Flammegis^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Celltrion Healthcare, Co. Ltd. (Republic of Korea)

Manufactured By

Gensenta Ilac Sanayi Ve Ticaret A.S. (Turkey)

Or

Celltrion, Inc. (Republic of Korea)

Labeled By

EGIS Pharmaceuticals, PLC (Hungary)

Packaging and Quality Control Release

NANOLEK, LLC (Russia)

Or

CELLTRION, Inc. (Republic of Korea)

ATC Code

L04AB02 (Infliximab)

Active Substance

Infliximab (Rec.INN registered by WHO)

Dosage Form

Flammegis®

Lyophilisate for the preparation of a concentrate for the preparation of an infusion solution 100 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a concentrate for the preparation of an infusion solution white or almost white in color.

* 1 ml of the reconstituted solution contains 10 mg of infliximab.

Excipients: sucrose – 500 mg, polysorbate 80 – 0.5 mg, sodium dihydrogen phosphate monohydrate – 2.2 mg, disodium hydrogen phosphate dihydrate – 6.1 mg.

100 mg – vials of colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Selective immunosuppressant. Monoclonal antibodies to TNF

Pharmacotherapeutic Group

Tumor necrosis factor alpha inhibitors

Pharmacological Action

Mechanism of action

Infliximab is a chimeric mouse-human monoclonal antibody that binds with high affinity to soluble and transmembrane forms of TNFα, but does not bind to lymphotoxin alpha (LTα).

Pharmacodynamics

Infliximab inhibits the functional activity of TNFα in various in vitro test systems. Administration of infliximab to transgenic mice prevented the development of polyarthritis associated with the constitutional expression of human TNFα. Administration of infliximab after the onset of the disease led to the healing of structural joint damage. In vivo, Infliximab rapidly forms stable complexes with human TNFα, which is accompanied by a decrease in the biological activity of 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 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, was 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 was detected in vitro. 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 areas of skin affected by the psoriatic process.

Histological examination of colon biopsies taken before and 4 weeks after the administration of infliximab 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 a nonspecific serum marker of inflammation – CRP. The total number of peripheral blood leukocytes changed minimally during infliximab therapy, although there was a tendency towards normalization of the numbers of lymphocytes, monocytes, and neutrophils. In patients receiving Infliximab, the proliferative response of peripheral blood mononuclear cells to stimulation did not decrease 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 mucosal biopsies showed that infliximab therapy causes a decrease in the number of cells expressing TNFα and interferon-γ. 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.

Pharmacokinetics

A single intravenous infusion of infliximab at doses of 1, 3, 5, 10, or 20 mg/kg was accompanied by a dose-proportional increase in C_max and AUC. The volume of distribution at steady state (median 3.0-4.1 L) was independent of the dose and indicated that infliximab circulates predominantly in the vascular bed. The pharmacokinetics were time-independent. The routes of elimination of infliximab have not been determined. Unchanged Infliximab was not detected in the urine. In patients with rheumatoid arthritis, clearance and V_d did not change depending on age or body weight. The pharmacokinetics of infliximab in elderly patients have not been studied. Studies in patients with hepatic or renal impairment have not been conducted.

After a single administration of doses of 3, 5, or 10 mg/kg, the median C_max was 77, 118, and 277 mcg/ml, respectively. The median terminal T_1/2 ranged from 8 to 9.5 days. Infliximab was detected in the serum for at least 8 weeks in most patients with Crohn’s disease (after a single administration of the recommended dose of 5 mg/kg) or rheumatoid arthritis (during maintenance therapy with 3 mg/kg every 8 weeks).

Repeated use of infliximab (5 mg/kg at weeks 0, 2, and 6 in patients with fistulizing Crohn’s disease, as well as 3 or 10 mg/kg every 4 or 8 weeks in patients with rheumatoid arthritis) was accompanied by slight accumulation of infliximab in the serum after the second dose. Subsequently, no clinically significant accumulation was observed. In most patients with fistulizing Crohn’s disease, Infliximab was detected in the serum for 12 weeks (range from 4 to 28 weeks) after administration in the specified regimen.

Children

A population analysis of pharmacokinetic data from patients with ulcerative colitis (n=60), Crohn’s disease (n=112), juvenile rheumatoid arthritis (n=117), and Kawasaki disease (n=16) aged from 2 months to 17 years showed that infliximab exposure depends non-linearly on body weight. When taking 5 mg/kg of infliximab every 8 weeks, the estimated median steady-state exposure (AUC_ss) in patients aged 6 to 17 years was approximately 20% lower than the estimated median steady-state exposure in adults. The median AUC_ss in patients aged 2 to less than 6 years is estimated to be 40% lower than in adult patients, although the number of patients whose data support this assumption is limited.

