фламмэгис

Overdose

Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic effects.

Contraindications

Фламмэгис at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating Фламмэгис in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), Фламмэгис treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure.

Фламмэгис should not be re-administered to patients who have experienced a severe hypersensitivity reaction to Фламмэгис. Additionally, Фламмэгис should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.

Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections.

Patients with moderate or severe heart failure (NYHA class III/IV).

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Undesirable effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described herein reflect exposure to Фламмэгис in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn’s disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Clinical Trials Experience] One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).

An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase 3 clinical studies, 18% of Фламмэгис-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of infliximab-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.

Among all Фламмэгис infusions, 3% were accompanied by nonspecific symptoms such as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued Фламмэгис because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. Фламмэгис infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in psoriasis through 1 year in psoriasis Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 psoriasis studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group.

Patients who became positive for antibodies to infliximab were more likely (approximately two-to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions.

In a clinical trial of patients with moderate to severe psoriasis designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of Фламмэгис following disease flare, 4% (8/219) of patients in the re-treatment therapy arm experienced serious infusion reactions versus <1% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, Фламмэгис treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.

In psoriasis studies, approximately 1% of Фламмэгис-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.

In Фламмэгис clinical studies, treated infections were reported in 36% of Фламмэгис-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among Фламмэгис-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with Фламмэгис and may reflect recrudescence of latent disease. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving Фламмэгис every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving Фламмэгис, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg Фламмэгис infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg Фламмэгис group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn’s II Study, 15% of patients with fistulizing Crohn’s disease developed a new fistula-related abscess.

In Фламмэгис clinical studies in patients with ulcerative colitis, infections treated with antimicrobials were reported in 27% of Фламмэгис-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with ulcerative colitis were similar to those reported in other clinical studies.

The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.

Approximately half of Фламмэгис-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of Фламмэгис-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.

In controlled trials, more Фламмэгис-treated patients developed malignancies than placebo-treated patients.

In a randomized controlled clinical trial exploring the use of Фламмэгис in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with Фламмэгис at doses similar to those used in rheumatoid arthritis and Crohn’s disease. Of these Фламмэгис-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 -14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 -9.10). The majority of the malignancies developed in the lung or head and neck.

In a randomized study evaluating Фламмэгис in moderate to severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of Фламмэгис 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg Фламмэгис dose. At 1 year, 8 patients in the 10 mg/kg Фламмэгис group had died compared with 4 deaths each in the 5 mg/kg Фламмэгис and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg Фламмэгис treatment groups, versus placebo. Фламмэгис has not been studied in patients with mild heart failure (NYHA Class I/II).

Treatment with Фламмэгис can be associated with the development of antibodies to infliximab. An enzyme immunoassay (EIA) method was originally used to measure antiinfliximab antibodies in clinical studies of Фламмэгис. The EIA method is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. A separate, drug-tolerant electrochemiluminescence immunoassay (ECLIA) method for detecting antibodies to infliximab was subsequently developed and validated. This method is 60-fold more sensitive than the original EIA. With the ECLIA method, all clinical samples can be classified as either positive or negative for antibodies to infliximab without the need for the inconclusive category.

The incidence of antibodies to infliximab was based on the original EIA method in all clinical studies of Фламмэгис except for the Phase 3 study in pediatric patients with ulcerative colitis where the incidence of antibodies to infliximab was detected using both the EIA and ECLIA methods.

The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of Фламмэгис treatment. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving Фламмэгис after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.

In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with Фламмэгис over the long term is not known.

The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an immunoassay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.

Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving Фламмэгис. Reactivation of hepatitis B virus has occurred in patients receiving TNF-blocking agents, including Фламмэгис, who are chronic carriers of this virus.

In clinical trials in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving Фламмэгис than in controls (Table 1), both when Фламмэгис was given as monotherapy and when it was used in combination with other immunosuppressive agents. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of Фламмэгис, or modification of concomitant medications.

Table 1: Proportion of patients with elevated ALT in clinical trials

During the placebo-controlled portion across the 3 clinical trials up to Week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg Фламмэгис group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg Фламмэгис group.

