Renflexis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Renflexis (Renflexis)

Composition:

active substance: infliximab;

1 vial contains 100 mg of infliximab;

excipients: sucrose; polysorbate 80 (E 433); sodium dihydrogen phosphate monohydrate; disodium hydrogen phosphate heptahydrate.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Basic physico-chemical properties: white to almost white mass, free from foreign particles.

Pharmacotherapeutic group. Immunosuppressants. Tumor necrosis factor-alpha (TNF-alpha) inhibitors. Infliximab. ATC code L04A B02.

Pharmacological Properties

Mechanism of Action

Infliximab is a chimeric human/mouse monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of tumor necrosis factor alpha (TNF-alpha), but not to lymphotoxin alpha (TNF-beta).

Pharmacodynamics

Infliximab inhibits the functional activity of TNF-alpha in a broad range of in vitro biological assays. Infliximab prevented disease development in transgenic mice in which polyarthritis developed due to constitutive expression of human TNF-alpha, and when administered at the onset of disease, promoted healing of affected joints. In vivo, infliximab rapidly forms stable complexes with human TN0-alpha, resulting in loss of TNF-alpha biological activity.

Elevated concentrations of TNF-alpha have been found in the joints of patients with rheumatoid arthritis, which correlates with increased disease activity. In rheumatoid arthritis, treatment with infliximab reduces infiltration of inflammatory cells into inflamed joint areas, as well as expression of molecules mediating cell adhesion, chemotaxis, and tissue destruction. After treatment with infliximab, decreased levels of interleukin-6 (IL-6) and C-reactive protein (CRP) in serum were observed, along with increased hemoglobin levels in patients with rheumatoid arthritis who had low baseline hemoglobin levels. No significant reduction in the number of peripheral blood lymphocytes or their proliferative response to mitogenic stimulation in vitro was observed compared to cells from patients before treatment. In patients with psoriasis, infliximab treatment reduced epidermal inflammation and normalized keratinocyte differentiation in psoriatic plaques. In psoriatic arthritis, short-term treatment with infliximab reduced the number of T-cells and blood vessels in the synovial membrane and psoriatic skin lesions.

Histological evaluation of intestinal biopsy specimens obtained before and 4 weeks after administration of infliximab demonstrated a significant reduction in detectable levels of TNF-alpha. Treatment of Crohn’s disease patients with infliximab was also associated with a significant reduction in the serum inflammatory marker CRP, which is typically elevated. Total peripheral blood leukocyte count remained nearly unchanged after infliximab treatment, although a trend toward normalization of lymphocyte, monocyte, and neutrophil levels was observed. Peripheral blood mononuclear cells (PBMCs) from patients receiving infliximab showed proliferative responses to stimuli no lower than those from untreated patients, and no substantial changes in cytokine production by stimulated PBMCs were observed after infliximab treatment. Analysis of mononuclear cells from mucosal biopsies of the intestinal mucosa showed that infliximab treatment led to a reduction in the number of cells capable of expressing TNF-alpha and gamma-interferon. Additional histological studies confirmed that infliximab treatment reduces infiltration of inflammatory cells into affected areas of the intestine and decreases the presence of inflammatory markers in these areas. Endoscopic evaluations demonstrated mucosal healing in the intestine of patients receiving infliximab.

Pharmacokinetics

Single intravenous infusions of infliximab at doses of 1, 3, 5, 10, or 20 mg/kg body weight showed dose-proportional increases in maximum serum concentration (Cmax) and area under the concentration–time curve (AUC). The volume of distribution at steady state (mean Vd from 3.0 to 4.1 L) was independent of the administered dose, indicating that infliximab is predominantly distributed within the vascular compartment. No time-dependent pharmacokinetics were observed. The elimination pathways of infliximab have not been defined. Unchanged infliximab was not detected in urine. In patients with rheumatoid arthritis, no significant differences in clearance or volume of distribution related to age or body weight were observed. The pharmacokinetics of infliximab in elderly patients have not been studied. Studies involving patients with hepatic or renal impairment have not been conducted.

After single doses of 3, 5, or 10 mg/kg, mean Cmax values were 77, 118, and 277 µg/mL, respectively. The mean terminal half-life at these doses ranged from 8 to 9.5 days. In most patients, infliximab was detectable in serum for at least 8 weeks after administration of the recommended single dose of 5 mg/kg in Crohn’s disease and the maintenance dose of 3 mg/kg every 8 weeks in rheumatoid arthritis.

Repeated administration of infliximab (5 mg/kg at weeks 0, 2, and 6 in fistulizing Crohn’s disease; 3 or 10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in minimal accumulation of infliximab in serum after the second dose. No further clinically significant accumulation was observed. In most patients with fistulizing Crohn’s disease, infliximab was detectable in serum for up to 12 weeks (ranging from 4 to 28 weeks) after administration according to the treatment regimen.

Children

Pharmacokinetic analysis in this patient population, based on data from patients with ulcerative colitis (N = 60), Crohn’s disease (N = 112), juvenile rheumatoid arthritis (N = 117), and Kawasaki syndrome (N = 16), aged from 2 months to 17 years, revealed a nonlinear relationship between infliximab concentration and body weight. Following administration of 5 mg/kg infliximab every 8 weeks, the expected mean steady-state concentration of infliximab (steady-state area under the concentration–time curve, AUCss) in children aged 6 to 17 years was approximately 20% lower than the expected mean steady-state concentration in adults.

The mean AUCss in children aged 2 to 6 years is expected to be approximately 40% lower than in adults, although the number of patients with data supporting this is limited.

Clinical characteristics.

Indications.

Rheumatoid arthritis (RA)

Remflexis in combination with methotrexate is indicated to reduce signs and symptoms and to improve physical function in:

• adult patients with active disease who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• adult patients with severe, active and progressive disease who have not previously been treated with methotrexate or other DMARDs.

In these patient groups, a reduction in the rate of progression of joint damage has been demonstrated and confirmed radiographically.

Crohn's disease (CD)

Remflexis is indicated for:

• treatment of moderate to severe active Crohn's disease in adult patients who have not responded despite a full and adequate course of therapy with corticosteroids and/or immunosuppressants, or in whom there is intolerance or medical contraindications to these therapies;
• treatment of moderate to severe active Crohn's disease with fistula formation in adult patients who have not responded despite a full and adequate course of conventional therapy (including antibiotics, drainage, and immunosuppressive therapy).

Crohn's disease (CD) in children

Remflexis is indicated for treatment of moderate to severe active Crohn's disease in children and adolescents aged 6 to 17 years who have not responded to conventional therapy, including corticosteroid therapy, immunomodulators, and primary dietary therapy, or in whom there is intolerance or contraindications to these therapeutic agents. Infliximab has been studied only in combination with conventional immunosuppressive therapy.

Ulcerative colitis (UC)

Remflexis is indicated for treatment of moderate to severe active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy, including corticosteroids and 6-mercaptopurine or azathioprine, or in whom there is intolerance or medical contraindications to these therapies.

Ulcerative colitis (UC) in children

Remflexis is indicated for treatment of moderate to severe active ulcerative colitis in children and adolescents aged 6 to 17 years who have had an inadequate response to conventional therapy, including corticosteroids and 6-mercaptopurine or azathioprine, or in whom there is intolerance or medical contraindications to these therapies.

Ankylosing spondylitis (AS)

Remflexis is indicated for treatment of severe active ankylosing spondylitis in adult patients who have had an inadequate response to conventional therapy.