Indications

• Rheumatoid arthritis. Therapy for patients with active rheumatoid arthritis in whom previous therapy with disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been ineffective, as well as therapy for patients with severe, progressive active rheumatoid arthritis who have not previously been treated with methotrexate or other DMARDs. Therapy is conducted in combination with methotrexate. Combination therapy with infliximab and methotrexate allows for a reduction in disease symptoms, improvement in functional status, and slowing of the progression of joint damage;
• Crohn’s disease in adults. Therapy for patients aged 18 years and older with active, moderate, or severe Crohn’s disease, including fistulizing disease, when standard therapy, including corticosteroids and/or immunosuppressants, has been ineffective, is not tolerated, or is contraindicated (for fistulizing disease – antibiotics, immunosuppressants, and drainage). Infliximab therapy helps reduce disease symptoms, achieve and maintain remission, heal mucous membranes and close fistulas, reduce the number of fistulas, reduce the dose or discontinue corticosteroids, and improve patients’ quality of life;
• Crohn’s disease in children and adolescents. Therapy for children and adolescents aged 6 to 17 years inclusive, with active, moderate, or severe Crohn’s disease when standard therapy, including corticosteroids and/or immunosuppressants, has been ineffective, is not tolerated, or is contraindicated. Infliximab therapy helps reduce disease symptoms, achieve and maintain remission, reduce the dose or discontinue corticosteroids, and improve patients’ quality of life;
• Ulcerative colitis in adults. Therapy for patients with ulcerative colitis in whom conventional therapy has been insufficiently effective, including the use of corticosteroids, 6-mercaptopurine, or azathioprine. Infliximab therapy helps heal the intestinal mucosa, reduce the need for hospitalization, establish and maintain remission, and improve patients’ quality of life;
• Ulcerative colitis in children and adolescents. Therapy for children and adolescents aged 6 to 17 years inclusive with moderate or severe ulcerative colitis with an inadequate response to standard therapy with corticosteroids, 6-mercaptopurine, or azathioprine, or in case of intolerance or contraindications to standard therapy;
• Ankylosing spondylitis. Therapy for patients with ankylosing spondylitis with significant axial symptoms and laboratory indicators of inflammatory activity who have not responded to standard therapy. Infliximab therapy allows for a reduction in disease symptoms and improvement in joint functional activity;
• Psoriatic arthritis. Therapy for patients with progressive active psoriatic arthritis with an inadequate response to DMARDs. Infliximab is used in combination with methotrexate or as monotherapy in cases of intolerance or contraindications to methotrexate. Infliximab therapy allows for a reduction in arthritis symptoms and improvement in patients’ functional activity, as well as a reduction in the degree of radiological progression in peripheral psoriatic polyarthritis;
• Psoriasis. Therapy for patients with severe psoriasis who are candidates for systemic therapy, as well as patients with moderate psoriasis when PUVA therapy has been ineffective, is not tolerated, or is contraindicated. Therapy leads to a reduction in inflammatory phenomena in the skin and normalization of the keratinocyte differentiation process.

ICD codes

Dosage Regimen

Administration of infliximab should be carried out under the supervision of physicians experienced in the diagnosis and therapy of rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriatic arthritis, or psoriasis. Infusions of the drug should be conducted under the supervision of a physician trained to identify infusion reactions.

When taking infliximab, concomitant therapy (corticosteroids or immunosuppressants) should be optimized.

The drug is administered intravenously by drip over at least 2 hours. All patients should remain under medical supervision for 1-2 hours after the infusion to prevent acute infusion reactions. Emergency equipment (such as epinephrine, antihistamines, corticosteroids, and artificial ventilation) must be available during the infusion. Pre-administration of antihistamines, hydrocortisone, and/or paracetamol, as well as a reduction in the infusion rate, is allowed to reduce the risk of developing infusion reactions, especially in patients who have experienced infusion reactions during previous administration of the drug.

When treating adult patients who have tolerated at least the first three 2-hour infusions (the induction phase of infliximab) and are on maintenance therapy, it is possible to reduce the duration of subsequent infusions to a minimum of 1 hour. If an infusion reaction occurs during subsequent accelerated administration of the drug, then if therapy is continued, a return to slower infusions is recommended.

The possibility of reducing infusion time when administering the drug at a dose of more than 6 mg/kg has not been studied.

Therapy for rheumatoid arthritis

The initial single dose of infliximab is 3 mg/kg IV. Then the drug is administered at the same dose 2 weeks and 6 weeks after the first administration (induction phase), and then every 8 weeks (maintenance phase of therapy).

Infliximab therapy should be conducted concurrently with the use of methotrexate.

A clinical response is achieved in most patients within 12 weeks. With an insufficient response or if the effect of therapy is lost subsequently, it is possible to increase the dose of infliximab in increments of 1.5 mg/kg, up to 7.5 mg/kg every 8 weeks, or to shorten the intervals between administrations of Infliximab at a dose of 3 mg/kg to 4 weeks. Upon achieving a clinical response, therapy should be continued at the appropriate dose and infusion regimen.

If there is no effect from therapy during the first 12 weeks, as well as in response to an increase in the dose of infliximab or a reduction in the intervals between infusions, the advisability of continuing therapy should be considered.

Therapy for severe or moderate active Crohn’s disease in adults

The initial dose of infliximab is 5 mg/kg IV, with a second infusion at the same dose 2 weeks after the first. If there is no response after two administrations, further use of infliximab is not advisable. For responding patients, infliximab therapy can be continued, and one of two possible options should be chosen: – the drug is administered at a dose of 5 mg/kg at 6 weeks after the first administration and then every 8 weeks; during the maintenance phase of therapy, some patients may require an increase in dose to 10 mg/kg to achieve an effect; the drug is re-administered at a dose of 5 mg/kg in case of disease relapse (see sections “Re-administration” and “Adverse Reactions”).

Despite the lack of comparative data, limited data indicate that some patients who initially responded to therapy with a dose of 5 mg/kg but subsequently lost the response may regain it when the dose is increased. The possibility of continuing therapy in patients who showed no signs of therapeutic improvement after changing the drug dose should be carefully evaluated.

