Biknu-100 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BiKNU-100 mg

Composition:

Active substance: carmustine;

1 vial contains carmustine 100 mg;

1 vial with sterile solvent contains anhydrous alcohol 3 ml.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: light-yellow, friable, brittle, inhomogeneous lumps or lyophilized mass, practically without visible inclusions;

solvent — clear, colorless, mobile liquid.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Alkylating agents. Nitrosourea derivatives.

ATC code L01A D01.

Pharmacological Properties

Pharmacodynamics

Carmustine causes alkylation of DNA and RNA, but does not exhibit cross-resistance with other alkylating agents. Like other nitrosourea compounds, it may inhibit several key enzymatic processes through carbamoylation of amino acids in proteins.

Pharmacokinetics

After intravenous administration, carmustine plasma levels exhibit a biphasic elimination pattern.

Following intravenous administration, carmustine undergoes rapid degradation, and the unchanged drug is no longer detectable within 15 minutes.

The alpha half-life is 1–4 minutes, and the beta half-life is 18–69 minutes.

Thus, the antineoplastic and toxic effects of carmustine are likely attributable to its metabolites.

Approximately 60–70% of the total dose of carmustine is excreted in the urine as metabolites within 96 hours. In cases of renal impairment, dosage should be reduced according to the glomerular filtration rate.

About 10% is excreted as CO₂ through respiration; the elimination pathway for the remaining 20–30% is not fully defined.

Due to its high lipid solubility and relatively low ionization at physiological pH values, carmustine effectively crosses the blood-brain barrier.

Clinical characteristics.

Indications.

Palliative treatment as monotherapy or in approved combination therapy regimens with other known chemotherapeutic agents for the following conditions:

• brain tumors: glioblastoma, brain stem glioma, medulloblastoma, astrocytoma, ependymoma, and metastatic brain tumors;
• multiple myeloma — in combination with prednisolone;
• Hodgkin’s lymphoma (Hodgkin’s disease) — as second-line therapy in combination with other approved agents in cases of disease relapse during initial therapy or failure of initial therapy;
• non-Hodgkin’s lymphomas — as second-line therapy in combination with other approved agents in cases of disease relapse during initial therapy or failure of initial therapy.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• hypersensitivity to other nitrosourea derivatives;
• severe bone marrow suppression;
• severe renal impairment;
• pregnancy and lactation (see section "Use in pregnancy or breastfeeding");
• pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

When this medicinal product is used concomitantly with other myelosuppressive agents such as vincristine, methotrexate, cyclophosphamide, procarbazine, chlorambucil (nitrogen mustard), fluorouracil, vinblastine, actinomycin (dactinomycin), bleomycin, doxorubicin (adriamycin), or when administered to patients whose bone marrow reserve is depleted due to the disease itself or previous therapy, a reduction in platelet or white blood cell counts (thrombocytopenia or leukopenia) may occur.

Increased myelotoxicity (e.g., leukopenia, neutropenia) has been observed with concomitant administration of carmustine and cimetidine.

Cross-resistance may occur with alkylating agents such as chlorambucil, cyclophosphamide (cytostatic medicinal products).

Special precautions for use

The medicinal product should be used only under the supervision of a physician experienced in chemotherapy.

The drug may affect the genetic material. Men should use reliable contraceptive methods for at least 6 months after treatment with this agent. They should also be informed about the risk of long-term irreversible infertility and the possibility of sperm preservation. Women being treated with carmustine must avoid pregnancy.

Myelosuppression

Bone marrow toxicity is a common and serious adverse effect of carmustine. The toxicity is delayed and cumulative in nature (especially thrombocytopenia and leukopenia) and may lead to bleeding and severe infections in at-risk patients. Blood cell counts (leukocytes, granulocytes, hemoglobin, platelets) should be checked before starting therapy and monitored weekly for at least 6 weeks after each dose administration (see section "Special precautions for use"). The interval between treatment cycles should be no less than 6 weeks.

The most common dose-limiting adverse reaction is reversible delayed-onset myelosuppression, which typically occurs 4–6 weeks after administration, with severity being dose-dependent. The myelosuppressive effect of carmustine is cumulative.

The lowest platelet count is usually observed 4–5 weeks after treatment initiation, and the lowest leukocyte count occurs 5–6 weeks after treatment. Thrombocytopenia is generally more pronounced than leukopenia, but both adverse effects may necessitate dose reduction.