Psoriatic arthritis (PsA)

Remflexis is indicated for treatment of active and progressive psoriatic arthritis in adult patients who have had an inadequate response to DMARD therapy. Remflexis should be administered:

• in combination with methotrexate;
• as monotherapy to patients with intolerance or medical contraindications to methotrexate.

Infliximab has been shown to improve physical function in patients with psoriatic arthritis and to slow the progression of peripheral joint damage in patients with polyarticular symmetric subtypes of the disease, as confirmed radiographically.

Psoriasis

Remflexis is indicated for treatment of moderate to severe plaque psoriasis in adult patients who have not responded or who have contraindications or intolerance to other conventional therapies, including cyclosporine, methotrexate, or psoralen in combination with long-wave ultraviolet light (PUVA).

Contraindications.

Hypersensitivity to infliximab, other mouse proteins, or to any of the excipients of the product.

Tuberculosis or other serious infections such as sepsis, abscesses, and opportunistic infections (see section "Special precautions").

Moderate or severe heart failure (NYHA functional class III or IV) (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

No formal drug interaction studies have been conducted.

Available data suggest that in patients with rheumatoid arthritis, psoriatic arthritis, and Crohn's disease, concomitant use of methotrexate and other immunomodulators reduces the formation of antibodies to infliximab and increases infliximab blood concentrations. However, results are imprecise due to limitations of the methods used to analyze infliximab and anti-infliximab antibody concentrations in serum.

Corticosteroids are unlikely to have a clinically significant effect on the pharmacokinetics of infliximab.

Concomitant use of infliximab and other biological medicinal products used to treat the same conditions as infliximab, including anakinra and abatacept, is not recommended (see section "Special precautions").

Concomitant administration of live vaccines and infliximab is not recommended. Live vaccines should also not be administered to infants exposed to infliximab in utero within 12 months after birth. If serum levels of infliximab in infants are undetectable or if infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine may be considered earlier if there is a clear clinical benefit for the individual infant (see section "Special precautions").

Administration of live vaccines to infants who are breastfed while the mother is receiving infliximab is not recommended, except when serum levels of infliximab in infants are undetectable (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Concomitant use of therapeutic infectious agents and infliximab is not recommended (see section "Special precautions").

Special precautions for use.

Tracking

To improve tracking of biological medicinal products, the patient reminder card should clearly state the brand name and batch number of the administered medicinal product.

Infusion reactions and hypersensitivity

Infliximab may cause acute infusion reactions, including anaphylactic shock and delayed-type hypersensitivity reactions (see section "Adverse reactions").

Acute infusion reactions, including anaphylactic reactions, may occur during infusion (within seconds) or within several hours after infusion. If acute infusion reactions occur, the infusion should be stopped immediately. Emergency medical supplies, such as epinephrine, antihistamines, corticosteroids, and airway management equipment to ensure airway patency, should be readily available. Premedication with antihistamines, hydrocortisone, and/or paracetamol may be administered to prevent mild and transient adverse effects.

Treatment may lead to the formation of antibodies against infliximab, which is associated with an increased incidence of infusion reactions. A small proportion of infusion reactions were severe allergic reactions. There is also an association between the formation of antibodies against infliximab and a reduced duration of response. Concomitant use of immunomodulators reduces the formation of antibodies against infliximab and decreases the frequency of infusion reactions. The effect of concomitant immunomodulator therapy was more pronounced in patients receiving episodic treatment than in those receiving maintenance therapy. Patients who discontinue immunosuppressants before or during infliximab therapy have a higher risk of developing antibodies. Antibodies against infliximab are not always detectable in serum. In the event of severe reactions, symptomatic treatment should be administered and infliximab therapy discontinued (see section "Adverse reactions").

Delayed-type hypersensitivity reactions have been observed in clinical trials. Available data suggest an increased risk of delayed-type hypersensitivity reactions with longer intervals between infliximab infusions. Patients should be advised to seek immediate medical attention if any delayed-type adverse reactions occur (see section "Adverse reactions"). Patients receiving re-treatment after a prolonged interval should be closely monitored for signs and symptoms of delayed-type hypersensitivity reactions.

Infections

Patients should be carefully evaluated for infections, including tuberculosis or other serious infections such as sepsis, abscesses, or opportunistic infections, before, during, and after treatment with infliximab. Since elimination of infliximab may continue for up to six months, monitoring should continue throughout this period. If a serious infection or sepsis develops, further treatment with infliximab should be discontinued.

Caution should be exercised when considering the use of infliximab, including concomitant immunosuppressant therapy, in patients with chronic or recurrent infections in their medical history. Patients should be advised to avoid exposure to potential risk factors for infection.

TNF-alpha mediates inflammation and modulates cellular immune responses. Experimental data indicate that TNF-alpha is necessary for the clearance of intracellular infections. Clinical experience shows impaired immune defense mechanisms against infection in some patients receiving infliximab.

Suppression of TNF-alpha may mask symptoms of infection, such as fever. Early recognition of atypical clinical manifestations of serious infections and typical clinical manifestations of rare and unusual infections is critical to minimize delays in diagnosis and treatment.

Patients receiving TNF inhibitors are more susceptible to serious infections. Cases of tuberculosis, mycobacterial infections, bacterial infections (including sepsis and pneumonia), invasive fungal, viral, and other opportunistic infections have been reported in patients treated with infliximab. Some of these infections have been fatal; the most common opportunistic infections with mortality rates >5% were aspergillosis, candidiasis, listeriosis, and pneumocystosis.

Patients who develop a new infection during treatment with infliximab require close monitoring and a complete diagnostic evaluation. If a serious infection or sepsis develops, further treatment with infliximab should be discontinued and appropriate antimicrobial or antifungal therapy initiated until infection control is achieved.

Tuberculosis

Cases of active tuberculosis have been reported in patients receiving infliximab. It should be noted that in most of these cases, tuberculosis was extrapulmonary, in localized or disseminated form.

All patients should be screened for active and inactive (latent) tuberculosis before initiating treatment with infliximab. This screening should include a detailed medical history assessing prior tuberculosis disease or possible prior contact with individuals with active tuberculosis, as well as prior and/or concomitant immunosuppressive therapy. Appropriate screening tests (e.g., tuberculin skin test, chest X-ray, and/or interferon-gamma release assay) should be performed in all patients according to local guidelines. It is recommended to document these tests in the patient reminder card. The risk of false-negative tuberculin skin test results should be considered, especially in critically ill patients or those with impaired immunity.

Treatment with infliximab should not be initiated if active tuberculosis is diagnosed (see section "Contraindications").

If latent tuberculosis is suspected, consultation with a physician experienced in the treatment of tuberculosis is recommended. The benefit-risk ratio of infliximab therapy should be carefully evaluated in all the following situations.

If latent tuberculosis is diagnosed, anti-tuberculosis treatment should first be administered according to local guidelines, followed by initiation of infliximab therapy.

Anti-tuberculosis treatment should be considered before starting infliximab in patients with multiple or significant risk factors for tuberculosis, despite a negative tuberculosis test. Anti-tuberculosis treatment should also be considered before initiating infliximab therapy in patients with a history of latent or active tuberculosis if there is no confirmation of adequate anti-tuberculosis treatment. Cases of active tuberculosis have been reported in patients receiving infliximab during and after treatment for latent tuberculosis.

Patients should consult a physician if signs/symptoms suggestive of tuberculosis infection (such as persistent cough, fatigue/weight loss, subfebrile temperature) occur during or after infliximab therapy.