The total duration of infliximab therapy is determined by the treating physician.

Therapy for severe or moderate active Crohn’s disease in children and adolescents aged 6 to 17 years inclusive

The initial dose of infliximab is 5 mg/kg IV. Then the drug is administered at the same dose 2 weeks and 6 weeks after the first administration, and then every 8 weeks. If there is no effect within the first 10 weeks, further use of infliximab is not recommended.

In some patients, a shorter interval between infusions may be required to maintain the clinical effect, while for some patients a longer interval may be sufficient. In patients for whom the interval between infusions is reduced to less than 8 weeks, there may be an increased risk of adverse events. The need to continue therapy should be carefully evaluated if there is no additional effect from therapy when changing the dosing interval.

Infliximab therapy should be conducted concurrently with the use of immunomodulators: 6-mercaptopurine, azathioprine, or methotrexate.

If there is a response to infliximab therapy, the total duration of therapy is determined by the treating physician.

The efficacy and safety of infliximab in patients under 6 years of age have not been studied.

Therapy for fistulizing Crohn’s disease in adults

The drug is administered as a single dose of 5 mg/kg IV, then the drug is administered at the same dose 2 weeks and 6 weeks after the first administration. If there is no response after administration of these three doses, continuation of infliximab therapy is not advisable. If there is a response, therapy can be continued, and one of two possible treatment strategy options should be chosen

• The drug is administered at a dose of 5 mg/kg at 2 weeks and 6 weeks after the first administration and then every 8 weeks; some patients may require an increase in dose to 10 mg/kg to achieve a therapeutic effect;
• The drug is re-administered at the same dose in case of disease relapse (see sections “Re-administration” and “Adverse Reactions”).

Despite the lack of comparative data, limited data indicate that some patients who initially responded to therapy with a dose of 5 mg/kg but subsequently lost the response may regain it when the dose is increased. The possibility of continuing therapy in patients who showed no signs of therapeutic improvement after changing the dose should be carefully evaluated. The total duration of infliximab therapy is determined by the treating physician.

Comparative studies of these two options for Crohn’s disease therapy have not been conducted. Available data on the use of the drug according to the second treatment option (re-administration in case of relapse) are limited.

Therapy for ulcerative colitis in adults

The initial dose of the drug infliximab is 5 mg/kg IV. Then the drug is administered at the same dose 2 weeks and 6 weeks after the first administration, and then every 8 weeks. Some patients may require an increase in dose to 10 mg/kg to achieve an effect. Available data indicate that the therapeutic effect occurs within up to 14 weeks (after administration of 3 doses). If no effect occurs during this time, the advisability of continuing therapy should be decided. If there is a response to therapy, the total duration of infliximab therapy is determined by the treating physician.

Treatment of ulcerative colitis in children and adolescents from 6 to 17 years inclusive

The initial dose of infliximab is 5 mg/kg IV. The drug is then administered at the same dose at 2 weeks and 6 weeks after the first administration, and then every 8 weeks. Available data do not support further use of infliximab in the absence of effect within 8 weeks after the first infusion.

If there is a response to infliximab therapy, the total duration of therapy is determined by the treating physician.

The efficacy and safety of infliximab in patients younger than 6 years have not been studied.

Treatment of ankylosing spondylitis

The initial dose of infliximab is 5 mg/kg IV. The drug is then administered at the same dose at 2 weeks and 6 weeks after the first administration, and then every 6-8 weeks. If there is no effect within 6 weeks (after two doses), it is not advisable to continue therapy.

Treatment of psoriatic arthritis

The initial dose of infliximab is 5 mg/kg IV. The drug is then administered at the same dose at 2 weeks and 6 weeks after the first administration, and then every 8 weeks.

Treatment of psoriasis

The initial dose of infliximab is 5 mg/kg IV. The drug is then administered at the same dose at 2 weeks and 6 weeks after the first administration, and then every 8 weeks. If there is no effect within 14 weeks (after four doses), it is not advisable to continue infliximab therapy. The total duration of the infliximab treatment course is determined by the treating physician.

Re-administration for rheumatoid arthritis and Crohn’s disease

In case of disease relapse, Infliximab may be re-administered within 16 weeks after the last dose. In clinical studies, hypersensitivity reactions were infrequent and were observed when the interval without infliximab use prior to re-administration was less than 1 year. The efficacy and safety of re-administration of the drug more than 16 weeks after the last dose without drug use have not been studied.

Re-administration for ulcerative colitis

The efficacy and safety of the drug upon its re-administration according to a different schedule (not every 8 weeks) have not been studied.

Re-administration for ankylosing spondylitis

The efficacy and safety of the drug upon its re-administration according to a different schedule (not every 6-8 weeks) have not been studied.

Re-administration for psoriatic arthritis

The efficacy and safety of the drug upon its re-administration according to a different schedule (not every 8 weeks) have not been studied.

Re-administration for psoriasis

Limited experience with re-administration of a single dose of infliximab after a 20-week interval suggests that therapy may be less effective and associated with a higher frequency of infusion reactions (mild and moderate) compared to the initial induction regimen. Limited experience with re-administration of infliximab in the induction regimen after disease exacerbation suggests that therapy may be associated with a higher frequency of infusion reactions (including severe ones) compared to the every 8-week administration regimen.