Organ function monitoring

Liver, kidney, and lung functions should be assessed before starting treatment and monitored regularly during therapy (see section "Adverse reactions").

Intra-arterial administration

Tolerability of intra-arterial administration has not been evaluated. In case of accidental intra-arterial injection, severe tissue damage is expected.

The drug has been administered via intra-arterial intracarotid route; this route of administration is experimental and associated with toxic effects on visual organs.

Ethanol

This medicinal product contains 0.57% v/v ethanol (alcohol), up to 7.68 g per dose. This is equivalent to 11.32 mL of beer or 4.72 mL of wine per dose. These quantities are based on a calculated example of 320 mg carmustine (200 mg/m² BSA for 1.6 m²), dissolved in 9.6 mL (sterile absolute ethanol), with a final infusion volume of 1696 mL. There is a health risk for patients suffering from alcoholism. The use of this medicinal product should be considered carefully in pregnant or breastfeeding women, children, and patients with increased risk of liver disease or epilepsy. The amount of alcohol in this product may affect the efficacy of other medicinal products. The alcohol content in this medicinal product may impair the ability to drive or operate machinery.

Pulmonary toxicity

Pulmonary toxicity has been observed in 30% of studied patients. Early pulmonary toxicity (within 3 years of treatment) led to the development of pulmonary infiltrates and/or pulmonary fibrosis, sometimes with fatal outcomes. Patient ages ranged from 22 months to 72 years. Risk factors include smoking, respiratory diseases, pre-existing radiological abnormalities, prior or concurrent chest irradiation, and concomitant use of other agents known to cause lung damage. The incidence of adverse reactions is likely dose-dependent. Cumulative doses of 1200–1500 mg/m² have been associated with an increased risk of pulmonary fibrosis. Pulmonary function tests (FVC, DLCO) should be performed regularly during treatment. Patients with baseline spirometry values < 70% of predicted forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) are at particular risk.

Cases of very late-onset pulmonary fibrosis (up to 17 years after treatment) have been reported in patients who received carmustine during childhood or adolescence.

Long-term follow-up of 17 patients treated for childhood brain tumors showed that 8 died from pulmonary fibrosis. Two of these 8 deaths occurred within the first 3 years of treatment, and 6 occurred 8–13 years after treatment. The mean age at treatment of patients who died was 2.5 years (range: 1–12 years), while the mean age of those who survived long-term was 10 years (range: 5–16 years). All patients who were under 5 years of age at the time of treatment died from pulmonary fibrosis. Neither carmustine dose, nor additional vincristine administration, nor spinal irradiation influenced the fatal outcome.

Pulmonary fibrosis was detected in all survivors who were available for follow-up. The risk-benefit ratio of carmustine therapy should be carefully considered due to the high risk of pulmonary toxicity.

Renal toxicity

Renal changes with reduced kidney size, progressive azotemia, and renal failure have been observed after high cumulative doses and prolonged treatment with carmustine and related nitrosourea derivatives.

Hepatic toxicity

Liver necrosis may occur after administration of doses higher than those recommended in this instruction.

High-dose therapy

High-dose carmustine therapy increases the risk and severity of infections, as well as cardiac, hepatic, gastrointestinal, and renal toxicities, neurologic disorders, and electrolyte imbalances (hypokalemia, hypomagnesemia, and hypophosphatemia).

Concomitant diseases and advanced disease stage

Patients with concomitant diseases and advanced disease stage have a higher risk of adverse effects. This is particularly important in elderly patients.

Local toxicity at the site of administration

Reactions at the site of administration may occur during or after drug administration (see section "Adverse reactions"). Due to the risk of extravasation during administration, the infusion site should be carefully monitored to prevent infiltration. There is no specific treatment for extravasation at this time. Accidental contact of the reconstituted infusion solution with the skin may cause burns and excessive pigmentation in affected areas. Local soft tissue toxicity due to carmustine extravasation has been reported. Infiltration of carmustine may cause swelling, pain, erythema, burning sensation, and skin necrosis.

Use during pregnancy or breastfeeding

Fertility and pregnancy

There are currently insufficient data on the use of carmustine in pregnant women. The medicinal product may affect genetic material and cause fetal harm (embryo- and fetotoxicity) when administered during pregnancy. Animal studies have shown reproductive toxicity. The medicinal product should not be used during pregnancy. Contraceptive measures are recommended for both men and women of reproductive potential during treatment with carmustine and for at least 6 months after completion of therapy. If pregnancy is desired after therapy completion, genetic counseling is mandatory.