Among patients in the 2 Phase 3 studies, 12.4% of patients receiving Фламмэгис 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving Фламмэгис 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.

One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg Фламмэгис. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving Фламмэгис 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving Фламмэгис 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg Фламмэгис group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting Фламмэгис.

In the placebo-controlled portion of the psoriasis studies, 7 of 1123 patients who received Фламмэгис at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.

In the psoriasis studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.

Safety data are available from 4779 Фламмэгис-treated adult patients, including 1304 with rheumatoid arthritis, 1106 with Crohn’s disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see ADVERSE REACTIONS]. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in Фламмэгис-treated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn’s disease patients except for abdominal pain, which occurred in 26% of Фламмэгис-treated patients with Crohn’s disease. In the Crohn’s disease studies, there were insufficient numbers and duration of follow-up for patients who never received Фламмэгис to provide meaningful comparisons.

Table 2: Adverse reactions occurring in 5% or more of patients receiving 4 or more infusions for rheumatoid arthritis

The most common serious adverse reactions observed in clinical trials were infections. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:

• Body as a whole: allergic reaction, edema
• Blood: pancytopenia
• Cardiovascular: hypotension
• Gastrointestinal: constipation, intestinal obstruction
• Central and Peripheral Nervous: dizziness
• Heart Rate and Rhythm: bradycardia
• Liver and Biliary: hepatitis
• Metabolic and Nutritional: dehydration
• Platelet, Bleeding and Clotting: thrombocytopenia
• Neoplasms: lymphoma
• Red Blood Cell: anemia, hemolytic anemia
• Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
• Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
• Skin and Appendages: increased sweating
• Vascular (Extracardiac): thrombophlebitis
• White Cell and Reticuloendothelial: leukopenia, lymphadenopathy

There were some differences in the adverse reactions observed in the pediatric patients receiving Фламмэгис compared to those observed in adults with Crohn’s disease. These differences are discussed in the following paragraphs.

The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn’s disease patients administered 5 mg/kg Фламмэгис through 54 weeks than in 385 adult Crohn’s disease patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).

Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn’s and in 50% of adult patients in Study Crohn’s I. In Study Peds Crohn’s, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.

In Study Peds Crohn’s, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn’s, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.

In Study Peds Crohn’s, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.

Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn’s disease clinical trials; 4% had ALT elevations.3 x ULN, and 1% had elevations ≥5 x ULN. (Median follow-up was 53 weeks.)

Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.

Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric Crohn’s disease study (Study Peds Crohn’s) but higher than the proportion in the adults’ ulcerative colitis studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.

In the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%) patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients had antibodies to infliximab . The higher incidence of antibodies to infliximab by the ECLIA method was due to the 60-fold higher sensitivity compared to the EIA method. While EIA-positive patients generally had undetectable trough infliximab concentrations, ECLIA-positive patients could have detectable trough concentrations of infliximab because the ECLIA assay is more sensitive and drug-tolerant.

Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 x ULN, and 2% (1/60) had elevations ≥5 x ULN (median follow-up was 49 weeks).

Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.

In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. The numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events. There were higher proportions of patients with serious adverse events (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).

Adverse reactions have been identified during post approval use of Фламмэгис in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions, some with fatal outcome, have been reported during post-approval use of Фламмэгис: neutropenia , agranulocytosis (including infants exposed in utero to infliximab), interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) , acute liver failure, jaundice, hepatitis, and cholestasis , serious infections , malignancies, including melanoma, Merkel cell carcinoma, and cervical cancer and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab.

In post-marketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with Фламмэгис administration.

Cases of transient visual loss have been reported in association with Фламмэгис during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported.

The following serious adverse reactions have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.

Serious adverse reactions in the post-marketing experience with Фламмэгис in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas , transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

Summary of the safety profile

Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical trials, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. The most serious ADRs associated with the use of TNF blockers that have been reported for infliximab include HBV reactivation, CHF, serious infections (including sepsis, opportunistic infections and TB), serum sickness (delayed hypersensitivity reactions), haematologic reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating disorders, hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cell carcinoma, melanoma, paediatric malignancy, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn's disease), and serious infusion reactions.