Re-administration regardless of indication

In case of an interruption in maintenance therapy and the need to resume therapy, re-administration of infliximab in the induction regimen is not recommended. Resumption of therapy should be carried out in the mode of a single infusion followed by infusions in the maintenance therapy regimen.

Patients over 65 years of age

The efficacy and safety of the drug in elderly patients have not been studied. No significant age-related differences in the distribution and elimination of the drug were observed in clinical studies. No dose adjustment is required.

Patients with impaired renal and hepatic function

The efficacy and safety of the drug in this category of patients have not been studied.

Instructions for preparation of the infusion solution

1. Calculate the dose and the required number of vials of infliximab (each vial contains 100 mg of infliximab) and the required volume of the finished drug solution.

2. Under aseptic conditions, dissolve the contents of each vial in 10 ml of Water for Injections using a syringe with a 21-gauge (0.8 mm) or smaller needle. Before introducing the solvent, remove the plastic cap from the vial and wipe the stopper with a 70% ethyl alcohol solution. Insert the syringe needle into the vial through the center of the rubber stopper, directing the stream of water along the wall of the vial.

Gently mix the solution by rotating the vial until the lyophilized powder is completely dissolved. Avoid prolonged and vigorous shaking.

DO NOT SHAKE. Foam may form upon dissolution; in this case, let the solution stand for 5 minutes.

The resulting solution should be colorless or pale yellow and opalescent. It may contain a small amount of small, translucent particles, as Infliximab is a protein. If opaque particles, foreign matter, or discoloration are present, the solution must not be used.

3. Bring the total volume of the prepared dose of infliximab solution to 250 ml with 0.9% Sodium Chloride solution for injections. To do this, from a glass bottle or infusion bag containing 250 ml of 0.9% Sodium Chloride solution, remove a volume equal to the volume of the prepared infliximab solution in Water for Injections. Then slowly add the previously prepared infliximab solution to the bottle or infusion bag with 0.9% Sodium Chloride solution and mix gently. THE UNDILUTED DRUG MUST NOT BE ADMINISTERED!

4. Perform the infusion over a period not less than the recommended time. Use only an infusion set with an integrated sterile, apyrogenic, low protein-binding filter (pore size no more than 1.2 µm). Since the drug contains no preservative, begin administration of the infusion solution as soon as possible, but no later than 3 hours after its preparation. Dissolution and dilution should be performed under aseptic conditions.

5. Do not administer Infliximab concomitantly with any other medicinal products through the same infusion system.

6. Visually inspect the infusion solution before administration. If opaque particles, foreign matter, or discoloration are present, the solution must not be used.

7. The unused portion of the infusion solution must not be used further and must be destroyed.

Adverse Reactions

Upper respiratory tract infections were the most common adverse reactions reported in clinical studies, with a frequency of 25.3% in patients receiving Infliximab compared to 16.5% in the control group. The most serious adverse reactions associated with the use of TNF inhibitors reported with infliximab included reactivation of hepatitis B virus, chronic heart failure, serious infections (including sepsis, opportunistic infections, and tuberculosis), serum sickness (delayed-type hypersensitivity reactions), hematological reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating syndrome, hepatobiliary disorders, lymphoma, hepatosplenic T-cell lymphoma, intestinal or perianal abscess (in Crohn’s disease), and serious infusion reactions.

Table of adverse reactions

Table 1 lists adverse reactions (including fatal ones) observed in clinical studies and reported during the post-marketing period. Adverse reactions are grouped by system organ class and categorized by frequency as follows: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), and very rare (<1/10,000), unknown (frequency cannot be estimated from the available data). Within each frequency column, adverse reactions are presented in order of decreasing severity.

Table 1. Adverse events identified in clinical studies and in the post-marketing period.

Infusion reactions

In the post-marketing period, cases of seizures and anaphylactoid reactions, including pharyngeal/laryngeal edema and severe bronchospasm, have been reported with infliximab use. Transient vision loss, myocardial ischemia, or myocardial infarction during or within 2 hours after infusion have been reported very rarely.

Infusion reactions after re-administration of infliximab

Most serious infusion reactions were noted during the 2nd infusion (week 2). The interval between the last maintenance dose and the first re-induction dose ranged from 35 to 231 days. Symptoms included (but were not limited to) dyspnea, urticaria, facial edema, and decreased blood pressure. In all cases, after discontinuation of infliximab therapy and/or initiation of other therapy, the signs and symptoms resolved completely.

Delayed-type hypersensitivity reactions (DHR)

In clinical studies, DHR were infrequent and occurred within an interval without infliximab of less than 1 year. In psoriasis studies, DHR occurred at the start of the treatment course. Signs and symptoms included myalgia and/or arthralgia accompanied by fever and/or rash; some patients experienced pruritus, facial, lip, or hand edema, dysphagia, urticaria, sore throat, and headache.

Data on the number of DHR cases after an interval without infliximab are insufficient, but limited clinical study data suggest an increased risk of DHR with an increased interval without infliximab.

Immunogenicity

Patients who developed antibodies to infliximab were more likely (approximately 2-3 times) to experience infusion reactions. Concomitant use of immunosuppressants reduced the likelihood of infusion reactions.

Infections

Tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal, viral, or other opportunistic infections have been observed in patients receiving Infliximab. Some of these infections were fatal; the more frequently reported opportunistic infections with a mortality rate of more than included pneumocystosis, candidiasis, listeriosis, and aspergillosis.

