Bendamustine - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Antineoplastic agents

Included in the formulation

Ribomustine

powder d / infusion

Astellas Farma Europe BV Netherlands

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

АТХ:

L.01.A.A.09 Bendamustine

Pharmacodynamics:

Bendamustine is a drug with an antitumor effect.

Bendamustine has an antineoplastic effect, confirmed in numerous studies in vitro on various tumor cell lines such as 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 models of tumors - melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer.

Bendamustine promotes cross-linking of DNA molecules due to alkylation. As a result, the matrix function of DNA and its synthesis are violated. There is also evidence that bendamustine has additional antimetabolic properties (purine analog effect).

Bendamustine practically does not demonstrate cross-resistance in human tumor cell lines with different resistance mechanisms.

In clinical studies, it has been found that there is no complete cross-resistance between bendamustine and anthracyclines or alkylates.

Pharmacokinetics:

Metabolism

Bendamustine hydrochloride is metabolized predominantly in the liver. The main way to remove bendamustine hydrochloride from the body is its hydrolysis. In the formation of gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4), the cytochrome P450 isoenzyme CYP1A2 is involved in the liver. In vitro bendamustine does not inhibit CYP1A4, CYP2C9 / 10, CYP2D6, CYP2E1 and CYP3A4.

Distribution

After a single 30-minute intravenous infusion, bendamustine at a dose of 120 mg / m² beta-phase elimination (half-life of β) is 28.3 minutes.

V_d with a 30-minute intravenous infusion is 19.3 liters, with the subsequent systematic introduction and achievement of CSS V_d - from 15.8 to 20.5 liters.

In the systemic circulation bendamustine actively binds to plasma proteins (> 95%), mainly with albumin.

The ability of bendamustine to bind to blood plasma proteins is not impaired at low concentrations of albumin in blood plasma in patients over the age of 70 and in advanced stages of tumors.

Elimination and excretion

The average value of total clearance after a 30-minute intravenous infusion of the drug to 12 subjects at a dose of 120 mg /m² was 639.4 ml / min.

About 20% of the administered dose of the drug was excreted by the kidneys for 24 hours.

Pharmacokinetics in different patient groups

Patients with impaired hepatic function: at 30-70% tumor damage to the liver and slightly reduced liver function (serum bilirubin <1.2 mg / dL), the pharmacokinetics did not differ significantly from that in patients with normal liver and kidney function in relation to C_max, T_max, AUC, elimination half-life, V_d and excretion.

Patients with renal dysfunction: pharmacokinetic parameters in patients with clearance creatinine> 10 ml / min, including those on dialysis, did not differ significantly from those in patients with normal renal function in relation to C_max, T_max, AUC, elimination half-life, V_d and deducing.

Elderly patients: patients older than 84 years were not included in the study of the pharmacokinetics of bendamustine, in patients older than 18 and under 84 years of age pharmacokinetic parameters did not differ significantly.

There were no differences in pharmacokinetics, depending on the race.

Indications:

Chronic lymphocytic leukemia; indolent non-Hodgkin's lymphomas in monotherapy in patients who have progressed with or against the background of or within 6 months after the end of therapy with rituximab and in combination therapy as first-line therapy.

ICD-10

II.C81-C96.C82 Follicular [nodular] non-Hodgkin's lymphoma

II.C81-C96.C83 Diffuse non-Hodgkin's lymphoma

II.C81-C96.C91.1 Chronic lymphocytic leukemia

Contraindications:

Surgical interventions less than 30 days before therapy; infection, especially accompanied by leukocytopenia; themeasured and severe hepatic impairment; jaundice; the number of neutrophils is less than 1500 / μL and / or platelets less than 75,000 / μL; children's age (lack of data on effectiveness and safety); pregnancy; lactation period (breastfeeding); hypersensitivity to the active substance or to any of the auxiliary components or their intolerance.

Carefully:

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

It should be prescribed with caution in patients with mild hepatic impairment, with impaired renal function.

Pregnancy and lactation:

The drug is contraindicated in pregnancy and lactation (breastfeeding).

Dosing and Administration:

Intravenously. For individual dose selection, reference should be made to the literature.

Chronic lymphocytic leukemia

Bendamustine 100 mg /m² intravenously as a 30-minute infusion on the 1st and 2nd days of each 28-day cycle (up to 6 cycles).

In the case of hematological toxicity grade 3/4 toxicity or hematological ≥ 2 minutes severity administering bendamustine should be delayed at least until the recovery indicators absolute neutrophil count ≥ 1,000 cells / mm and platelet count ≥ 75,000 / mm and / or reduce the severity non-hematologic toxicity up to 1 st degree or less.

Modification of doses for hematological toxicity: with the development of toxicity of the 3-4th degree, the dose of the drug in subsequent cycles should be reduced to 50 mg /m². In case of recurrence of hematological toxicity of the 3rd-4th degree, the dose of the drug should be reduced to 25 mg /m².

Modification of doses for non-hematologic toxicity: with clinically significant signs of the 3-4th degree of toxicity, the dose of bendamustine in subsequent cycles should be reduced to 50 mg /m².

Non-Hodgkin's Lymphoma

Monotherapy. Bendamustine 120 mg /m² in the form of a 60-minute infusion on the 1 st and 2 nd days of each 21-day cycle (up to 8 cycles).

Modification of doses for hematologic toxicity: with the development of toxicity of the 4th degree, the dose of the drug in subsequent cycles should be reduced to 90 mg /m². In the case of repeated occurrence of hematological toxicity of the 4th degree, the dose of the drug should be reduced to 60 mg /m².