Invasive fungal infections

In patients receiving infliximab, invasive fungal infections such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis, or blastomycosis should be suspected if they develop a severe systemic illness. In such cases, patients should consult a physician experienced in the diagnosis and treatment of invasive fungal infections.

Invasive fungal infections are more often disseminated than localized, and antigen and antibody tests may be negative in some patients with active infection. The risk-benefit ratio of fungal infection and risks associated with antifungal therapy should be considered during diagnostic evaluation and when initiating empirical antifungal therapy.

For patients who have lived in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefit-risk ratio should be assessed before initiating infliximab therapy.

Crohn's disease with fistula formation

Patients with Crohn's disease and acute purulent fistulas should not initiate treatment with infliximab until the source of possible infection, especially an abscess, has been resolved (see section "Contraindications").

Hepatitis B virus (HBV) reactivation

HBV reactivation has been observed in patients receiving TNF antagonists, including infliximab, who were chronic carriers of the virus. Some of these cases were fatal.

Before initiating infliximab therapy, patients should be tested for HBV infection. Patients with a positive HBV test result should consult a physician experienced in the treatment of hepatitis B. Patients who are HBV carriers and require infliximab therapy should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months after discontinuation of therapy. There are insufficient data on the use of antiviral therapy in combination with TNF inhibitors in HBV carriers to prevent HBV reactivation. Patients who develop HBV reactivation should discontinue infliximab therapy and initiate effective antiviral therapy with appropriate supportive care.

Hepatobiliary disorders

During post-marketing surveillance, cases of jaundice and non-infectious hepatitis, sometimes with features of autoimmune hepatitis, have been reported. Isolated cases of liver failure leading to liver transplantation or fatal outcomes have occurred. Patients with symptoms of liver dysfunction should be evaluated for liver injury. If jaundice and/or ALT levels ≥5 times the upper limit of normal occur, infliximab treatment should be discontinued and a thorough evaluation of the findings conducted.

Concomitant use of a TNF-alpha inhibitor and anakinra

Severe infections and neutropenia have been observed in clinical trials with concomitant use of anakinra and another TNF-alpha inhibitor, etanercept, without clinical benefit compared to etanercept monotherapy. Due to the nature of adverse reactions observed with concomitant etanercept and anakinra therapy, similar toxic reactions may also occur with the combination of anakinra and other TNF-alpha inhibitors. Therefore, the concomitant use of infliximab and anakinra is not recommended.

Concomitant use of a TNF-alpha inhibitor and abatacept

In clinical trials, concomitant use of TNF inhibitors and abatacept was associated with an increased risk of infections, including serious infections, compared to TNF inhibitor monotherapy, without an increase in clinical benefit. Concomitant use of infliximab and abatacept is not recommended.

Concomitant use with other biological medicinal products

There are insufficient data on the concomitant use of infliximab with other biological medicinal products used to treat the same conditions as infliximab. Concomitant use of infliximab with these biological medicinal products is not recommended due to the potential for increased risk of infection and other potential pharmacological interactions.

Switching from one biological DMARD to another

The clinical status of patients should be closely monitored when switching from one biological medicinal product to another, as cross-biological activity may increase the risk of adverse reactions, including infection.

Vaccination

It is recommended that patients, if possible, receive all vaccinations according to current immunization guidelines before starting infliximab therapy. Patients receiving infliximab may undergo vaccination, except for live vaccines (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").

In a subgroup of 90 adult patients with rheumatoid arthritis in the ASPIRE study, a similar proportion of patients in each treatment group (methotrexate plus: placebo [n = 17], 3 mg/kg [n = 27], or 6 mg/kg infliximab [n = 46]) achieved a two-fold increase in titers to polyvalent pneumococcal vaccine, indicating that infliximab does not affect T-cell-independent humoral immune responses. However, studies from published literature on various indications (e.g., rheumatoid arthritis, psoriasis, Crohn's disease) suggest that vaccination with inactivated vaccines during TNF inhibitor therapy, including infliximab, may result in a lower immune response than in patients not receiving TNF inhibitor therapy.

Live vaccines/therapeutic infectious agents

Limited available data on the response to live vaccines or secondary transmission of infection from live vaccines in patients receiving TNF inhibitor therapy. Administration of live vaccines may lead to clinical manifestations of infection, including disseminated infections. Concomitant administration of live vaccines and infliximab is not recommended.

In utero exposure in infants

Fatal cases of disseminated Bacillus Calmette-Guérin (BCG) infection after BCG vaccination following birth have been reported in infants exposed in utero to infliximab. A 12-month waiting period after birth is recommended before administering live vaccines to infants exposed in utero to infliximab. If infliximab levels in infant serum are undetectable or infliximab administration was limited to the first trimester of pregnancy, live vaccination may be considered earlier if there is clear clinical benefit for the individual infant (see section "Use during pregnancy or breastfeeding").

Infant exposure through breast milk

Administration of live vaccines to infants breastfed by mothers receiving infliximab is not recommended, except in cases where infliximab levels in infant serum are undetectable (see section "Use during pregnancy or breastfeeding").

Therapeutic infectious agents

Other uses of therapeutic infectious agents, such as live attenuated bacteria (e.g., intravesical instillation of BCG for cancer treatment), may lead to clinical manifestations of infection, including disseminated infections. Concomitant use of therapeutic infectious agents and infliximab is not recommended.

Autoimmune processes

Relative deficiency of TNF-alpha caused by TNF inhibitor therapy may lead to the development of autoimmune processes. If symptoms suggestive of lupus-like syndrome occur after infliximab treatment and antibodies against double-stranded DNA are positive, further infliximab therapy should be discontinued (see section "Adverse reactions").

Neurological disorders

Cases of new onset or exacerbation of clinical and/or radiological signs of demyelinating diseases of the central nervous system, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré syndrome, have been reported with the use of TNF inhibitors, including infliximab. Patients with existing or recently developed demyelinating disorders should have a careful benefit-risk assessment before initiating TNF inhibitor therapy. Discontinuation of infliximab should be considered if these disorders develop.

Malignant neoplasms and lymphoproliferative disorders

In controlled clinical trials of TNF inhibitors, malignant neoplasms, including lymphoma, were reported more frequently in patients receiving TNF inhibitors than in control group patients. During clinical trials of infliximab for all approved indications, the incidence of lymphoma in patients receiving infliximab was higher than expected in the general population, although cases of lymphoma were rare. During post-marketing use, cases of leukemia have been reported in patients receiving a TNF inhibitor. There is an increased risk of lymphoma and leukemia in patients with rheumatoid arthritis with long-standing, highly active inflammatory disease, which complicates risk assessment.

In a clinical trial evaluating the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), an increased incidence of malignant neoplasms was reported in patients receiving infliximab compared to the control group. All patients had a history of heavy smoking. Caution should be exercised when making treatment decisions for patients with an increased risk of malignant neoplasms due to heavy smoking.

The risk of developing lymphoma or other malignant neoplasms in patients receiving a TNF inhibitor cannot be excluded (see section "Adverse reactions"). Caution should be exercised when making treatment decisions for patients with a history of malignant neoplasms or when continuing treatment in patients who develop a malignant neoplasm.

Caution should also be exercised in patients with psoriasis and a history of intensive immunosuppressive therapy or long-term PUVA treatment.

During post-marketing use, malignant neoplasms, some with fatal outcomes, have been reported in children, adolescents, and young adults (up to 22 years), who received TNF inhibitors (treatment initiation at age ≤18 years), including infliximab. Approximately half of the cases were lymphomas. Other cases included various types of malignant neoplasms and included rare malignancies typically associated with immunosuppression. The risk of developing malignant neoplasms in patients receiving TNF inhibitors cannot be excluded.