Tabulated list of adverse reactions

Table 1 lists the ADRs based on experience from clinical studies as well as adverse reactions, some with fatal outcome, reported from post-marketing experience. Within the organ system classes, adverse reactions are listed under headings of 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1

Adverse reactions in clinical studies and from post-marketing experience

Infusion-related reactions

An infusion-related reaction was defined in clinical studies as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase III clinical studies, 18% of infliximab-treated patients compared with 5% of placebo-treated patients experienced an infusion-related reaction. Overall, a higher proportion of patients receiving infliximab monotherapy experienced an infusion-related reaction compared to patients receiving infliximab with concomitant immunomodulators. Approximately 3% of patients discontinued treatment due to infusion-related reactions and all patients recovered with or without medical therapy. Of infliximab-treated patients who had an infusion reaction during the induction period, through week 6, 27% experienced an infusion reaction during the maintenance period, week 7 through week 54. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.

In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administered over 2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not less than 40 minutes in patients who did not experience serious infusion reactions. In this trial, sixty six percent of the patients (686 out of 1,040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1,040) received at least one shortened infusion of 60 minutes or less. Of the infliximab-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of patients and serious infusion reactions occurred in 0.4% of patients.

In a clinical study of patients with Crohn's disease (SONIC), infusion-related reactions occurred in 16.6% (27/163) of patients receiving infliximab monotherapy, 5% (9/179) of patients receiving infliximab in combination with AZA, and 5.6% (9/161) of patients receiving AZA monotherapy. One serious infusion reaction (<1%) occurred in a patient on infliximab monotherapy.

In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema and severe bronchospasm, and seizure have been associated with infliximab administration. Cases of transient visual loss occurring during or within 2 hours of infliximab infusion have been reported. Events (some fatal) of myocardial ischaemia/infarction and arrhythmia have also been reported, some in close temporal association with infusion of infliximab.

Infusion reactions following re-administration of infliximab

A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safety of long-term maintenance therapy versus re-treatment with an induction regimen of infliximab (maximum of four infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receive any concomitant immunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion reaction versus <1% (1/222) on maintenance therapy. The majority of serious infusion reactions occurred during the second infusion at week 2. The interval between the last maintenance dose and the first re-induction dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnoea, urticaria, facial oedema, and hypotension. In all cases, infliximab treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.

Delayed hypersensitivity

In clinical studies delayed hypersensitivity reactions have been uncommon and have occurred after infliximab-free intervals of less than 1 year. In the psoriasis studies, delayed hypersensitivity reactions occurred early in the treatment course. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash, with some patients experiencing pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache.

There are insufficient data on the incidence of delayed hypersensitivity reactions after infliximab-free intervals of more than 1 year but limited data from clinical studies suggest an increased risk for delayed hypersensitivity with increasing infliximab-free interval.

In a 1-year clinical study 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 were more likely (approximately 2-3 fold) to develop infusion-related reactions. Use of concomitant immunosuppressant agents appeared to reduce the frequency of infusion-related reactions.

In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% of patients without immunosuppressant therapy.: "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 have been fatal; the most frequently reported opportunistic infections with a mortality rate of >5% include pneumocystosis, candidiasis, listeriosis and aspergillosis.

In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% of placebo-treated patients.

In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was higher in infliximab plus methotrexate-treated patients compared with methotrexate alone especially at doses of 6 mg/kg or greater.

In post-marketing spontaneous reporting, infections are the most common serious adverse event. Some of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have been associated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extra-pulmonary location have been reported.

Malignancies and lymphoproliferative disorders

In clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patient years, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing 941 patient years.

In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6,234 patients-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.

Cases of malignancies, including lymphoma, have also been reported in the post-marketing setting.

In an exploratory clinical study involving patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 adult patients were treated with infliximab at doses similar to those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65%-10.6%]. There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03%-7.0%]). The majority of the malignancies developed in the lung or head and neck.

A population-based retrospective cohort study found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age.