Malignant neoplasms and lymphoproliferative disorders

In clinical studies of infliximab, in which 5780 patients received therapy (5494 patient-years), 5 cases of lymphoma and 26 cases of malignant neoplasm (other than lymphoma) were diagnosed, compared to no cases of lymphoma and 1 case of malignant neoplasm (other than lymphoma) in 1600 patients receiving placebo (941 patient-years).

During long-term follow-up (up to 5 years) of 3210 patients (6234 patient-years) after clinical studies of infliximab, 5 cases of lymphoma and 38 cases of malignant neoplasm (other than lymphoma) were reported.

In the post-marketing period, rare cases of hepatosplenic T-cell lymphoma have been reported in patients with Crohn’s disease and ulcerative colitis receiving Infliximab; most patients were adolescent or young adult males.

Cardiovascular failure

In the post-marketing period, cases of worsening heart failure during infliximab use with or without additional factors have also been reported. Furthermore, there have been rare reports of new-onset heart failure, including in patients with no prior cardiovascular disease. Some of these patients were under 50 years of age.

Changes in liver and biliary tract

In clinical studies, mild or moderate increases in ALT and AST activity without the development of significant liver damage were observed in patients during infliximab therapy. In the post-marketing period, very rare reports of jaundice and hepatitis, in some cases with features of autoimmune hepatitis, have been received in patients receiving Infliximab.

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

Antibodies to double-stranded native DNA (anti-dsDNA) became detectable in approximately 17% of patients. However, reports of the development of lupus or lupus-like syndrome remained infrequent.

Pediatric patients

Pediatric patients with Crohn’s disease

Adverse events that were observed more frequently in children than in adult patients with Crohn’s disease: anemia, blood in stool, leukopenia, flushing, viral infections, neutropenia, bone fractures, bacterial infections, respiratory tract allergic reactions.

Infusion reactions

One or more infusion reactions may occur in 17.5% of patients. Serious infusion reactions were absent; in very rare cases, patients experienced non-serious anaphylactic reactions.

Immunogenicity

Antibodies to infliximab were very rarely detected in pediatric patients.

Infections

The most common infectious complications were upper respiratory tract infections and pharyngitis; the most common serious infectious complication was abscess, pneumonia, activation of Herpes zoster virus.

Post-marketing data

In the post-marketing period, spontaneous serious adverse events in pediatric patients included cases of malignant neoplasms (including hepatosplenic T-cell lymphoma), transient elevations of liver enzymes, lupus-like syndrome, and autoantibody appearance.

Special populations

Elderly patients (>65 years)

In patients diagnosed with rheumatoid arthritis receiving methotrexate and Infliximab, the frequency of serious infections was higher than in patients under 65 years of age.

Contraindications

• Hypersensitivity to infliximab and other murine proteins, as well as to any of the excipients of the drug;
• Severe infectious process, e.g., sepsis, abscess, tuberculosis, opportunistic infections;
• Chronic heart failure of NYHA functional class III-IV;
• Pregnancy and breastfeeding;
• Age less than 18 years (for Crohn’s disease and ulcerative colitis – less than 6 years).

With caution

• History of chronic or recurrent infections, including during concomitant therapy with immunosuppressants;
• History of intensive immunosuppressive therapy or long-term PUVA therapy;
• Carriage of hepatitis B virus;
• Demyelinating diseases;
• Increased risk of malignant neoplasms due to smoking;
• History of malignant neoplasms, continuation of therapy in patients who have developed malignant neoplasms;
• Chronic heart failure of NYHA functional class I-II.

Use in Pregnancy and Lactation

Women of childbearing potential should use reliable methods of contraception during infliximab therapy and for at least 6 months after its completion.

Pregnancy

Data from approximately 450 patients who received Infliximab during pregnancy (including about 230 in the first trimester) do not indicate the possibility of unforeseen effects on pregnancy outcome.

Due to TNFα inhibition, administration of infliximab during pregnancy may affect the normal immune response of the newborn. According to toxicity studies in mice using a similar antibody (selectively inhibiting the activity of murine TNFα), no signs of toxicity to pregnant females, embryotoxicity, or teratogenicity were detected.

The available clinical experience is limited, and to exclude possible risk, the use of infliximab is not recommended during pregnancy.

Infliximab crosses the placenta and is detected in the serum of newborns for up to 6 months after infusion of infliximab to a pregnant patient. Consequently, such children may have an increased risk of infection, and the use of live vaccines is not recommended in them for 6 months after the mother’s last infliximab infusion during pregnancy.

Breastfeeding period

It is not known whether Infliximab is excreted in human milk or absorbed systemically after oral ingestion. Since human immunoglobulins are excreted in breast milk, a woman should not breastfeed for at least 6 months after administration of infliximab.

Effect on fertility

Data from studies are insufficient to draw conclusions about the effect of infliximab on fertility and reproductive function.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age (for Crohn’s disease and ulcerative colitis – less than 6 years).

Geriatric Use

No dose adjustment of the drug is required for elderly patients.

Special Precautions

In order to improve the traceability of biological medicinal products, it is recommended to record the name and batch number of the drug in the patient’s medical record.

The dissolved drug has been demonstrated to maintain chemical and physical stability for 48 hours at 2-8°C (35.6-46.4°F) and 30±2°C (86±3.6°F)/relative humidity 65±5%. From a microbiological point of view, the drug should be used as soon as possible within 3 hours after reconstitution and dilution.