During post-marketing use, cases of hepatosplenic T-cell lymphoma have been reported in patients receiving TNF inhibitors, including infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive course and usually has a fatal outcome. Almost all patients received treatment with azathioprine or 6-mercaptopurine concomitantly with or immediately before TNF inhibitor therapy. The majority of cases associated with infliximab use occurred in patients with Crohn's disease or ulcerative colitis, mostly in adolescents or young adult males. The potential risk of concomitant use of azathioprine or 6-mercaptopurine with infliximab should be carefully evaluated. The risk of developing hepatosplenic T-cell lymphoma in patients receiving infliximab cannot be excluded (see section "Adverse reactions").

Melanoma and Merkel cell carcinoma have been reported in patients receiving TNF inhibitor therapy, including infliximab (see section "Adverse reactions"). Periodic skin examinations are recommended, especially for patients with risk factors for skin cancer.

A population-based retrospective cohort study using Swedish national health registries data found an increased incidence of cervical cancer in women with rheumatoid arthritis receiving infliximab compared to patients not receiving biological medicinal products or the general population, including patients over 60 years of age. Women, including those aged 60 years and older, receiving infliximab should undergo regular medical examinations.

All patients with ulcerative colitis who have an increased risk of dysplasia or colorectal cancer (e.g., patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or patients with a history of dysplasia or colorectal cancer, should be regularly evaluated for dysplasia before starting therapy and throughout the course of the disease. Evaluation should include colonoscopy and biopsy according to local guidelines. Available data do not allow conclusions on the impact of infliximab treatment on the risk of dysplasia or colorectal cancer.

Since the potential for increased risk of cancer in patients with newly diagnosed dysplasia receiving infliximab is not established, physicians should carefully evaluate the benefit-risk ratio of continuing therapy individually for each patient.

Heart failure

Infliximab should be used with caution in patients with mild heart failure (NYHA functional class I or II). Patients should be closely monitored, and infliximab therapy should be discontinued if new or worsening symptoms of heart failure occur (see sections "Contraindications" and "Adverse reactions").

Hematological reactions

Pancytopenia, leukopenia, neutropenia, and thrombocytopenia have been reported in patients receiving TNF inhibitors, including infliximab. Patients should seek immediate medical attention if signs and symptoms suggestive of blood dyscrasias (such as persistent fever, bruising, bleeding, pallor) occur. Discontinuation of infliximab therapy should be considered in patients with confirmed serious hematological disorders.

Other diseases

The long half-life of infliximab should be considered when planning surgical procedures. Patients requiring surgery during infliximab therapy should be closely monitored for infectious and non-infectious complications, and appropriate measures should be taken (see section "Adverse reactions"). Lack of response to Crohn's disease treatment may indicate the presence of a fixed fibrotic stricture, which may require surgical treatment. There is no evidence that infliximab causes the development or progression of fibrotic strictures.

Special patient groups

Elderly patients

The incidence of serious infections in patients aged 65 years and older receiving infliximab was higher than in patients under 65 years of age. Some cases were fatal. Particular attention should be paid to the risk of infection when treating elderly patients (see section "Adverse reactions").

Children

Infections

During clinical trials, infections were reported more frequently in children compared to adult patients (see section "Adverse reactions").

Vaccination

It is recommended that children, if possible, receive all vaccinations according to current immunization guidelines before starting infliximab therapy. Children receiving infliximab may undergo vaccination, except for live vaccines (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").

Malignant neoplasms and lymphoproliferative disorders

During post-marketing use, malignant neoplasms, some with fatal outcomes, have been reported in children, adolescents, and young adults (up to 22 years), who received TNF inhibitors (treatment initiation at age ≤18 years), including infliximab. Approximately half of the cases were lymphomas. Other cases were associated with various other malignant neoplasms, including rare malignancies associated with immunosuppression. The risk of developing malignant neoplasms in children and adolescents receiving TNF inhibitors cannot be excluded.

During post-marketing use, cases of hepatosplenic T-cell lymphoma have been reported in patients receiving TNF inhibitors, including infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive course and usually has fatal outcomes. Almost all patients received treatment with azathioprine or 6-mercaptopurine concomitantly or immediately before TNF inhibitor therapy. The majority of cases associated with infliximab use occurred in patients with Crohn's disease or ulcerative colitis and occurred predominantly in adolescents or young adult males. The potential risk of concomitant use of azathioprine or 6-mercaptopurine with infliximab should be carefully evaluated. The risk of developing hepatosplenic T-cell lymphoma in patients receiving infliximab cannot be excluded (see section "Adverse reactions").

Sodium content

Renflexis contains less than 1 mmol of sodium (23 mg) per dose, i.e., practically sodium-free. However, Renflexis is diluted in 0.9% sodium chloride solution for infusion. This should be considered when administering to patients on a sodium-controlled diet.

Polysorbate 80

Renflexis contains 0.5 mg of polysorbate 80 in each vial (20 mL vial), equivalent to 0.5 mg/10 mL after reconstitution in 10 mL of water for injection. Polysorbates may cause allergic reactions. Inform the physician if you/your child have known allergies.

Use during pregnancy or breastfeeding.

Women of childbearing potential

To prevent pregnancy, women of childbearing potential should consider using reliable contraception methods during treatment and for at least 6 months after the last dose of infliximab.

Pregnancy

Prospective analysis of data from pregnant women treated with infliximab, with known outcomes of live births, including approximately 1100 pregnant women who received the drug during the first trimester, did not show an increased frequency of congenital malformations in newborns.

Based on an observational study conducted in Nordic countries, an increased risk (RR, 95% CI; p-value) of cesarean section (1.50, 1.14–1.96; p = 0.0032), preterm birth (1.48, 1.05–2.09; p = 0.024), small for gestational age (2.79, 1.54–5.04; p = 0.0007), and low birth weight (2.03, 1.41–2.94; p = 0.0002) was observed in women treated with infliximab during pregnancy (with or without immunomodulators/corticosteroids, 270 pregnancies) compared to women who received only immunomodulators and/or corticosteroids (6460 pregnancies). The potential impact of infliximab and/or the severity of the underlying disease on these outcomes remains unclear.

Since infliximab inhibits TNF-alpha, its administration during pregnancy may affect the normal immune response in newborns. Toxicity studies in mice using a similar antibody selectively inhibiting TNF-alpha did not demonstrate signs of toxicity in pregnant females, embryotoxicity, or teratogenicity.

Available clinical experience is limited. Infliximab should be used during pregnancy only if clearly necessary.

Infliximab crosses the placenta and is detected in infant serum for up to 12 months after birth. Infants exposed to infliximab in utero have an increased risk of infections, including severe disseminated infection, which may lead to fatal outcomes. Administration of live vaccines (e.g., BCG vaccine) to such infants is not recommended within 12 months after birth (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction"). If infliximab levels in infant serum are undetectable or infliximab administration was limited to the first trimester of pregnancy, live vaccination may be considered earlier if there is clear clinical benefit for the individual infant. Cases of agranulocytosis have also been reported (see section "Adverse reactions").

Breastfeeding period

Limited data from published literature indicate that infliximab is present in low levels in breast milk at concentrations up to 5% of maternal serum levels. Infliximab is also detected in infant serum after exposure through breast milk. Although systemic effects on breastfed infants are expected to be low due to significant degradation of infliximab in the gastrointestinal tract, administration of live vaccines to infants breastfed by mothers receiving infliximab is not recommended, except in cases where infliximab levels in infant serum are undetectable. Infliximab may be considered for use during breastfeeding.

