive agents, reduce the BiCNU dose accordingly.

Adjust the dosage for patients with compromised bone marrow function due to prior radiotherapy or chemotherapy.

Reconstitute the 100 mg vial with 3 ml of the supplied sterile ethanol solvent.

Further dilute the reconstituted solution with 27 ml of Sterile Water for Injection to yield a concentration of approximately 3.3 mg/ml.

Administer the final preparation only by intravenous infusion.

Discard any unused solution, as it contains no preservatives.

Protect the reconstituted and diluted solution from light.

Adverse Reactions

Infections opportunistic infections, sometimes fatal.

From the hematopoietic system: leukopenia, thrombocytopenia, neutropenia, bleeding, acute leukemia, bone marrow dysplasia, anemia.

From the respiratory system: pulmonary infiltration, pulmonary fibrosis (with fatal outcome).

From the digestive system: nausea, vomiting, decreased appetite.

From the nervous system: asthenia, dizziness, headache.

From the urinary system: decrease in kidney size, renal failure.

From the cardiovascular system: decrease in blood pressure, tachycardia.

From the organ of vision: visual impairment, neuroretinitis.

Allergic reactions: rash, itching, swelling and redness of the conjunctiva, facial flushing.

From laboratory parameters: increased activity of serum transaminases, alkaline phosphatase, increased concentration of bilirubin in serum, azotemia.

Other chest pain.

Reactions at the injection site: burning sensation, pain and swelling at the injection site, phlebitis, erythema, skin necrosis.

Contraindications

Hypersensitivity to carmustine; pregnancy, breastfeeding period; childhood.

With caution suppression of bone marrow function (including against the background of concomitant chemotherapy or radiation therapy, especially with irradiation of the mediastinum area), acute infectious diseases of viral, fungal or bacterial nature (including chickenpox, herpes zoster), hepatic insufficiency, respiratory failure, chronic renal failure, smoking (due to an increased risk of toxic effects on the lungs).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding). If it is necessary to use during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Should be used with caution in hepatic insufficiency.

Use in Renal Impairment

Should be used with caution in chronic renal failure. In case of impaired renal function, accumulation of carmustine is possible (decreased renal filtration).

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated (safety and efficacy of use have not been established).

Geriatric Use

In elderly patients, accumulation of carmustine is possible (decreased renal filtration).

Special Precautions

Treatment with carmustine should be carried out under the supervision of a physician experienced in chemotherapy.

During treatment, monitoring of the peripheral blood picture, liver and kidney function, and radiographic examination of the lungs is necessary. Since a distinctive feature of carmustine is the delayed manifestation of the suppressive effect on hematopoiesis, monitoring of the peripheral blood picture should be carried out weekly for 6 weeks after the end of use.

Most adverse reactions are reversible if the necessary measures are taken in a timely manner. If side effects are detected, the dose of carmustine should be reduced or treatment should be discontinued; if necessary, appropriate corrective measures are prescribed. Resumption of treatment with carmustine should be carried out with caution, after assessing the need for further use of the drug due to the possible recurrence of side effects.

There are reports of the development of secondary malignant tumors due to prolonged use of nitrosourea drugs.

Drug Interactions

Due to the increased risk of thrombosis in cancer patients, they are often prescribed anticoagulant therapy. In the case of a course of treatment with a cytostatic drug against the background of taking oral anticoagulants, it is necessary to regularly conduct studies of the blood clotting factor due to the possible interaction of the anticoagulant and the cytostatic drug.

Due to the possible decrease in the absorption of phenytoin and fosphenytoin in the gastrointestinal tract under the action of a cytostatic drug, the development of convulsions is possible; in addition, as a result of the possible enhancement of the hepatic metabolism of the cytotoxic drug under the action of phenytoin and fosphenytoin, an increase in the toxicity or loss of efficacy of the cytotoxic drug is possible.

Carmustine reduces the production of antibodies in response to the administration of a weakened live virus vaccine; it is also possible to enhance the process of virus replication and enhance the side effects caused by it. The interval between discontinuation of carmustine treatment and vaccination should be from 3 months to 1 year.

When vaccinating against yellow fever during treatment with carmustine, there is a risk of developing fatal generalized vaccinia.

With the combined use of carmustine and cimetidine, leukopenia and neutropenia are more severe than with the use of carmustine alone. It is not recommended to prescribe simultaneously with other drugs that have myelosuppressive, nephrotoxic or hepatotoxic effects.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.