In addition, post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with infliximab with the vast majority of cases occurring in Crohn's disease and ulcerative colitis, and most of whom were adolescent or young adult males.

Heart failure

In a Phase II study aimed at evaluating infliximab in congestive heart failure (CHF), higher incidence of mortality due to worsening of heart failure were seen in patients treated with infliximab, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction ≤35%) were treated with 3 infusions of infliximab 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with infliximab (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients on placebo.

There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.

Hepatobiliary events

In clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab without progression to severe hepatic injury. Elevations of ALT >5 x Upper Limit of Normal (ULN) have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving infliximab than in controls, both when infliximab was given as monotherapy and when it was used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of infliximab, or modification of concomitant therapy. In post-marketing surveillance, cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving infliximab.

Table 2

Proportion of patients with increased ALT activity in clinical studies

1 Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate.

2 Placebo patients in the 2 Phase III studies in Crohn's disease, ACCENT I and ACCENT II, received an initial dose of 5 mg/kg infliximab at study start and were on placebo in the maintenance phase. Patients who were randomised to the placebo maintenance group and then later crossed over to infliximab are included in the infliximab group in the ALT analysis. In the Phase IIIb trial in Crohn's disease, SONIC, placebo patients received AZA 2.5 mg/kg/day as active control in addition to placebo infliximab infusions.

3 Number of patients evaluated for ALT.

4 Median follow-up is based on patients treated.

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

Approximately half of infliximab-treated patients in clinical studies who were ANA negative at baseline developed a positive ANA during the study compared with approximately one fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% of infliximab-treated patients compared with 0% of placebo-treated patients. At the last evaluation, 57% of infliximab-treated patients remained anti-dsDNA positive. Reports of lupus and lupus-like syndromes, however, remain uncommon.

Paediatric population

Juvenile rheumatoid arthritis patients

Infliximab was studied in a clinical study in 120 patients (age range: 4-17 years old) with active juvenile rheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as 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 occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kg compared with 17.5% of patients receiving 6 mg/kg. 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 which were among the 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.

Immunogenicity

Antibodies to infliximab developed in 38% of patients receiving 3 mg/kg compared with 12% of patients receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6 mg/kg group.

Infections

Infections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of children receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 weeks.

Paediatric Crohn's disease patients

The following adverse events were reported more commonly in paediatric Crohn's disease patients in the REACH study than in adult Crohn's disease patients: anaemia (10.7%), blood in stool (9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). Other special considerations are discussed below.

Infusion-related reactions

In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions. There were no serious infusion reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.

Immunogenicity

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

Infections

In the REACH study, infections were reported in 56.3% of randomised subjects treated with infliximab. Infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.

Paediatric ulcerative colitis patients

Overall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse event was worsening of ulcerative colitis, the incidence of which was higher in patients on the q12 week vs. the q8 week dosing regimen.

Infusion-related reactions

Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were

Preclinical safety data

Infliximab does not cross react with TNFα from species other than human and chimpanzees. Therefore, conventional preclinical safety data with infliximab are limited. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. In a fertility and general reproductive function study, the number of pregnant mice was reduced following administration of the same analogous antibody. It is not known whether this finding was due to effects on the males and/or the females. In a 6-month repeated dose toxicity study in mice, using the same analogous antibody against mouse TNFα, crystalline deposits were observed on the lens capsule of some of the treated male mice. No specific ophthalmologic examinations have been performed in patients to investigate the relevance of this finding for humans.

Long-term studies have not been performed to evaluate the carcinogenic potential of infliximab. Studies in mice deficient in TNFα demonstrated no increase in tumours when challenged with known tumour initiators and/or promoters.

Therapeutic indications

Фламмэгис is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.

Фламмэгис is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.

Фламмэгис is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.

Фламмэгис is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

Фламмэгис is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.

Фламмэгис, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.

Фламмэгис is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.

Фламмэгис is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.

Фламмэгис is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. Фламмэгис should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

Rheumatoid arthritis

Фламмэгис, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in:

- adult patients with active disease when the response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate.

- adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.