Fertility

There are insufficient preclinical data to draw conclusions about the effect of infliximab on fertility and reproductive function in general.

Ability to affect reaction speed when driving or operating machinery.

Renflexis may have a negligible effect on the ability to drive or operate machinery, for example, due to adverse reactions such as vertigo and dizziness (see section "Adverse reactions").

Method of Administration and Dosage

Renflexis therapy must be prescribed and monitored by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis, or psoriasis. Renflexis should be administered intravenously. Infusions of Renflexis must be performed by qualified healthcare professionals trained to recognize any infusion-related reactions. Patients receiving Renflexis should be provided with the patient information leaflet and a patient reminder card.

During treatment with Renflexis, concomitant therapies such as corticosteroids and immunosuppressants should be optimized.

Dosage

Adults (≥ 18 years of age)

Rheumatoid arthritis

Administer 3 mg/kg body weight by intravenous infusion, followed by additional infusions of 3 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks.

Renflexis should be used in combination with methotrexate.

Available data indicate that clinical response is generally achieved within 12 weeks of treatment. For some patients who do not show an adequate response or whose response diminishes after this period, dose escalation by approximately 1.5 mg/kg body weight up to a maximum dose of 7.5 mg/kg body weight every 8 weeks may be considered. Alternatively, administration of 3 mg/kg body weight every 4 weeks may be considered. Once an adequate response is achieved, patients should continue treatment at the selected dose and frequency. For patients who do not achieve a therapeutic effect within the first 12 weeks of treatment or after dose adjustment, the continued need for therapy should be carefully evaluated.

Moderate to severe active Crohn's disease

Administer 5 mg/kg body weight by intravenous infusion, followed by an additional infusion of 5 mg/kg body weight at week 2 after the first infusion. If the patient does not respond after the second dose, further treatment with infliximab should not be continued. There are no available data supporting continued infliximab treatment in patients who do not respond within 6 weeks after the first infusion.

In patients who achieve a response to treatment, alternative continuation regimens are:

• Maintenance therapy – an additional infusion of 5 mg/kg body weight at week 6 after the initial dose, followed by infusions every 8 weeks, or
• Re-treatment – an infusion of 5 mg/kg body weight upon signs of disease relapse and symptoms (see section "Special precautions for use").

Despite insufficient comparative data, some patients who initially responded to a dose of 5 mg/kg body weight but subsequently lost response may regain response with dose escalation. The continued need for therapy should be carefully evaluated in patients who do not achieve a therapeutic effect after dose adjustment.

Fistulizing Crohn's disease

Administer 5 mg/kg body weight by intravenous infusion, followed by additional infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion. If the patient does not respond after three doses, further treatment with infliximab should be discontinued.

In patients who achieve a response to treatment, alternative continuation regimens are:

• Maintenance therapy – additional infusions of 5 mg/kg body weight every 8 weeks, or
• Re-treatment – an infusion of 5 mg/kg body weight upon signs of disease relapse and symptoms, followed by infusions of 5 mg/kg body weight every 8 weeks (see section "Special precautions for use").

Despite insufficient comparative data, some patients who initially responded to a dose of 5 mg/kg body weight but subsequently lost response may regain response with dose escalation. The continued need for therapy should be carefully evaluated in patients who do not achieve a therapeutic effect after dose adjustment.

Experience with re-treatment of patients with Crohn's disease upon signs of relapse and symptoms is limited, and comparative data on the benefit/risk ratio of alternative continuation regimens are lacking.

Ulcerative colitis

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks.

Available data indicate that clinical response is generally achieved within 14 weeks of treatment, i.e., after receiving three doses. The continued need for therapy should be carefully evaluated in patients who do not achieve a therapeutic effect within this time period.

Ankylosing spondylitis

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 6–8 weeks. If the patient does not respond by week 6 (i.e., after receiving the second dose), further treatment with infliximab should be discontinued.

Psoriatic arthritis

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks.

Psoriasis

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks. If the patient does not respond by week 14 (i.e., after receiving the fourth dose), further treatment with infliximab should be discontinued.

Re-treatment in Crohn's disease and rheumatoid arthritis

Re-treatment with infliximab may be considered within 16 weeks after the last infusion if signs of disease relapse and symptoms occur. During clinical trials, delayed-type hypersensitivity reactions were rarely observed and occurred within 1 year after infliximab administration (see sections "Special precautions for use" and "Adverse reactions"). The safety and efficacy of re-treatment after a treatment interruption longer than 16 weeks have not been established. This applies to both patients with Crohn's disease and patients with rheumatoid arthritis.

Re-treatment in ulcerative colitis

The safety and efficacy of re-treatment, other than administration every 8 weeks, have not been established (see sections "Special precautions for use" and "Adverse reactions").

Re-treatment in ankylosing spondylitis

The safety and efficacy of re-treatment, other than administration every 6–8 weeks, have not been established (see sections "Special precautions for use" and "Adverse reactions").

Re-treatment in psoriatic arthritis

The safety and efficacy of re-treatment, other than administration every 8 weeks, have not been established (see sections "Special precautions for use" and "Adverse reactions").

Re-treatment in psoriasis

Limited experience with re-treatment of infliximab as a single dose in psoriasis after a 20-week interval indicates reduced efficacy and increased frequency of mild to moderate infusion reactions compared to the initial induction therapy regimen.

Limited experience with re-treatment after disease flare-up using a re-induction regimen indicates increased frequency of infusion reactions, including severe reactions, compared to 8-week maintenance therapy (see section "Adverse reactions").

Re-treatment for various indications

If maintenance therapy has been interrupted and treatment needs to be resumed, a re-induction regimen is not recommended (see section "Adverse reactions"). In such cases, re-treatment with infliximab should begin with a single dose, followed by adherence to the recommended maintenance dosing schedule described above.

Special patient groups

Elderly patients

Specific clinical studies of infliximab in elderly patients have not been conducted. Clinical trials have not shown significant age-related differences in clearance or volume of distribution. Dose adjustment is not required. For additional information on the safety of infliximab use in elderly patients, see sections "Special precautions for use" and "Adverse reactions".

Patients with renal and/or hepatic impairment

The use of infliximab in these patient groups has not been studied. Recommendations for dose modification are not available.

Pediatric patients

Crohn's disease in children aged 6 to 17 years

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks. There are no available data supporting continued infliximab treatment in children and adolescents who do not respond within the first 10 weeks of treatment.

Some patients may require a shorter dosing interval to maintain clinical effect, while others may maintain response with a longer interval. Patients receiving the drug at intervals shorter than 8 weeks have an increased risk of adverse reactions. The continued need for therapy at shortened intervals should be carefully evaluated in patients who do not achieve a therapeutic effect after interval adjustment.

The safety and efficacy of infliximab in children under 6 years of age with Crohn's disease have not been established. Available pharmacokinetic data are described in the section "Pharmacological properties", but dosing recommendations for children under 6 years of age are not available.

Ulcerative colitis in children aged 6 to 17 years

Administer 5 mg/kg body weight by intravenous infusion, followed by infusions of 5 mg/kg body weight at weeks 2 and 6 after the first infusion, and then every 8 weeks. There are no available data supporting continued infliximab treatment in children who do not respond within the first 8 weeks of treatment.

