Mabthera^® (Solution, Concentrate) Instructions for Use

ATC Code

L01FA01 (Rituximab)

Active Substance

Rituximab

Clinical-Pharmacological Group

Antitumor drug. Monoclonal antibodies

Pharmacotherapeutic Group

Antineoplastic agents, monoclonal antibodies

Pharmacological Action

Antitumor and immunomodulatory agent. It is a chimeric mouse/human monoclonal antibody that specifically binds to the transmembrane antigen CD20.

This antigen is located on pre-B-lymphocytes and mature B-lymphocytes but is absent on hematopoietic stem cells, pro-B-cells, healthy plasma cells, and healthy cells of other tissues. The antigen is expressed in more than 95% of B-cell non-Hodgkin lymphomas.

After binding with the antibody, CD20 is no longer internalized and does not leave the cell membrane into the environment. CD20 does not circulate in the plasma as a free antigen and therefore does not compete for binding with antibodies.

Rituximab binds to the CD20 antigen on B-lymphocytes and initiates immunological reactions that mediate B-cell lysis.

Possible mechanisms of cell lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab increases the sensitivity of human B-cell lymphoma lines to the cytotoxic action of certain chemotherapeutic drugs in vitro.

Indications

Non-Hodgkin lymphoma (including for subcutaneous administration). Chronic lymphocytic leukemia. Rheumatoid arthritis. Granulomatosis with polyangiitis (Wegener’s granulomatosis) and microscopic polyangiitis.

ICD codes

Dosage Regimen

Administer Mabthera^® as an intravenous infusion or subcutaneous injection. The dosage regimen is individualized based on indication, disease stage, and concurrent therapy.

For follicular lymphoma, administer 375 mg/m² body surface area by intravenous infusion once weekly for 4 weeks. For diffuse large B-cell lymphoma, administer 375 mg/m² on day 1 of each chemotherapy cycle for up to 8 cycles.

For chronic lymphocytic leukemia, administer 375 mg/m² on day 1 of the first cycle, followed by 500 mg/m² on day 1 of subsequent cycles for up to 6 cycles in combination with chemotherapy.

For rheumatoid arthritis, administer two 1000 mg intravenous infusions separated by 2 weeks. Repeat courses every 24 weeks or based on clinical evaluation.

For granulomatosis with polyangiitis and microscopic polyangiitis, administer a 375 mg/m² intravenous infusion once weekly for 4 weeks in combination with glucocorticoids.

For subcutaneous administration in follicular lymphoma and diffuse large B-cell lymphoma, administer a fixed dose of 1400 mg following an initial intravenous infusion.

Premedicate with an antihistamine and analgesic/antipyretic approximately 30 minutes prior to each infusion to reduce the frequency and severity of infusion-related reactions.

Do not administer as an intravenous push or bolus. Initiate the intravenous infusion at a rate of 50 mg/hour. If no infusion-related reactions occur, escalate the infusion rate in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

For subsequent infusions, if the initial infusion is well tolerated, initiate at a rate of 100 mg/hour and increase by 100 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

Interrupt or slow the infusion rate for infusion-related reactions. Resume the infusion at half the previous rate upon symptom resolution.

Monitor patients closely during and for several hours following the infusion. Ensure immediate access to resuscitation equipment and medications for the management of severe reactions.

Adverse Reactions

From the digestive system nausea, vomiting, diarrhea, dyspepsia, anorexia, abdominal pain, increased LDH activity, taste disturbance; in isolated cases – a slight transient increase in liver function tests.

From the nervous system weakness, headache, dizziness, anxiety, depression, paresthesia, hyperesthesia, agitation, insomnia, nervousness, drowsiness, neuritis, lacrimation disorders, ear pain.

From the cardiovascular system transient arterial hypotension, arterial hypertension, bradycardia, tachycardia, orthostatic hypotension, vasodilation, flushing, arrhythmia, exacerbation of pre-existing heart diseases (including angina, chronic heart failure), peripheral edema, facial edema.