Infusion reactions and hypersensitivity reactions

The use of infliximab may be associated with the development of acute infusion reactions, including anaphylactic shock and DHR.

Acute infusion reactions, including anaphylactic ones, may develop during (within seconds) or within a few hours after the infusion. If an acute reaction occurs, the infusion should be stopped immediately. Emergency equipment (such as epinephrine, antihistamines, hydrocortisone, and/or artificial ventilation) should be available during the infusion. Pre-administration of antihistamines, hydrocortisone, and/or paracetamol may be allowed to prevent mild and transient effects.

Formation of antibodies to infliximab is possible, which may be associated with an increased frequency of infusion reactions. A small proportion of infusion reactions were serious allergic reactions. An association was observed between the formation of antibodies to infliximab and a reduction in the duration of response to therapy. Concomitant use with immunomodulators was associated with a reduction in the number of cases of antibody formation to infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant therapy with immunomodulators was more pronounced in patients receiving episodic therapy than in patients on maintenance therapy. In patients who discontinued immunosuppressants before or during infliximab therapy, the risk of antibody formation is increased. Antibodies to infliximab may not always be detectable in serum samples. If a serious reaction develops, symptomatic therapy should be prescribed, and subsequent infliximab infusions should not be performed. Cases of DHR development were reported in clinical studies. Available data suggest that increasing the interval without infliximab increases the risk of DHR. Patients should seek medical attention immediately if any adverse event develops. When resuming therapy in patients after a long break, they should be carefully monitored for signs and symptoms of DHR.

Infections

Patients should be carefully monitored for signs of possible infection before, during, and after therapy. Since infliximab elimination may take up to 6 months, monitoring should continue throughout this period. Infliximab therapy should be discontinued if a patient develops a serious infection or sepsis.

Caution should be exercised when using infliximab in patients with a history of chronic or recurrent infections, including those receiving concomitant immunosuppressive therapy. Patients should avoid exposure to potential risk factors for developing infections.

TNFα is a mediator of inflammation and a modulator of cellular immunity. Experimental data have shown that TNFα is necessary for clearing intracellular infections. Clinical experience indicates that immunological defense against infections may be compromised in some patients receiving infliximab therapy.

It should be kept in mind that inhibition of TNFα activity may mask symptoms of infection, such as fever. Early recognition of atypical clinical presentations of serious infections and typical clinical presentations of rare and atypical infections is critical to reducing diagnostic and therapeutic delays.

Patients receiving TNF inhibitor therapy are at greater risk of developing serious infections.

Tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal, viral, or other opportunistic infections have been observed in patients treated with Infliximab. Some of these infections were fatal; the most frequently reported opportunistic infections with a mortality rate exceeding 5% included pneumocystosis, candidiasis, listeriosis, and aspergillosis.

Patients who develop an infection during infliximab therapy should be closely monitored and undergo a complete diagnostic evaluation. Infliximab should be discontinued if a patient develops a new serious infection or sepsis, and antibacterial or antifungal therapy should be initiated until the infectious process is controlled.

Tuberculosis

Cases of active tuberculosis have been reported in patients receiving Infliximab. Most cases of tuberculosis were extrapulmonary, localized, or disseminated.

Before initiating infliximab therapy, patients should be carefully evaluated for both active and latent tuberculosis. The evaluation should include a thorough medical history, including whether the patient has had tuberculosis in the past, contact with tuberculosis patients, and whether they are receiving or have received immunosuppressive therapy. Necessary screening tests (chest X-ray, tuberculin test) should be performed. It should be taken into account that severely ill patients and patients with immunosuppression may have a false-negative tuberculin test.

If active tuberculosis is diagnosed, infliximab therapy should not be initiated.

If latent tuberculosis is suspected, consultation with a phthisiatrician is recommended. In all cases described below, the risk/benefit of infliximab therapy should be carefully assessed.

If latent tuberculosis is diagnosed, appropriate therapy should be initiated before starting infliximab.

In patients with multiple or significant risk factors for tuberculosis but in whom latent tuberculosis is not confirmed by testing, the need for anti-tuberculosis therapy before starting infliximab should be considered.

The need for anti-tuberculosis therapy before starting infliximab should be considered in patients with a history of active or latent tuberculosis for whom an adequate course of therapy cannot be confirmed.

Patients should consult a physician if signs or symptoms of tuberculosis (persistent cough, wasting/weight loss, low-grade fever) appear during or after infliximab therapy.

Invasive Fungal Infections

In patients treated with Infliximab, suspicion of invasive fungal infections such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis, or blastomycosis should always arise if the patient develops a serious systemic illness; early consultation with a specialist in the diagnosis and treatment of invasive fungal diseases should be sought when examining such patients. Invasive fungal infections may present as disseminated rather than localized lesions, and antigen and antibody test results may be negative in some patients with active infection. The need for empiric antifungal therapy, pending laboratory results, should be assessed, considering both the risk of developing a serious fungal infection and the consequences of antifungal therapy.

For patients who have resided in or visited regions endemic for invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis, the benefits and risks of infliximab therapy should be carefully assessed before initiating treatment.

Fistulizing Crohn’s Disease

Patients with Crohn’s disease with acute purulent fistulas should not start infliximab therapy until another possible source of infection, especially an abscess, is identified and eliminated.