The safety and efficacy of infliximab in children under 6 years of age with ulcerative colitis have not been established. Available pharmacokinetic data are described in the section "Pharmacological properties", but dosing recommendations for children under 6 years of age are not available.

Psoriasis

The safety and efficacy of infliximab for the treatment of psoriasis in children and adolescents (under 18 years of age) have not been established. Available data are described in the section "Pharmacological properties", but dosing recommendations are not available.

Juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis

The safety and efficacy of infliximab for the treatment of juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis in children and adolescents (under 18 years of age) have not been established. Available data are described in the section "Pharmacological properties", but dosing recommendations are not available.

Juvenile rheumatoid arthritis

The safety and efficacy of infliximab for the treatment of juvenile rheumatoid arthritis in children and adolescents (under 18 years of age) have not been established. Available data are described in the sections "Pharmacological properties" and "Adverse reactions", but dosing recommendations are not available.

Method of administration

Infliximab should be administered intravenously over 2 hours. All patients receiving infliximab should be monitored for at least 1–2 hours after infusion to detect acute infusion reactions promptly. Emergency resuscitation equipment and medications, such as epinephrine, antihistamines, corticosteroids, and an airway device to ensure airway patency, must be available. To reduce the risk of infusion reactions, especially in patients with a history of such reactions, premedication with antihistamines, hydrocortisone, and/or paracetamol may be administered, and the infusion rate may be reduced (see section "Special precautions for use").

Shortened infusion time for adult patients

For carefully selected adult patients who have successfully tolerated at least the first three 2-hour infusions (induction phase) and are on maintenance therapy, subsequent infusions may be administered over at least 1 hour. If an infusion reaction occurs during shortened administration, it is recommended to revert to a longer infusion duration if therapy is continued. Studies on shortened infusion times for doses > 6 mg/kg have not been conducted (see section "Adverse reactions").

Preparation of the solution:

1. Calculate the required dose and number of Renflexis vials. Each vial contains 100 mg of infliximab. Calculate the total required volume of reconstituted product.
2. Under aseptic conditions, reconstitute the contents of each vial with 10 mL of water for injections using a syringe with a 21-gauge (0.8 mm) or smaller needle. Remove the flip-off cap and wipe the top with a 70% alcohol swab. Insert the needle through the center of the rubber stopper and direct the stream of water for injections along the vial wall. Gently swirl the vial until the lyophilized powder is completely dissolved. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming may occur during reconstitution. Allow the solution to stand for 5 minutes. The solution should be colorless or pale yellow and opalescent. Since infliximab is a protein, a small number of fine translucent particles may be present. Do not use the solution if opaque particles or other foreign matter are visible, or if discoloration occurs.
3. Dilute the total volume of prepared Renflexis solution to 250 mL with 0.9% sodium chloride solution. Do not dilute Renflexis solution with any other diluent. To do this, remove a volume equal to the volume of the prepared Renflexis solution from a glass vial or infusion bag containing 250 mL of 0.9% sodium chloride solution. Then slowly add the prepared drug solution to the vial or infusion bag with 0.9% sodium chloride solution and gently mix. For volumes exceeding 250 mL, use a larger infusion bag (e.g., 500 mL, 1000 mL) or multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL. If the infusion solution is stored in a refrigerator after reconstitution and dilution, allow it to reach room temperature (up to 25°C) for 3 hours before step 4 (infusion administration). Storage for more than 24 hours at 2–8°C is permitted only if the Renflexis solution is prepared in an infusion bag.
4. The infusion solution should be administered over a time no shorter than the recommended infusion duration (see section "Method of administration and dosage"). Use only an infusion set equipped with a built-in sterile, non-pyrogenic, low-protein-binding filter with a pore size of 1.2 micrometers or smaller. Due to the absence of a preservative, the infusion solution should be administered as soon as possible and no later than 3 hours after reconstitution and dilution. If not used immediately, the user is responsible for storage time and conditions prior to administration; generally, storage should not exceed 24 hours at 2–8°C, provided that reconstitution and dilution were not performed under controlled and validated aseptic conditions. Do not store any unused portion of the infusion solution for later use.
5. Physical and biochemical compatibility studies to assess co-administration of Renflexis with other medicinal products have not been conducted. Renflexis should not be administered simultaneously with other medicinal products using the same infusion system.
6. Before administration, visually inspect Renflexis for the presence of particulate matter or discoloration. Do not use the solution if visible opaque or foreign particles are present or if discoloration occurs.
7. Any unused medicinal product or waste material should be disposed of in accordance with current regulations.

Children.

Renflexis is administered to children according to the information provided in the section "Method of administration and dosage".

Overdose.

Cases of overdose have not been reported. Single doses up to 20 mg/kg body weight did not show direct toxic effects.

Adverse Reactions

Summary of Safety Profile

Upper respiratory tract infection was the most commonly reported adverse reaction (AR) in clinical trials: observed in 25.3% of patients receiving infliximab compared to 16.5% of patients in the control group. The most serious adverse reactions associated with the use of TNF inhibitors, reported during treatment with infliximab, included reactivation of hepatitis B virus, chronic heart failure, severe infections (including sepsis, opportunistic infections, and tuberculosis), serum sickness (delayed-type hypersensitivity reactions), hematological reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating disorders, hepatic and biliary disorders, lymphoma, hepatosplenic T-cell lymphoma, leukemia, Merkel cell carcinoma, melanoma, malignancies in children, sarcoidosis/sarcoidosis-like reaction, intestinal or perianal abscess (in Crohn’s disease), and severe infusion reactions (see section "Dosage and Administration").

List of Adverse Reactions in Tabular Form

Table 1 presents adverse reactions (some with fatal outcomes) observed during clinical and post-marketing studies. Adverse reactions are categorized by system organ class and frequency, using the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in descending order of severity.

Table 1

Adverse reactions observed during clinical studies and post-marketing surveillance

* Including bovine tuberculosis (disseminated infection caused by BCG), see section "Special warnings and precautions for use".

1 At month 12 of the controlled period of clinical trials in adult patients across all indications, median body weight increase was 3.50 kg in patients receiving infliximab compared with 3.00 kg in patients receiving placebo. Median body weight increase in patients with inflammatory bowel disease was 4.14 kg in patients receiving infliximab compared with 3.00 kg in patients receiving placebo, and median body weight increase in patients with rheumatic diseases was 3.40 kg in patients receiving infliximab compared with 3.00 kg in patients receiving placebo.

Specific adverse reactions

Infusion reactions

During clinical trials, an infusion reaction was defined as any adverse event occurring during or within 1 hour after infusion. During Phase III clinical trials, infusion reactions occurred in 18% of patients receiving infliximab compared with 5% of patients receiving placebo. Overall, infusion reactions occurred more frequently in patients receiving infliximab as monotherapy compared with patients receiving infliximab concomitantly with immunomodulators. Approximately 3% of patients discontinued treatment due to infusion reactions, all of which resolved with or without medical treatment. Among patients who received infliximab and experienced an infusion reaction during the induction period up to week 6, 27% had a recurrent infusion reaction during the maintenance therapy period from week 7 to week 54. Among patients who did not experience an infusion reaction during the induction period, 9% experienced an infusion reaction during maintenance therapy.

In a clinical trial in patients with rheumatoid arthritis (ASPIRE), the first 3 infusions were administered over 2 hours. Subsequent infusions could be shortened to no less than 40 minutes for patients who did not experience serious infusion reactions. In this study, 66% of patients (686 out of 1040) received at least one shortened infusion of 90 minutes or less, and 44% of patients (454 out of 1040) received at least one shortened infusion of 60 minutes or less. Infusion reactions occurred in 15%, and serious infusion reactions occurred in 0.4% of patients who received at least one shortened infusion of infliximab.