From the hematopoietic system severe thrombocytopenia, severe neutropenia, severe anemia, leukopenia, lymphadenopathy.

From metabolism hyperglycemia, weight loss, hypocalcemia, hypercalcemia.

From the musculoskeletal system arthralgia, myalgia, bone pain, back pain, chest pain, neck pain, muscle hypertonia; rarely – increased CPK activity, spontaneous fractures.

From the urinary system dysuria, hematuria, hyperuricemia.

Dermatological reactions increased sweating (including at night), dry skin.

Allergic reactions urticaria, itching, bronchospasm, shortness of breath, swelling of the tongue or pharynx, (angioedema), rhinitis, increased cough, bronchial asthma, pseudolaryngitis; in isolated cases – obliterative bronchiolitis.

Other fever and chills may occur (develop mainly during the first infusion, usually within the first 2 hours), pain at the tumor site, general malaise, abdominal enlargement, pain at the infusion site; rarely – blood clotting disorders, increased frequency of infectious diseases, recurrence of pre-existing skin tumors.

The relationship between the development of these adverse reactions and the use of rituximab has not been precisely established.

Contraindications

Hypersensitivity to rituximab or mouse proteins; acute infectious diseases, severe primary or secondary immunodeficiency; severe heart failure (NYHA class IV) in rheumatoid arthritis; children and adolescents under 18 years of age; pregnancy, breastfeeding period.

With caution history of respiratory failure or tumor infiltration of the lungs; number of circulating malignant cells >25 thousand/µl or high tumor burden; neutropenia (less than 1.5 thousand/µl), thrombocytopenia (less than 75 thousand/µl); chronic infections.

Use in Pregnancy and Lactation

Clinical data on the safety of rituximab use during pregnancy are not available. The effect on the reproductive system and fertility in humans has not been studied.

Use during pregnancy is possible according to indications in cases where the expected benefit to the mother outweighs the potential risk to the fetus. It should be borne in mind that IgG can cross the placental barrier, so Rituximab may cause depletion of the B-cell pool in the fetus.

It is not known whether Rituximab is excreted in breast milk. Considering that IgG circulating in the mother’s blood are excreted in breast milk, Rituximab should not be used during lactation (breastfeeding).

Women of childbearing potential should use reliable methods of contraception during treatment and for 12 months after its completion.

Experimental studies on the effect of rituximab on reproductive function have not been conducted.

Pediatric Use

Use in children and adolescents under 18 years of age is contraindicated. Safety and efficacy of use in this category of patients have not been established.

Geriatric Use

Should be used with caution in elderly patients.

Special Precautions

Rituximab should be administered under the close supervision of an oncologist, hematologist, or rheumatologist with the necessary conditions for resuscitation measures available.

During treatment, a detailed analysis of peripheral blood, including platelet count, should be performed regularly.

Antihypertensive drugs should be discontinued 12 hours before the start of rituximab infusion and during the infusion. Patients with a history of heart disease require careful monitoring during the infusion.

Anaphylactoid reactions are possible after the administration of protein preparations, therefore, means for the immediate relief of severe hypersensitivity reactions (including norepinephrine, antihistamines, corticosteroids) should always be available when using rituximab.

When administering other monoclonal antibodies for diagnostic or therapeutic purposes to patients who have antibodies against mouse proteins or anti-chimeric antibodies, hypersensitivity reactions may develop.

Vaccination with live viral vaccines is not recommended after treatment with rituximab. Vaccination with inactivated vaccines is possible, but the response rate may be reduced.

Drug Interactions

Data on drug interactions of rituximab are limited. In patients with chronic lymphocytic leukemia, the pharmacokinetic parameters do not change with the simultaneous use of rituximab, fludarabine, and cyclophosphamide. Concurrent use of methotrexate does not affect the pharmacokinetics of rituximab in patients with rheumatoid arthritis. When prescribed with other monoclonal antibodies for diagnostic or therapeutic purposes to patients who have antibodies against mouse proteins or anti-chimeric antibodies, the risk of allergic reactions increases.

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.