Merkudies (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

ATC Code

L01AA09 (Bendamustine)

Active Substance

Bendamustine (Rec.INN registered by WHO)

Dosage Forms

	Merkudies	Lyophilisate for preparation of concentrate for solution for infusion 25 mg: vial 1, 2, 4, 5, 10 or 20 pcs.
		Lyophilisate for preparation of concentrate for solution for infusion 100 mg: vial 1, 2, 4, 5 or 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of concentrate for solution for infusion as a white or almost white lyophilized mass.

Excipients: mannitol – 42.5 mg.

Dark glass vials (1) – cardboard packs.
Dark glass vials (2) – cardboard packs.
Dark glass vials (4) – cardboard packs.
Dark glass vials (5) – cardboard packs.
Dark glass vials (10) – cardboard packs.
Dark glass vials (20) – cardboard packs.

Lyophilisate for preparation of concentrate for solution for infusion as a white or almost white lyophilized mass.

Excipients: mannitol – 170 mg.

Dark glass vials (1) – cardboard packs.
Dark glass vials (2) – cardboard packs.
Dark glass vials (4) – cardboard packs.
Dark glass vials (5) – cardboard packs.
Dark glass vials (10) – cardboard packs.

Clinical-Pharmacological Group

Antitumor drug. Alkylating compound

Pharmacotherapeutic Group

Antineoplastic agents; alkylating agents; nitrogen mustard analogues

Pharmacological Action

Antitumor agent with bifunctional alkylating activity. The mechanism of action is primarily associated with the formation of cross-links between single-stranded and double-stranded DNA molecules due to alkylation. As a result, the template function of DNA and its synthesis are disrupted. There is also evidence that Bendamustine has additional antimetabolic properties (purine analogue effect).

The antineoplastic effect of bendamustine has been confirmed in numerous in vitro studies on various tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian cancer, and various types of leukemia, as well as colon cancer, melanoma, renal cell carcinoma, malignant neoplasms of the prostate and brain) and in vivo on various experimental tumor models (melanoma, breast cancer, sarcoma, lymphoma, leukemia, and small cell lung cancer). The absence or only a slight degree of cross-resistance in human tumor cell lines with various resistance mechanisms has been shown.

This is partly explained by the interaction with DNA, which, compared to other alkylating agents, lasts longer (for example, only partial cross-resistance with other alkylating agents such as cyclophosphamide, carmustine, or cisplatin was found). Furthermore, clinical studies have found that there is no complete cross-resistance between bendamustine and anthracyclines or alkylates.

Pharmacokinetics

After a single 30-minute intravenous infusion of bendamustine at a dose of 120 mg/m² body surface area, the T_1/2 in the beta phase is 28.3 min. The V_d after a 30-minute IV infusion is 19.3 L, with subsequent systematic administration and reaching equilibrium concentration, the V_d ranges from 15.8 to 20.5 L. In the systemic bloodstream, Bendamustine actively binds to plasma proteins (> 95%), mainly albumin. The ability of bendamustine to bind to plasma proteins is not impaired at low plasma albumin concentrations, in patients over 70 years of age, and in advanced stages of tumors.

Bendamustine is metabolized primarily in the liver, mainly by hydrolysis to form monohydroxy- and dihydroxybendamustine. The formation of gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) in the liver involves the cytochrome P450 isoenzyme CYP1A2. In vitro, Bendamustine does not inhibit CYP1A4, CYP2C9/10, CYP2D6, CYP2E1, and CYP3A4.

The mean total clearance after a 30-minute IV infusion of the drug to 12 subjects at a dose of 120 mg/m² body surface area was 639.4 ml/min. Approximately 20% of the administered drug dose was excreted by the kidneys within 24 hours.

The amount of unchanged bendamustine and its metabolites excreted by the kidneys is in descending order as follows: monohydroxybendamustine > Bendamustine > dihydroxybendamustine > oxidized metabolite > N-desmethylbendamustine.

Polar metabolites are excreted mainly with bile.

With 30-70% liver tumor involvement and slightly reduced liver function (serum bilirubin <1.2 mg/dL), the pharmacokinetics did not differ significantly from those in patients with normal liver and kidney function regarding C_max, T_max, AUC, T_1/2β, V_d, and elimination.

Pharmacokinetic parameters in patients with CrCl > 10 ml/min, including those on dialysis, did not differ significantly from those in patients with normal renal function regarding C_max, T_max, AUC, T_1/2β, V_d, and elimination.

In individuals older than 18 and younger than 84 years, the pharmacokinetic parameters did not differ significantly.

Indications

Chronic lymphocytic leukemia (the efficacy of use in first-line therapy compared to other chemotherapeutic drugs except chlorambucil has not been established).

Indolent non-Hodgkin’s lymphomas in monotherapy in patients who progressed during or within 6 months after the end of therapy including rituximab and in combination therapy as first-line therapy.

ICD codes

Dosage Regimen

Administer intravenously as a 30-60 minute infusion.

Calculate the dose individually based on body surface area.

For chronic lymphocytic leukemia, administer 100 mg/m² on days 1 and 2 of a 28-day cycle for up to 6 cycles.

For indolent non-Hodgkin’s lymphoma, administer 120 mg/m² on days 1 and 2 of a 21-day cycle for up to 8 cycles.

Delay treatment if neutrophil count is below 1,000/µL or platelet count is below 75,000/µL.

Consider dose reduction for severe hematologic toxicity or non-hematologic toxicity ≥ Grade 3.