Reactivation of Hepatitis B Virus

Reactivation of hepatitis B virus has been observed in chronic carriers of the virus receiving TNF antagonists, including Infliximab, in some cases with fatal outcomes. Carriers of hepatitis B virus who require infliximab therapy should be closely monitored for signs and symptoms of infection activation throughout the course of therapy and for several months after its completion. Sufficient data on the efficacy of concomitant antiviral therapy (to prevent virus reactivation) and TNFα inhibitors in chronic virus carriers are lacking.

If hepatitis B reactivates, infliximab therapy should be discontinued and appropriate antiviral therapy initiated.

Disorders of Liver and Biliary Tract Function

In the post-marketing period, very rare cases of jaundice and non-infectious hepatitis, sometimes with features of autoimmune hepatitis, have been observed with infliximab. Isolated cases of liver failure leading to death or requiring liver transplantation have been reported. Patients with signs or symptoms of liver dysfunction should be evaluated for liver damage. If jaundice appears or ALT activity increases to levels exceeding 5 times the upper limit of normal, Infliximab should be discontinued and a thorough investigation of the disorder conducted.

Concomitant Use of TNFα Inhibitor and Anakinra

Concomitant use of anakinra and another TNF inhibitor (etanercept) in clinical studies was associated with the development of serious infections and neutropenia and did not lead to additional clinical benefit compared to etanercept monotherapy. Due to the nature of the adverse effects observed with concomitant therapy with anakinra and etanercept, similar types of toxicity may occur with combination therapy of anakinra and other TNF inhibitors. Therefore, concomitant use of infliximab and anakinra is not recommended.

Concomitant Use of TNFα Inhibitor and Abatacept

In clinical studies, concomitant use of TNF inhibitors and abatacept was associated with an increased risk of infections, including serious infections, compared with the use of TNF inhibitors alone, without enhanced clinical effect. Concomitant use of infliximab and abatacept is not recommended.

Concomitant Use with Other Biological Drugs

There is insufficient data regarding the concomitant use of infliximab and other biological drugs intended for the same indications. Concomitant use of infliximab with these drugs is not recommended due to the possible increased risk of infections and other potential pharmacological interactions.

Switching from Another Biological Drug

Caution should be exercised when switching from one biological drug to another, as cross-biological activity may increase the risk of adverse events, including infections.

Live Vaccines and Medicinal Products Containing Infectious Agents

Data on the response to vaccination or the possibility of secondary transmission of infection with the use of live vaccines in patients are insufficient. The use of live vaccines may lead to the clinical manifestation of infections, including disseminated infection. Concomitant use of infliximab and live vaccines is not recommended.

The use of drugs containing infectious agents, such as live attenuated bacteria (e.g., intravesical BCG instillations for cancer therapy), may lead to the clinical manifestation of infections, including disseminated infection. Concomitant use of infliximab and medicinal products containing infectious agents is not recommended.

Autoimmune Processes

In rare cases, relative TNFα deficiency caused by anti-TNF therapy may initiate the development of an autoimmune process. If symptoms of a lupus-like syndrome appear during infliximab therapy and tests for antibodies to double-stranded DNA are positive, infliximab therapy should be discontinued.

Neurological Disorders

The use of TNF inhibitors, including Infliximab, has in rare cases been associated with the appearance or worsening of clinical and/or radiological signs of demyelinating diseases of the central nervous system (including multiple sclerosis) and peripheral nervous system, including Guillain-Barré syndrome. In patients with existing or recently developed demyelinating diseases, the benefit and risk of anti-TNF therapy should be carefully weighed before prescribing infliximab. If such diseases develop, infliximab therapy should be discontinued.

Malignant Tumors and Lymphoproliferative Disorders

In clinical trials with anti-TNF agents, the development of lymphoma was more frequent in patients receiving an anti-TNF agent than in control patients. In infliximab clinical trials across all approved indications, the occurrence of lymphoma was rare, although more frequent than expected in the general population. In the post-marketing period, the development of leukemias has been reported in patients receiving TNF antagonists. Since the risk of developing lymphoma and leukemia is increased in patients with rheumatoid arthritis with prolonged highly active inflammatory disease, risk assessment is difficult.

In clinical trials investigating the use of infliximab for a potential new indication – COPD (severe and moderate) – in patients who were smokers (or former smokers), the incidence of neoplasms was higher in the group receiving Infliximab than in the control group. Caution should be exercised when prescribing anti-TNF therapy to patients at increased risk of developing malignancies due to smoking.

Based on available data, the risk of developing lymphomas or other malignancies in patients receiving TNF inhibitors cannot be excluded. Caution should be exercised when prescribing TNF inhibitors to patients with a history of malignancies or when continuing therapy in patients who have developed malignancies.

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

During post-marketing studies, cases of malignant tumor formation, some fatal, have been reported among children, adolescents, and young adults (under 22 years of age) who received TNF inhibitors (therapy initiation at age ≤18 years), including Infliximab. Approximately half of the cases reported lymphomas. Other cases represented a range of different malignant tumors, including malignancies typically associated with immunosuppression. The risk of developing malignancies in patients receiving TNF inhibitors cannot be excluded.