In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated.

Adult Crohn's disease

Фламмэгис is indicated for:

- treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.

- treatment of fistulising, active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).

Paediatric Crohn's disease

Фламмэгис is indicated for treatment of severe, active Crohn's disease in children and adolescents aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. Infliximab has been studied only in combination with conventional immunosuppressive therapy.

Ulcerative colitis

Фламмэгис is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

Paediatric ulcerative colitis

Фламмэгис is indicated for treatment of severely 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-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.

Ankylosing spondylitis

Фламмэгис is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy.

Psoriatic arthritis

Фламмэгис is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate.

Фламмэгис should be administered

- in combination with methotrexate

- or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated.

Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease.

Psoriasis

Фламмэгис is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen ultra-violet A (PUVA).

Pharmacotherapeutic group

Pharmacodynamic properties

Elevated concentrations of TNFα have been found in involved tissues and fluids of patients with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. In rheumatoid arthritis, treatment with Фламмэгис reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)] and tissue degradation [matrix metalloproteinase (MMP) 1 and 3]. In Crohn’s disease, treatment with Фламмэгис reduced infiltration of inflammatory cells and TNFα production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNFα and interferon. After treatment with Фламмэгис, patients with rheumatoid arthritis or Crohn’s disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline. Peripheral blood lymphocytes from Фламмэгис-treated patients showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients. In psoriatic arthritis, treatment with Фламмэгис resulted in a reduction in the number of T-cells and blood vessels in the synovium and psoriatic skin lesions as well as a reduction of macrophages in the synovium. In plaque psoriasis, Фламмэгис treatment may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which Фламмэгис exerts its clinical effects is unknown.

Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB02

Фламмэгис is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Mechanism of action

Infliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of TNFα but not to lymphotoxin α (TNFβ).

Pharmacodynamic effects

Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximab prevented disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity.

Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients and correlate with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction and tissue degradation. After infliximab treatment, patients exhibited decreased levels of serum interleukin 6 (IL-6) and C-reactive protein (CRP), and increased haemoglobin levels in rheumatoid arthritis patients with reduced haemoglobin levels, compared with baseline. Peripheral blood lymphocytes further showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared with untreated patients' cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermal inflammation and normalisation of keratinocyte differentiation in psoriatic plaques. In psoriatic arthritis, short term treatment with infliximab reduced the number of T-cells and blood vessels in the synovium and psoriatic skin.

Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration of infliximab, revealed a substantial reduction in detectable TNFα. Infliximab treatment of Crohn's disease patients was also associated with a substantial reduction of the commonly elevated serum inflammatory marker, CRP. Total peripheral white blood cell counts were minimally affected in infliximab-treated patients, although changes in lymphocytes, monocytes and neutrophils reflected shifts towards normal ranges. Peripheral blood mononuclear cells (PBMC) from infliximab-treated patients showed undiminished proliferative responsiveness to stimuli compared with untreated patients, and no substantial changes in cytokine production by stimulated PBMC were observed following treatment with infliximab. Analysis of lamina propria mononuclear cells obtained by biopsy of the intestinal mucosa showed that infliximab treatment caused a reduction in the number of cells capable of expressing TNFα and interferon γ. Additional histological studies provided evidence that treatment with infliximab reduces the infiltration of inflammatory cells into affected areas of the intestine and the presence of inflammation markers at these sites. Endoscopic studies of intestinal mucosa have shown evidence of mucosal healing in infliximab-treated patients.

Clinical efficacy and safety

Adult rheumatoid arthritis

The efficacy of infliximab was assessed in two multicentre, randomised, double-blind, pivotal clinical studies: ATTRACT and ASPIRE. In both studies concurrent use of stable doses of folic acid, oral corticosteroids (≤10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.