In a clinical trial in patients with Crohn's disease (SONIC), infusion reactions occurred in 16.6% (27 out of 163) of patients receiving infliximab monotherapy, in 5% (9 out of 179) of patients receiving infliximab in combination with azathioprine, and in 5.6% (9 out of 161) of patients receiving azathioprine monotherapy. One serious infusion reaction (<1%) was reported in a patient receiving infliximab monotherapy.

Post-marketing surveillance studies have reported cases of anaphylactic reactions such as laryngeal/pharyngeal edema and severe bronchospasm, as well as seizures (see section "Special warnings and precautions for use"). Cases of transient vision loss occurring during or within 2 hours after infliximab infusion have been reported. Cases (some fatal) of myocardial ischemia/infarction and arrhythmias, some closely temporally associated with infliximab infusion, have also been reported, as well as acute cerebrovascular events occurring in close temporal association with infliximab infusion.

Infusion reactions upon re-administration of infliximab

A clinical trial was conducted in patients with moderate to severe psoriasis to evaluate the efficacy and safety of long-term maintenance therapy compared with a re-induction regimen of infliximab (maximum of four infusions at weeks 0, 2, 6, and 14) after disease flare. Patients did not receive any concomitant immunosuppressant therapy. In the re-treatment group, 4% (8 out of 219) of patients experienced a serious infusion reaction compared with <1% (1 out of 122) in the maintenance therapy group. Most serious infusion reactions occurred during the second infusion at week 2. The interval between the last maintenance dose and the first re-treatment dose ranged from 35 to 231 days. Symptoms included (but were not limited to) dyspnea, urticaria, facial swelling, and hypotension. In all cases, infliximab therapy was discontinued and/or alternative therapy was initiated until complete resolution of signs and symptoms.

Delayed-type hypersensitivity reactions

In clinical trials, delayed-type hypersensitivity reactions were rare and occurred during treatment interruptions of up to 1 year. In psoriasis trials, delayed-type hypersensitivity reactions occurred early in the treatment course. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash; some patients also experienced pruritus, facial swelling, hand or lip swelling, dysphagia, urticaria, sore throat, and headache.

There are insufficient data on the frequency of delayed-type hypersensitivity reactions after treatment interruptions longer than 1 year, but limited clinical trial data suggest an increased risk of such reactions with longer intervals between doses (see section "Special warnings and precautions for use").

In a 1-year clinical trial with repeated infusions in patients with Crohn's disease (ACCENT I study), the incidence of serum sickness-like reactions was 2.4%.

Immunogenicity

Patients who developed antibodies to infliximab had a higher frequency of infusion reactions (approximately 2–3 times higher). Concomitant use of immunosuppressants reduces the frequency of infusion reactions.

In clinical trials using single and multiple doses of infliximab from 1 to 20 mg/kg, antibodies to infliximab were detected in 14% of patients receiving any immunosuppressive therapy and in 24% of patients not receiving immunosuppressive therapy. Antibodies to infliximab were detected in 8% of patients with rheumatoid arthritis receiving recommended re-treatment dosing regimens. Antibodies developed in 15% of all patients with psoriatic arthritis receiving 5 mg/kg of the drug with or without methotrexate (antibodies developed in 4% of patients receiving methotrexate and in 26% of patients not receiving methotrexate at baseline). In patients with Crohn's disease receiving maintenance therapy, antibodies to infliximab were detected in 3.3% of patients receiving immunosuppressants and in 13.3% of patients not receiving immunosuppressants. The frequency of antibody formation was 2–3 times higher in patients receiving episodic treatment. Due to methodological limitations, a negative result does not exclude the presence of antibodies to infliximab. In some patients with high titers of antibodies to infliximab, signs of reduced therapeutic efficacy were observed. In patients with psoriasis receiving infliximab according to a maintenance regimen without concomitant immunomodulators, antibodies to infliximab developed in approximately 28% (see section "Special warnings and precautions for use": Infusion reactions and hypersensitivity).

Infections

Tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients receiving infliximab. Some of these infections were fatal; the most common opportunistic infections with a mortality rate >5% were Pneumocystis pneumonia, candidiasis, listeriosis, and aspergillosis (see section "Special warnings and precautions for use").

In clinical trials, infections occurred in 36% of patients receiving infliximab compared with 25% of patients receiving placebo.

In clinical trials of rheumatoid arthritis, the frequency of serious infections, including pneumonia, was higher in patients receiving infliximab with methotrexate compared with methotrexate monotherapy, especially at doses of 6 mg/kg or higher (see section "Special warnings and precautions for use").

In spontaneous post-marketing surveillance reports, infections are the most common serious adverse reaction. Some cases resulted in death. Approximately 50% of fatal outcome reports were associated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and extrapulmonary tuberculosis, have been reported (see section "Special warnings and precautions for use").

Malignant neoplasms and lymphoproliferative disorders

In clinical trials of infliximab involving 5780 patients (5494 patient-years), 5 cases of lymphoma and 26 cases of other malignancies were observed compared with the placebo group of 1600 patients (941 patient-years), in which no cases of lymphoma were observed and 1 case of another malignancy was reported.

During long-term safety monitoring of infliximab use in clinical trials lasting up to 5 years (6234 patient-years, 3210 patients), 5 cases of lymphoma and 38 cases of other malignancies were recorded.

In post-marketing surveillance, cases of malignancies, including lymphoma, have also been reported with infliximab use (see section "Special warnings and precautions for use").

In an experimental clinical trial involving patients with moderate to severe COPD who were current or former smokers, 157 adult patients received infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The mean duration of observation was 0.8 years (incidence 5.7% [95% CI 2.65–10.6%]). One case of malignancy was recorded in the control group of 77 patients (mean observation duration 0.8 years; incidence 1.3% [95% CI 0.03–7.0%]). Most malignancies occurred in the lungs or head and neck.

A population-based retrospective cohort study identified an increased incidence of cervical cancer in women with rheumatoid arthritis receiving infliximab compared with patients not receiving biological medicinal products or compared with the general population, including patients over 60 years of age (see section "Special warnings and precautions for use").

In post-marketing surveillance, cases of hepatosplenic T-cell lymphoma in patients with Crohn's disease and ulcerative colitis receiving infliximab have been reported; most cases occurred in adolescents or young adult males (see section "Special warnings and precautions for use").

Heart failure

In a Phase II clinical trial of infliximab use in chronic heart failure, an increased number of deaths due to worsening cardiovascular failure was observed, particularly with doses higher than 10 mg/kg (i.e., twice the maximum recommended dose). In this trial, 150 patients with chronic heart failure of NYHA functional class III–IV (left ventricular ejection fraction ≤35%) received 3 infusions of infliximab at doses of 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, fatal events were reported in 9 out of 101 patients receiving infliximab (2 patients at 5 mg/kg and 7 patients at 10 mg/kg) compared with 1 fatal event out of 49 patients receiving placebo.

In post-marketing surveillance, cases of worsening heart failure, with or without identified precipitating factors, have also been reported in patients receiving infliximab. Additionally, new-onset heart failure, including in patients without prior cardiovascular disease, has been reported in post-marketing surveillance. Some of these patients were under 50 years of age.

