Remicade^® (Lyophilisate) Instructions for Use

ATC Code

L04AB02 (Infliximab)

Active Substance

Infliximab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Drug with anti-inflammatory action. Tumor necrosis factor-alpha (TNF-α) inhibitor

Pharmacotherapeutic Group

Immunosuppressive agent – monoclonal antibodies

Pharmacological Action

TNFα inhibitor. Infliximab is a chimeric murine-human monoclonal antibody. It has a high affinity for TNFα, which is a cytokine with a wide spectrum of biological activity, is also a mediator of the inflammatory response and is involved in the processes of immune system modulation. It is evident that TNFα plays a role in the development of autoimmune and inflammatory diseases.

Infliximab rapidly binds and forms a stable complex with both forms (soluble and transmembrane) of human TNFα, thereby reducing the functional activity of TNFα. The specificity of infliximab for TNFα is confirmed by its inability to neutralize the cytotoxic effect of lymphotoxin alpha ( LTα or TNFβ) – a cytokine that interacts with the same receptors as TNFα.

Elevated concentrations of TNFα were detected in the joints of patients with rheumatoid arthritis and correlated with disease activity. In patients with rheumatoid arthritis, therapy with infliximab led to a reduction in the infiltration of inflammatory cells into the inflamed areas of the joints, as well as a decrease in the expression of molecules mediating cell adhesion, chemotaxis, and tissue destruction.

After therapy with infliximab, a decrease in serum concentrations of interleukin-6 ( IL-6) and C-reactive protein ( CRP), as well as an increase in hemoglobin concentration in patients with rheumatoid arthritis with a baseline low hemoglobin concentration, were noted. No significant decrease in the number of lymphocytes in peripheral blood or their proliferative response to mitogenic stimulation compared to the response of cells from untreated patients in vitro was detected.

In patients with psoriasis, therapy with infliximab led to a reduction in inflammation in the epidermal layer and normalization of keratinocyte differentiation in psoriatic plaques. In patients with psoriatic arthritis, short-term therapy with infliximab was accompanied by a reduction in the number of T-cells and blood vessels in the synovial membrane and skin areas affected by the psoriatic process.

Histological examination of colon biopsies taken before and 4 weeks after infliximab administration revealed a significant decrease in TNFα concentration. Therapy with infliximab in patients with Crohn’s disease was accompanied by a significant decrease in the concentration of the nonspecific serum marker of inflammation – CRP.

The total number of peripheral blood leukocytes changed minimally during infliximab therapy, although a trend towards normalization of the numbers of lymphocytes, monocytes, and neutrophils was observed. In patients receiving Infliximab, the proliferative response of peripheral blood mononuclear cells to stimulation was not reduced compared to that in untreated patients.

No significant changes in cytokine secretion by stimulated peripheral blood mononuclear cells after infliximab therapy were detected. Examination of mononuclear cells from lamina propria biopsies of the intestinal mucosa showed that infliximab therapy causes a decrease in the number of cells expressing TNFα and interferon gamma. Additional histological studies confirmed that Infliximab reduces the infiltration of inflammatory cells and the content of inflammatory markers in the affected areas of the intestine. Endoscopic studies demonstrated healing of the intestinal mucosa in patients receiving Infliximab.

Indications

Active rheumatoid arthritis in patients 18 years of age and older (in combination with methotrexate) when previous therapy, including treatment with methotrexate, has been ineffective.

Severe active Crohn’s disease (including with fistula formation) in patients 18 years of age and older, not responding to standard therapy, including corticosteroids and/or immunosuppressants.

Moderate to severe active Crohn’s disease in children and adolescents aged 6 to 17 years inclusive – in case of inefficacy, intolerance, or contraindications to standard therapy, including corticosteroids and/or immunosuppressants.

Ulcerative colitis in adults when standard therapy is ineffective.

Moderate to severe ulcerative colitis in children and adolescents aged 6 to 17 years – with insufficient efficacy of standard therapy with corticosteroids, 6-mercaptopurine or azathioprine, or in case of intolerance or contraindications to standard therapy.

Ankylosing spondylitis.

Psoriatic arthritis.

Psoriasis.

ICD codes

Dosage Regimen

Administer intravenously over a period not less than two hours using an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size no greater than 1.2 µm).

Reconstitute each 100 mg vial with 10 mL of Water for Injections using a syringe with a 21-gauge or smaller needle. Direct the stream to the glass wall. Swirl vial gently; do not shake. Allow reconstituted solution to stand for 5 minutes. Inspect for particulates and discoloration; solution should be opalescent and colorless to light yellow.

Further dilute the total volume of reconstituted solution in 250 mL of 0.9% Sodium Chloride infusion solution. The final concentration must be between 0.4 mg/mL and 4 mg/mL. Mix gently. Do not infuse with other medicinal products.

For rheumatoid arthritis, administer an initial dose of 3 mg/kg, followed by additional doses of 3 mg/kg at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Administer in combination with methotrexate.

For Crohn’s disease in adults and pediatric patients (6-17 years), administer an initial dose of 5 mg/kg, followed by additional doses of 5 mg/kg at 2 and 6 weeks after the first infusion, then every 8 weeks. For fistulizing Crohn’s disease, administer 5 mg/kg at 0, 2, and 6 weeks.

For ulcerative colitis in adults and pediatric patients (6-17 years), administer an initial dose of 5 mg/kg, followed by additional doses of 5 mg/kg at 2 and 6 weeks after the first infusion, then every 8 weeks.