Reconstitute the 25 mg vial with 5 mL and the 100 mg vial with 20 mL of sterile water for injection to yield a 5 mg/mL concentrate.

Shake vial vigorously until a clear, colorless to pale yellow solution is obtained; complete dissolution typically occurs within 5 minutes.

Immediately after reconstitution, further dilute with 500 mL of 0.9% sodium chloride solution (or 500 mL of 2.5% glucose/0.45% sodium chloride solution).

Use the diluted infusion solution within 24 hours of reconstitution when stored at 2°C-8°C (36°F-46°F) and infused within 3 hours of removal from refrigeration.

Administer subsequent cycles only after adequate hematologic recovery (ANC ≥1,000/µL, platelets ≥75,000/µL).

Monitor blood counts and liver function tests weekly.

Premedicate with antiemetics and consider antihistamines and corticosteroids to minimize infusion reactions and nausea.

Adverse Reactions

From the hematopoietic system: very often – leukopenia, neutropenia, lymphocytopenia, anemia, thrombocytopenia; often – bleeding; very rarely – hemolysis.

From the digestive system: very often – nausea, vomiting, anorexia, inflammation of the mucous membranes of the gastrointestinal tract, abdominal pain, dyspepsia; often – diarrhea, constipation, gastroesophageal reflux, dry mouth, increased activity of ALT, AST, ALP, bilirubin concentration; very rarely – hemorrhagic esophagitis, gastrointestinal bleeding.

From the cardiovascular system: often – arrhythmia, tachycardia, decreased blood pressure; infrequently – pericardial effusion; rarely – acute vascular insufficiency; very rarely – myocardial infarction, cardiopulmonary failure, phlebitis.

From the respiratory system: often – impaired respiratory function, cough, shortness of breath, wheezing, nasopharyngitis; very rarely – pulmonary fibrosis, primary atypical pneumonia.

From the nervous system: very often – headache, dizziness, insomnia; often – taste disturbances, anxiety, depression; rarely – increased drowsiness, aphonia; very rarely – paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, ataxia, encephalitis.

Dermatological reactions: very often – alopecia; often – skin rash, skin itching, dry skin, increased night sweats, hyperhidrosis; very rarely – erythema, dermatitis, itching, maculopapular rash.

From the musculoskeletal system: very often – back pain; often – arthralgia, limb pain, bone pain.

Allergic reactions: often – hypersensitivity reactions (allergic dermatitis, urticaria); rarely – anaphylactic/anaphylactoid reactions; very rarely – anaphylactic shock.

From the reproductive system: often – amenorrhea; very rarely – infertility.

Local reactions: often – pain at the injection site, erythema; rarely – necrosis of surrounding tissues.

Other: very often – fever, chills, increased pain, weakness, increased fatigue, weight loss, dehydration, secondary infections, hyperuricemia; often – peripheral edema, hypokalemia; rarely – sepsis; very rarely – tumor lysis syndrome.

Analysis of safety data by gender or race did not reveal clinically significant differences.

Contraindications

Moderate and severe hepatic insufficiency, jaundice, neutrophil count less than 1500/µL and/or platelet count less than 75000/µL, surgical interventions less than 30 days before the start of therapy, infections, especially those accompanied by leukocytopenia, childhood, pregnancy, lactation (breastfeeding), hypersensitivity to bendamustine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Bendamustine has teratogenic and mutagenic effects. Patients during therapy and for at least 6 months after its completion should use reliable methods of contraception. Men are recommended to resort to sperm cryopreservation before starting treatment due to the risk of infertility associated with the use of bendamustine.

Use in Hepatic Impairment

Contraindicated in moderate and severe hepatic insufficiency, jaundice.

Should be used with caution in patients with mild hepatic insufficiency.

Use in Renal Impairment

Should be used with caution in patients with impaired renal function.

Pediatric Use

Contraindicated in children.

Geriatric Use

In elderly patients, the risk of adverse reactions should be considered.

Special Precautions

Should be used with caution in patients with mild hepatic insufficiency, and in patients with impaired renal function.

Patients with a history of serious cardiac diseases (myocardial infarction, episodes of ischemia, arrhythmia) require careful monitoring of water and electrolyte balance, especially potassium, and ECG monitoring during therapy with bendamustine.

Treatment with bendamustine should be carried out under the supervision of a physician experienced in working with antitumor drugs.

During therapy, peripheral blood counts and liver enzyme activity indicators should be regularly monitored, at least once a week. A decrease in leukocytes, neutrophils, and platelets is usually observed on days 14-20, with recovery occurring in 3-5 weeks.

Changes in kidney function have been noted with the use of bendamustine, so careful monitoring of kidney function should be ensured during treatment.

If it comes into contact with skin and mucous membranes, they should be washed with water and soap.

Drug Interactions

The active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-Bendamustine (M4), are formed under the action of CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) may potentially increase the concentration of bendamustine and decrease the concentration of active metabolites in plasma. Inducers of CYP1A2 (e.g., omeprazole, smoking) may potentially decrease plasma concentrations of bendamustine and increase the concentration of its active metabolites in plasma. Caution is required when used concomitantly with inhibitors or inducers of CYP1A2, or consideration of alternative treatment should be given.

Bendamustine in combination with other myelosuppressive drugs enhances the bone marrow suppression effect and toxic properties. Like other cytostatics, Bendamustine suppresses antibody production, increasing the risk of infection during vaccination.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.