Hepatobiliary disorders

During clinical trials, mild or moderate elevations in ALT and AST levels were observed in patients receiving infliximab, without development of severe liver injury. ALT elevations ≥5 times the upper limit of normal were observed. Elevations in aminotransferases (ALT more frequently than AST) were recorded in a higher proportion of patients receiving infliximab than in control groups, both in infliximab monotherapy and in combination with other immunosuppressants. In most cases, aminotransferase elevations were transient; however, in a small number of patients, elevations were more prolonged. Overall, patients with elevated ALT and AST levels were asymptomatic, and abnormalities decreased or resolved with continued or discontinued infliximab treatment or modification of concomitant therapy. In post-marketing surveillance, cases of jaundice and hepatitis have been reported, some of which showed features of autoimmune hepatitis (see section "Special warnings and precautions for use").

Antinuclear antibodies (ANA)/anti-double-stranded DNA (dsDNA) antibodies

Approximately half of patients receiving infliximab in clinical trials who had a negative ANA test at baseline developed a positive ANA test during the study, compared with approximately 1/5 of patients receiving placebo. Anti-dsDNA antibodies were newly detected in approximately 17% of patients receiving infliximab compared with 0% of patients receiving placebo. At the last assessment, dsDNA test results remained positive in 57% of patients receiving infliximab. Reports of lupus and lupus-like syndromes remain uncommon (see section "Special warnings and precautions for use").

Pediatric

Patients with juvenile idiopathic arthritis

Infliximab was studied in a clinical trial in 120 patients (aged 4–17 years) with active juvenile idiopathic arthritis despite methotrexate therapy. Patients received 3 or 6 mg/kg of infliximab in a 3-dose induction regimen (weeks 0, 2, 6 or weeks 14, 16, 20, respectively) followed by maintenance therapy every 8 weeks in combination with methotrexate.

Infusion reactions

Infusion reactions were observed in 35% of patients with juvenile idiopathic arthritis receiving the 3 mg/kg dose compared with 17.5% of patients receiving the 6 mg/kg dose. In the 3 mg/kg infliximab group, 4 out of 60 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of whom had serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction (see section "Special warnings and precautions for use").

Immunogenicity

Antibodies to infliximab developed in 38% of patients receiving the 3 mg/kg dose compared with 12% of patients receiving the 6 mg/kg dose. Antibody titers were significantly higher with the 3 mg/kg dose than with the 6 mg/kg dose.

Infections

Infections occurred in 68% (41 out of 60) of children receiving the 3 mg/kg dose over 52 weeks, in 65% (37 out of 57) of children receiving the 6 mg/kg dose over 38 weeks, and in 47% (28 out of 60) of children receiving placebo over 14 weeks (see section "Special warnings and precautions for use").

Crohn's disease

Adverse reactions reported more frequently in children with Crohn's disease than in adults with Crohn's disease were: anemia (10.7%), blood in stool (9.7%), leukopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bacterial infection (5.8%), and allergic respiratory reaction (5.8%). Bone fractures (6.8%) were reported, although a causal relationship was not established. Other specific aspects are described below.

Infusion reactions

In a study of infliximab use in children with Crohn's disease, 17.5% of randomized patients experienced one or more infusion reactions. No serious infusion reactions were observed; 2 patients experienced non-serious anaphylactic reactions.

Immunogenicity

Antibodies to infliximab were detected in 3 (2.9%) pediatric patients.

Infections

In a study of infliximab use in children with Crohn's disease, infections were reported in 56.3% of randomized patients. Infections were reported more frequently in patients receiving infusions every 8 weeks compared with those receiving infusions every 12 weeks (73.6% vs. 38.0%, respectively), while serious infections were recorded in 3 patients in the maintenance therapy group every 8 weeks and in 4 patients in the maintenance therapy group every 12 weeks. Upper respiratory tract infections and pharyngitis were the most commonly reported infections, with abscess being the most common serious infection. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.

Ulcerative colitis

Overall, adverse reactions reported in the pediatric ulcerative colitis study and adult ulcerative colitis studies were generally similar. In the pediatric ulcerative colitis study, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse reaction was exacerbation of ulcerative colitis, which occurred more frequently in patients on the every-12-week regimen compared with the every-8-week regimen.

Infusion reactions

Overall, one or more infusion reactions were observed in 8 (13.3%) out of 60 patients, with 4 out of 22 (18.2%) in the every-8-week regimen and 3 out of 23 (13.0%) in the every-12-week maintenance therapy group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in severity.

Immunogenicity

Antibodies to infliximab were detected in 4 (7.7%) patients by week 54.

Infections

In the pediatric ulcerative colitis study, infections were reported in 31 (51.7%) out of 60 patients, and 22 (36.7%) patients required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric ulcerative colitis study was similar to that in the pediatric Crohn's disease study but higher than in adult ulcerative colitis studies. The overall incidence of infections in the pediatric ulcerative colitis study was 13/22 (59%) in the every-8-week maintenance therapy group and 14/23 (60.9%) in the every-12-week maintenance therapy group. Upper respiratory tract infections (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most common respiratory infections. Serious infections were recorded in 12% (7/60) of all treated patients.

In this study, more patients were aged 12 to 17 years (45/60 [75.0%]) than 6 to 11 years (15/60 [25.0%]). The number of patients in each subgroup was too small to draw definitive conclusions regarding the impact of age on drug safety; however, the number of patients with serious adverse reactions and treatment discontinuation due to serious adverse reactions was higher in the younger age group than in the older age group. The number of patients with infections was also higher in the younger age group, but the number of patients with serious infections was the same in both age groups. The overall proportion of adverse reactions and infusion reactions was similar in the 6–11 and 12–17 age groups.

Post-marketing period

During post-marketing use of infliximab, serious adverse reactions in the pediatric group included malignancies, particularly hepatosplenic T-cell lymphomas, transient abnormalities in liver enzyme activity, lupus-like syndromes, and positive autoantibody test results (see sections "Special warnings and precautions for use" and "Adverse reactions").

Additional information on specific patient groups

Elderly patients

In clinical trials of rheumatoid arthritis, the incidence of serious infections in patients receiving infliximab and methotrexate was higher in patients aged 65 years and older (11.3%) than in patients under 65 years (4.6%). In patients receiving methotrexate alone, the incidence of serious infections was 5.2% in patients aged 65 years and older compared with 2.7% in patients under 65 years (see section "Special warnings and precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

4 years.

After reconstitution and dilution

Chemical and physical stability of the diluted solution has been demonstrated for use over 34 days when stored at 2–8°C and for an additional 24 hours at 25°C after removal from the refrigerator. From a microbiological standpoint, the product should be used as soon as possible. If not used immediately, the responsibility for storage duration and conditions lies with the user. Generally, storage should not exceed 24 hours at 2–8°C, except when reconstitution is performed under controlled, validated aseptic conditions.

Storage conditions.

Store in the original packaging in a refrigerator (at 2–8°C).

Storage at temperatures not exceeding 25°C for a single period of up to 6 months within the shelf life indicated on the packaging is permitted.

Keep out of reach and sight of children.

Incompatibilities.

Due to lack of compatibility studies, Renflexis should not be mixed with other medicinal products.

Packaging.

100 mg in a 20 ml vial made of clear type I borosilicate glass with a rubber stopper and an aluminum cap with a flip-off cap; 1 vial per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Samsung Bioepis NL B.V.

Manufacturer's address and place of business.

Olof Palmestraat 10, Delft, 2616 LR, The Netherlands.

Marketing authorization holder.

SAMSUNG BIOEPIS CO., LTD.

Address of marketing authorization holder.

76, Songdojeok-ro, Yeonsu-gu, Incheon, Republic of Korea.