Rituximab (Concentrate) Instructions for Use

Marketing Authorization Holder

NANOLEK LLC (Russia)

Manufactured By

Sinergium Biotech S.A. (Argentina)

ATC Code

L01FA01 (Rituximab)

Active Substance

Rituximab (Rec.INN registered by WHO)

Dosage Form

Rituximab

Concentrate for solution for infusion 10 mg/1 ml: vial 10 ml 2 pcs. or 50 ml 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion is a clear to opalescent, colorless to pale yellow liquid.

Excipients: sodium citrate dihydrate – 7.35 mg, sodium chloride – 9 mg, polysorbate 80 (tween 80) – 0.7 mg, hydrochloric acid or sodium hydroxide – to adjust pH to 6.5, water for injection – up to 1 ml.

10 ml – colorless glass vials (2) – plastic blisters (1) – cardboard packs.
50 ml – colorless glass vials (1) – plastic blisters (1) – cardboard packs.

Pharmacotherapeutic Group

Antineoplastic and immunomodulating agent – monoclonal antibodies

Pharmacological Action

Antineoplastic and immunomodulating 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 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 mediating B-cell lysis. Possible mechanisms of cellular lysis include complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab increases the sensitivity of human B-cell lymphoma cell lines to the cytotoxic action of some 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

Determine the dosage regimen individually based on the specific indication, disease stage, hematopoietic status, and anticancer therapy protocol.

For intravenous infusion, dilute the concentrate in an infusion bag containing 0.9% sodium chloride or 5% dextrose solution to a final concentration of 1 mg/ml to 4 mg/ml. Gently invert the bag to mix. Do not mix or dilute with other drugs.

Administer the initial infusion at a rate of 50 mg/hour. If no infusion-related reactions occur, gradually escalate the infusion rate in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.

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

Premedicate approximately 30 minutes before each infusion with an antihistamine and an analgesic/antipyretic (e.g., acetaminophen/paracetamol). Administer corticosteroid premedication as per the specific protocol for the indicated condition.

Interrupt or temporarily slow the infusion immediately if an infusion-related reaction occurs. Manage reactions symptomatically. Upon resolution, resume the infusion at half the previous rate.

Do not administer as an intravenous push or bolus. Monitor patients closely throughout the infusion, particularly during the first infusion.

For subcutaneous administration, use only the specific, approved subcutaneous formulation. Inject into the abdominal subcutaneous tissue. Do not inject into areas where the skin is tender, bruised, red, or hard. Rotate injection sites.

Adhere strictly to the prescribed treatment schedule and duration for the specific indication, whether as monotherapy or in combination with other chemotherapeutic agents.

Adverse Reactions

From the digestive system: nausea, vomiting, diarrhea, dyspepsia, anorexia, abdominal pain, increased LDH activity, taste disturbance; in isolated cases – 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, pruritus, bronchospasm, dyspnea, 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 lung tumor infiltration; 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 lacking. The effect on the human reproductive system and fertility has not been studied. During pregnancy, it can be used 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 unknown 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

Contraindicated in children and adolescents under 18 years of age. Safety and efficacy 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 complete blood count, 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 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, pharmacokinetic parameters do not change with simultaneous use of rituximab, fludarabine, and cyclophosphamide. Concurrent administration 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.