The primary endpoints were the reduction of signs and symptoms as assessed by the American College of Rheumatology criteria (ACR20 for ATTRACT, landmark ACR-N for ASPIRE), the prevention of structural joint damage, and the improvement in physical function. A reduction in signs and symptoms was defined to be at least a 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following 5 criteria: (1) evaluator's global assessment, (2) patient's global assessment, (3) functional/disability measure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rate or C-reactive protein. ACR-N uses the same criteria as the ACR20, calculated by taking the lowest percent improvement in swollen joint count, tender joint count, and the median of the remaining 5 components of the ACR response. Structural joint damage (erosions and joint space narrowing) in both hands and feet was measured by the change from baseline in the total van der Heijde-modified Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) was used to measure patients' average change from baseline scores over time, in physical function.

The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% of patients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab at weeks 0, 2 and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexate doses (median 15 mg/wk) for 6 months prior to enrolment and were to remain on stable doses throughout the study.

Results from week 54 (ACR20, total van der Heijde-modified Sharp score and HAQ) are shown in Table 3. Higher degrees of clinical response (ACR50 and ACR70) were observed in all infliximab groups at 30 and 54 weeks compared with methotrexate alone.

A reduction in the rate of the progression of structural joint damage (erosions and joint space narrowing) was observed in all infliximab groups at 54 weeks (Table 3).

The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatment withdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone group cannot be defined.

Table 3

Effects on ACR20, Structural Joint Damage and Physical Function at week 54, ATTRACT

The ASPIRE study evaluated responses at 54 weeks in 1,004 methotrexate naive patients with early (≤3 years disease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tender joint count of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk by week 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter. Results from week 54 are shown in Table 4.

After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statistically significantly greater improvement in signs and symptoms compared to methotrexate alone as measured by the proportion of patients achieving ACR20, 50 and 70 responses.

In ASPIRE, more than 90% of patients had at least two evaluable X-rays. Reduction in the rate of progression of structural damage was observed at weeks 30 and 54 in the infliximab + methotrexate groups compared to methotrexate alone.

Table 4

Effects on ACRn, Structural Joint Damage and Physical Function at week 54, ASPIRE

Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the START study. START was a randomised, multicentre, double-blind, 3-arm, parallel-group safety study. In one of the study arms (group 2, n=329), patients with an inadequate response were allowed to dose titrate with 1.5 mg/kg increments from 3 up to 9 mg/kg. The majority (67%) of these patients did not require any dose titration. Of the patients who required a dose titration, 80% achieved clinical response and the majority (64%) of these required only one adjustment of 1.5 mg/kg.

Adult Crohn's disease

Induction treatment in moderately to severely active Crohn's disease

The efficacy of a single dose treatment with infliximab was assessed in 108 patients with active Crohn's disease (Crohn's Disease Activity Index (CDAI) >220 ≤400) in a randomised, double-blinded, placebo-controlled, dose-response study. Of these 108 patients, 27 were treated with the recommended dosage of infliximab 5 mg/kg. All patients had experienced an inadequate response to prior conventional therapies. Concurrent use of stable doses of conventional therapies was permitted, and 92% of patients continued to receive these therapies.

The primary endpoint was the proportion of patients who experienced a clinical response, defined as a decrease in CDAI by >70 points from baseline at the 4-week evaluation and without an increase in the use of medicinal products or surgery for Crohn's disease. Patients who responded at week 4 were followed to week 12. Secondary endpoints included the proportion of patients in clinical remission at week 4 (CDAI <150) and clinical response over time.

At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patients receiving a 5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients (p <0.001). Also at week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission (CDAI <150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within 2 weeks, with a maximum response at 4 weeks. At the last observation at 12 weeks, 13/27 (48%) of infliximab-treated patients were still responding.

Maintenance treatment in moderately to severely active Crohn's disease in adults

The efficacy of repeated infusions with infliximab was studied in a 1-year clinical study (ACCENT I).

A total of 573 patients with moderately to severely active Crohn's disease (CDAI >220 ≤400) received a single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were defined as having severe disease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants) corresponding to the population defined in the indication. At week 2, all patients were assessed for clinical response and randomised to one of 3 treatment groups; a placebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenance group. All 3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.

Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients were classified as week-2 responders and were included in the primary analysis (see Table 5). Among patients classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and 42% (68/163) in the infliximab group achieved clinical response by week 6. There was no difference between groups in the number of late responders thereafter.