Modification of doses for non-hematologic toxicity: in the development of toxicity of the 3-4th degree, the dose of bendamustine in subsequent cycles should be reduced to 90 mg /m². In case of recurrence of non-hematological toxicity of the 3rd-4th degree, the dose of the drug should be reduced to 60 mg /m².

Combined therapy. Bendamustine in a dose of 60 mg /m² the surface of the body intravenously in the form of a 30-minute infusion daily from day 1 to day 5, vincristine intravenously on the 1st day, prednisolone 100 mg /m² intravenously every day from the 1st to the 5th days of each 21-day cycle.

Use in patients with impaired liver function

Based on the pharmacokinetic data, there is no need for dose adjustment at serum bilirubin concentration <1.2 mg / dl. For mild hepatic insufficiency, the drug should be used with caution. At moderate (ALT and / or ACT activity is 2.5-10 times higher than the upper limit of the norm or serum bilirubin concentration is 1.5-3 times higher than the upper limit of the norm) or severe hepatic insufficiency (serum bilirubin concentration above the upper limit of the norm more than 3 times) bendamustine can not be applied.

Use in patients with impaired renal function

Based on pharmacokinetic data, there is no need for dose adjustment in patients with creatinine clearance> 10 ml / min.

Recommendations for the preparation of a solution for infusions

The contents of the 25 mg vial are diluted in 10 ml of water for injection and shaken until completely dissolved.

The contents of the 100 mg bottle are diluted in 40 ml of water for injection and shaken until completely dissolved.

The resulting colorless transparent concentrate contains 2.5 mg / ml bendamustine. After 5-10 minutes exposure, the required dose of bendamustine is dissolved in 500 ml of 0.9% sodium chloride solution for infusion.The chemical and physical stability of this solution is maintained for 5 hours at room temperature and 5 days when stored in a refrigerator.

From the microbiological point of view, the preparation should be administered immediately after the preparation of the solution, if the breeding method does not exclude the possibility of its microbial contamination. If the ready-for-use preparation is not introduced immediately after preparation, the person who prepared it is responsible for the time and conditions for storing the finished solution.

Side effects:

From the cardiovascular system: often - arrhythmia, tachycardia, lowering blood pressure; infrequent - effusion in the pericardial cavity; rarely acute vascular insufficiency; very rarely - myocardial infarction, cardiopulmonary insufficiency, phlebitis.

From the respiratory system: often - a violation of the function of breathing, coughing, shortness of breath, wheezing, nasopharyngitis; very rarely - pulmonary fibrosis, primary atypical pneumonia.

From the hemopoietic 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, indigestion; often - diarrhea, constipation, gastroesophageal reflux, dry mouth, increased activity of ALT, AST, alkaline phosphatase, bilirubin concentration; very rarely - hemorrhagic esophagitis, gastrointestinal bleeding.

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

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

From the musculoskeletal system: very often - back pain; often - arthralgia, pain in the limbs, pain in the bones.

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

On the part of 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, pain, weakness, fatigue, weight loss, dehydration, secondary infections, hyperuricemia; often - periiferedema, hypokalemia; rarely - sepsis; very rarely - tumor lysis syndrome.

Overdose:

When applying the maximum single dose of 280 mg / m² patients on days 7-21 had ECG abnormalities, including prolongation of the QT interval, sinus tachycardia, changes in the ST segment and T wave, and blockage of the anterior branch of the left branch of the bundle.

The specific antidote is unknown. In the event of a possible overdose, the patient should be carefully monitored, including monitoring of hematological and ECG parameters. Treatment is symptomatic. Dialysis is ineffective.

Interaction:

No special studies of drug interactions were conducted.

Bendamustine in combination with other myelosuppressive drugs enhances the effect of bone marrow suppression and toxicproperties. Like other cytotoxic drugs, bendamustine suppresses the production of antibodies, increasing the risk of infection during vaccination.

Active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4) are formed by the action of CYP1A2. Inhibitors of CYP1A2 (eg, fluvoxamine, ciprofloxacin) can potentially increase the concentration of bendamustine and reduce the concentration of active metabolites in the blood plasma. Inductors CYP1A2 (for example, omeprazole, smoking) can potentially reduce plasma concentrations of bendamustine and increase the concentration of its active metabolites in blood plasma. Caution should be exercised while using inhibitors or inducers of CYP1A2 or considering the possibility of alternative treatment.

Special instructions:

Reduction of leukocytes, neutrophils and platelets, usually observed on days 14-20, recovery - after 3-5 weeks.

With the use of bendamustine, there has been a change in the function of the kidneys, so during the treatment it is necessary to ensure a careful monitoring of the kidney function.

Treatment with bendamustine should be performed under the supervision of a doctor who has experience with antitumor drugs.

On the background of therapy should be regularly, at least once a week to monitor the performance of peripheral blood and liver enzymes activity.

Bendamustine has a teratogenic and mutagenic effect. Patients on the background of therapy and at least six months after the end should use reliable methods of contraception. Men are recommended to resort to cryopreservation of sperm before the start of treatment due to the risk of infertility caused by the use of this drug.

In case of contact with skin and mucous membranes, wash with soap and water.

Impact on the ability to drive vehicles and manage mechanisms

Studies of the effect of the drug on the ability to drive vehicles and mechanisms were not conducted. However, during therapy with the drug there were ataxia, peripheral neuropathy, drowsiness. If such events are noted, patients should avoid driving and handling machinery.

Instructions

Bendamustine (Bendamustinum)