Breastfeeding

It is unknown whether carmustine or its metabolites are excreted in human milk. A risk to the newborn/infant cannot be excluded. Breastfeeding is contraindicated during treatment with this medicinal product due to the potential for serious adverse reactions in the infant/child.

Effect on ability to drive vehicles or operate machinery

No studies on the effect of the medicinal product on the ability to drive vehicles or operate machinery have been conducted. However, the potential impact of the alcohol content in this medicinal product on the ability to drive or operate machinery should be taken into account.

Dosage and Administration.

The medicinal product is administered in a hospital setting by qualified oncology specialists experienced in chemotherapy treatment.

The recommended dose of BiCNU-100 mg administered intravenously for monotherapy in patients who have not previously received carmustine treatment is 150 to 200 mg/m² as a single dose every 6 weeks or 75–100 mg/m² for 2 consecutive days.

After administration of the initial dose, subsequent doses must be adjusted according to the patient's hematological response to the previous dose.

The dose adjustment schedule is provided below.

A repeat course of carmustine for injection should not be administered until blood cell counts have recovered to acceptable levels (platelets > 100,000/mm³, leukocytes > 4,000/mm³). An adequate number of neutrophils should be present in peripheral blood. Blood parameters should be monitored weekly. The interval between repeat courses should be at least 6 weeks due to the prolonged cumulative hematotoxicity of the drug.

Administration method.

As with handling other potentially toxic substances, caution should be exercised when preparing the BiCNU-100 mg solution.

The drug should be administered by intravenous infusion using the solvent provided in the package. It should not be given by rapid intravenous injection. The drug should be administered diluted over 1–2 hours. If the infusion time of BiCNU-100 mg is less than 1–2 hours, it may cause pain and burning sensation at the injection site, as well as skin flushing and conjunctival hemorrhage.

Special patient groups.

Patients with impaired renal function

In patients with impaired renal function, the dose of carmustine should be reduced according to glomerular filtration rate.

Elderly patients

There are no clinical studies with carmustine confirming differences in response to the drug in patients over 65 years of age compared to younger patients.

Dose selection for elderly patients should be cautious, starting with the lowest dose, considering the increased frequency of hepatic, renal, and cardiac function impairments, concomitant diseases, and use of other medications in this patient group.

Since carmustine and its metabolites are primarily excreted by the kidneys, patients with impaired renal function are at increased risk of toxic reactions. Drug dosing should be carefully adjusted, and renal function should be monitored in elderly patients due to their predisposition to renal complications.

Children

The safety and efficacy of the drug in children have not been established.

In long-term studies, cases of late-onset pulmonary fibrosis have been reported up to 17 years after treatment in patients who received carmustine during childhood or early adolescence (1–16 years of age). Therefore, the benefit-risk ratio should be carefully evaluated when prescribing the drug due to the potential for pulmonary toxicity.

Overdose.

The most significant symptom of intoxication is myelosuppression. In addition, severe adverse effects may include liver necrosis, interstitial pneumonitis, and encephalomyelitis.

There is no known antidote for carmustine overdose. No effective agents for bone marrow protection are known. Bone marrow transplantation may be an effective intervention.

Adverse reactions.

The table below lists adverse events observed during treatment with the medicinal product, but which do not necessarily have a causal relationship with the product. Since clinical trials are conducted under highly specific conditions, the observed incidence rates of adverse effects may not reflect those observed in clinical practice. Adverse events are generally included in the list if they were reported in more than 1% of patients and/or considered clinically significant. If data from placebo-controlled studies are available, adverse events are included if the event rate in the treatment group is >5% higher.

Adverse effects of the medicinal product are categorized according to MedDRA terminology and by frequency of occurrence: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

1 Pulmonary toxicity also manifests as pneumonitis and interstitial lung disease (post-marketing experience).

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the use of this medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at 2–8 °C in the original packaging.

Keep out of reach of children.

Storage conditions after reconstitution with diluent – 24 hours at 2 to 8 °C.

Incompatibilities.

Do not mix with other medicinal products.

Use only the diluent provided.

Packaging.

1 vial of the medicinal product and 1 vial of diluent per cardboard package.

Prescription status. Prescription only.

Manufacturer.

Emcure Pharmaceuticals Ltd.

Manufacturer's address and site of operations.

Plot No. P-1 and P-2, ITVT Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.