For ankylosing spondylitis, administer 5 mg/kg at 0, 2, and 6 weeks, then every 6 to 8 weeks.

For psoriatic arthritis and plaque psoriasis, administer 5 mg/kg at 0, 2, and 6 weeks, then every 8 weeks.

Monitor patients for hypersensitivity reactions during and for at least 1-2 hours post-infusion. Premedication with an antihistamine, antipyretic, and/or hydrocortisone may be considered. Discontinue infusion for severe reactions.

Adverse Reactions

Nervous system disorders frequent – headache, dizziness, feeling of fatigue; rare – depression, psychosis, anxiety, amnesia, apathy, nervousness, drowsiness.

Digestive system disorders frequent – nausea, diarrhea, abdominal pain, dyspepsia; rare – constipation, gastroesophageal reflux, cheilitis, diverticulitis, impaired liver function, cholecystitis.

Blood and lymphatic system disorders rare – anemia, leukopenia, lymphadenopathy, lymphocytosis, lymphopenia, neutropenia, thrombocytopenia.

Cardiovascular system disorders frequent – flushing, chest pain; rare – arterial hypertension, arterial hypotension, syncope, thrombophlebitis, bradycardia, palpitations, vasospasm, cyanosis, peripheral circulatory disorder, arrhythmia, edema.

Respiratory system disorders frequent – dyspnea, viral infection (influenza, herpes), fever, upper respiratory tract infections, bronchitis, pneumonia; rare – bronchospasm, pleurisy, pulmonary edema.

Eye disorders rare – conjunctivitis, keratoconjunctivitis, endophthalmitis.

Urinary system disorders rare – urinary tract infections, pyelonephritis.

Blood clotting system disorders rare – ecchymosis/hematoma, petechiae, epistaxis.

Dermatological reactions frequent – rash, skin rash, itching, urticaria, sweating, dry skin; rare – fungal dermatitis (onychomycosis, eczema), seborrhea, erysipelas, warts, furunculosis, periorbital edema, hyperkeratosis, skin pigmentation disorder, alopecia, bullous rash.

Allergic reactions urticaria, itching, swelling of the face, lips, hands, myalgia and/or arthralgia with fever, formation of autoantibodies, lupus-like syndrome.

Other frequent – fever; rare – abscesses, cellulitis, sepsis, bacterial and fungal infections, myalgia, arthralgia, vaginitis, infusion syndrome, injection site reaction.

Contraindications

Severe infectious process (including abscess, sepsis, tuberculosis, opportunistic infections), hypersensitivity to infliximab and other murine proteins.

Use in Pregnancy and Lactation

Infliximab is not recommended for use during pregnancy, as it may affect the development of the fetal immune system. Women of childbearing potential during treatment and for at least 6 months after its completion should use reliable methods of contraception.

It is not known whether Infliximab is excreted in human breast milk. If use during lactation is necessary, breastfeeding should be discontinued. Resumption of breastfeeding is allowed no earlier than 6 months after the end of treatment.

Use in Hepatic Impairment

The efficacy and safety of infliximab in patients with liver diseases have not been established.

Use in Renal Impairment

The efficacy and safety of infliximab in patients with kidney diseases have not been established.

Pediatric Use

The safety and efficacy of infliximab in children and adolescents under 17 years of age with rheumatoid arthritis or Crohn’s disease have not been studied.

Geriatric Use

The efficacy and safety of infliximab in elderly patients have not been established.

Special Precautions

The development of acute allergic reactions and delayed-type allergic reactions is possible with the use of infliximab.

Some patients may develop antibodies to infliximab, which in rare cases cause severe allergic reactions. In the absence of tolerance to methotrexate or to other non-steroidal immunosuppressants (e.g., azathioprine, 6-mercaptopurine) and their discontinuation before or during infliximab use, the risk of formation of these antibodies increases.

Delayed-type hypersensitivity reactions were observed with high frequency (25%) in Crohn’s disease after re-treatment was administered 2-4 hours after the initial treatment.

Since the elimination of infliximab occurs over 6 months, the patient should be under medical supervision during this period for the timely detection of signs of an infectious process. The use of infliximab should be discontinued in case of a severe infection or sepsis.

If active tuberculosis is suspected, treatment should be discontinued until the diagnosis is established and appropriate treatment is carried out.

Before starting therapy with infliximab, patients should be thoroughly examined for both active and latent tuberculosis. It should be taken into account that in severely ill patients and patients with immunosuppression, a false-negative tuberculin test may be obtained. If latent tuberculosis is detected, measures must be taken to prevent activation of the process, and the ratio of expected benefit to potential risk of using infliximab in this category of patients should be assessed.

If symptoms resembling lupus-like syndrome (persistent rash, fever, joint pain, fatigue) appear during treatment, and antibodies to DNA are detected, Infliximab should be discontinued.

The efficacy and safety of infliximab in elderly patients, as well as in patients with liver and kidney diseases, have not been established.

The safety and efficacy of infliximab in children and adolescents under 17 years of age with rheumatoid arthritis or Crohn’s disease have not been studied. Until relevant data are obtained, use in this category of patients should be avoided.

Drug Interactions

In patients with rheumatoid arthritis, simultaneous use of methotrexate reduces the formation of antibodies to infliximab and increases its plasma concentration.

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.