In the post-marketing period, rare cases of hepatosplenic T-cell lymphoma have been reported during therapy with TNF inhibitors, including Infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive disease course and is usually fatal. All cases during infliximab therapy were reported in patients with Crohn’s disease or ulcerative colitis, most of them in adolescent or young adult males. All reported cases of hepatosplenic T-cell lymphoma were noted in patients concurrently receiving azathioprine or 6-mercaptopurine. The potential risk of concomitant use of azathioprine or 6-mercaptopurine and infliximab should be carefully evaluated. The risk of developing hepatosplenic lymphoma in patients receiving Infliximab cannot be excluded.

Cases of Merkel cell carcinoma and melanoma have been reported in patients receiving TNFα blockers, including Infliximab. Periodic skin examination is recommended for patients, especially those with risk factors for skin malignancies.

All patients with ulcerative colitis who are at increased risk of developing dysplasia or colon carcinoma (e.g., patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or in whom these conditions have been previously diagnosed, should be regularly monitored for dysplasia before and after therapy. Monitoring should include colonoscopy and biopsy according to accepted guidelines. It is not known whether infliximab therapy affects the risk of developing dysplasia or colon cancer.

Since the possibility of an increased risk of developing malignancies in patients with newly diagnosed dysplasia receiving infliximab therapy has not been established, the risks and benefits of infliximab therapy should be carefully assessed and a decision made to continue or discontinue therapy.

Heart Failure

Infliximab should be used with caution in patients with chronic heart failure of NYHA functional class I-II. Patients should be monitored, and if new or worsening signs of heart failure occur, infliximab therapy should be discontinued.

Hematological Reactions

There are reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving TNF inhibitors, including Infliximab. All patients developing signs and symptoms of blood dyscrasia (persistent fever, bruising, bleeding, pallor) should be immediately evaluated. In case of severe hematological disorders, infliximab therapy should be discontinued.

Other

Safety data on the use of infliximab in patients who have undergone surgery, including arthroplasty, are limited. The long half-life of infliximab must be considered when planning surgeries. Patients undergoing surgery while receiving infliximab therapy require careful monitoring for infections and prompt treatment if they occur.

Lack of response to Crohn’s disease therapy may indicate the presence of a fixed fibrotic stricture, which may require surgical intervention. Available data suggest that Infliximab does not contribute to the worsening or formation of strictures.

Special Patient Groups

Elderly Patients (≥65 years)

The frequency of serious infections in elderly patients (≥65 years) was higher than in patients under 65 years. Some of these infections were fatal. When treating elderly patients, particular attention should be paid to the risk of developing infections.

Pediatric Patients

Infections

In clinical trials, infections were reported more frequently in pediatric patients than in adults.

Vaccinations

Patients are advised to complete all vaccinations according to the current immunization schedule, if possible, before starting infliximab therapy.

Malignancies and Lymphoproliferative Disorders

During post-marketing studies, cases of malignant tumor formation, some fatal, have been reported among children, adolescents, and young adults (under 22 years of age) who received TNF inhibitors (therapy initiation at age ≤18 years), including Infliximab. Approximately half of the cases reported lymphomas. Other cases represented a range of different malignant tumors, including malignancies typically associated with immunosuppression. The risk of developing malignancies in patients receiving TNF inhibitors cannot be excluded.

In the post-marketing period, rare cases of hepatosplenic T-cell lymphoma have been reported during therapy with TNF inhibitors, including Infliximab. This rare type of T-cell lymphoma is characterized by a very aggressive disease course and is usually fatal. All cases during infliximab therapy were reported in patients with Crohn’s disease or ulcerative colitis, most of them in adolescent or young adult males. All reported cases of hepatosplenic T-cell lymphoma were noted in patients concurrently receiving azathioprine or 6-mercaptopurine. The potential risk of concomitant use of azathioprine or 6-mercaptopurine and infliximab should be carefully evaluated. The risk of developing hepatosplenic lymphoma in patients receiving Infliximab cannot be excluded.

Therapy with infliximab in children and adolescents up to 17 years of age inclusive with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, or psoriasis, as well as therapy in children under 6 years of age with Crohn’s disease or ulcerative colitis, has not been studied. Until data on the safety and efficacy of infliximab are obtained, the drug should not be used for these indications in the respective age groups.

Effect on Ability to Drive and Use Machines

Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions, as the drug may cause dizziness and other side effects that may affect these abilities.

Overdose

A single administration of infliximab at a dose of 20 mg/kg did not cause a toxic effect. There are no clinical data on overdose. If necessary, symptomatic therapy should be administered.

Drug Interactions

No specific interaction studies have been conducted.

In patients with rheumatoid arthritis, psoriatic arthritis, and Crohn’s disease, concomitant use with methotrexate or other immunomodulators reduces the formation of antibodies to infliximab and increases its plasma concentration. However, due to limitations of the method used to determine the concentration of infliximab and antibodies to infliximab in serum, the results are not conclusive.

Corticosteroids do not have a clinically significant effect on the pharmacokinetics of infliximab.

Concomitant use of infliximab and other biological agents used for the same indications, including with anakinra and abatacept, is not recommended.

Concomitant use of the drug infliximab and live vaccines is not recommended.

Concomitant use of the drug infliximab and therapeutic agents containing infectious pathogens is not recommended.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 2°C and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

If the drug is not used immediately, the storage time and condition prior to administration are the responsibility of the user; the drug should not be stored for longer than 24 hours at a temperature of 2°C to 8°C (46.4°F).

Dispensing Status

The drug is dispensed by prescription.

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.