The co-primary endpoints were the proportion of patients in clinical remission (CDAI <150) at week 30 and time to loss of response through week 54. Corticosteroid tapering was permitted after week 6

Table 5

Effects on response and remission rate, data from ACCENT I (Week-2 responders)

Beginning at week 14, patients who had responded to treatment, but subsequently lost their clinical benefit, were allowed to cross over to a dose of infliximab 5 mg/kg higher than the dose to which they were originally randomised. Eighty nine percent (50/56) of patients who lost clinical response on infliximab 5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab 10 mg/kg.

Improvements in quality of life measures, a reduction in disease-related hospitalisations and corticosteroid use were seen in the infliximab maintenance groups compared with the placebo maintenance group at weeks 30 and 54.

Infliximab with or without AZA was assessed in a randomised, double-blind, active comparator study (SONIC) of 508 adult patients with moderate to severe Crohn's disease (CDAI >220 ≤450) who were naive to biologics and immunosuppressants and had a median disease duration of 2.3 years. At baseline 27.4% of patients were receiving systemic corticosteroids, 14.2% of patients were receiving budesonide, and 54.3% of patients were receiving 5-ASA compounds. Patients were randomised to receive AZA monotherapy, infliximab monotherapy, or infliximab plus AZA combination therapy. Infliximab was administered at a dose of 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks. AZA was given at a dose of 2.5 mg/kg daily.

The primary endpoint of the study was corticosteroid-free clinical remission at week 26, defined as patients in clinical remission (CDAI of <150) who, for at least 3 weeks, had not taken oral systemic corticosteroids (prednisone or equivalent) or budesonide at a dose >6 mg/day. For results see Table 6. The proportions of patients with mucosal healing at week 26 were significantly greater in the infliximab plus AZA combination (43.9%, p<0.001) and infliximab monotherapy groups (30.1%, p=0.023) compared to the AZA monotherapy group (16.5%).

Table 6

Percent of patients achieving corticosteroid-free clinical remission at Week 26, SONIC

Similar trends in the achievement of corticosteroid-free clinical remission were observed at week 50. Furthermore, improved quality of life as measured by IBDQ was observed with infliximab.

Induction treatment in fistulising active Crohn's disease

The efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patients with fistulising Crohn's disease who had fistulae that were of at least 3 months' duration. Thirty one of these patients were treated with infliximab 5 mg/kg. Approximately 93% of the patients had previously received antibiotic or immunosuppressive therapy.

Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued to receive at least one of these therapies. Patients received three doses of either placebo or infliximab at weeks 0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportion of patients who experienced a clinical response, defined as >50% reduction from baseline in the number of fistulae draining upon gentle compression on at least two consecutive visits (4 weeks apart), without an increase in the use of medicinal products or surgery for Crohn's disease.

Sixty eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved a clinical response vs. 26% (8/31) placebo-treated patients (p=0.002). The median time to onset of response in the infliximab-treated group was 2 weeks. The median duration of response was 12 weeks. Additionally, closure of all fistulae was achieved in 55% of infliximab-treated patients compared with 13% of placebo-treated patients (p=0.001).

Maintenance treatment in fistulising active Crohn's disease

The efficacy of repeated infusions with infliximab in patients with fistulising Crohn's disease was studied in a 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab 5 mg/kg at week 0, 2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominal fistulae, 9% had rectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patients were assessed for clinical response and randomised to receive either placebo or 5 mg/kg infliximab every 8 weeks through week 46.

Week-14 responders (195/282) were analysed for the primary endpoint, which was time from randomisation to loss of response (see Table 7). Corticosteroid tapering was permitted after week 6.

Table 7

Effects on response rate, data from ACCENT II (Week-14 responders)

Beginning at week 22, patients who initially responded to treatment and subsequently lost their response were eligible to cross over to active re-treatment every 8 weeks at a dose of infliximab 5 mg/kg higher than the dose to which they were originally randomised. Among patients in the infliximab 5 mg/kg group who crossed over because of loss of fistula response after week 22, 57% (12/21) responded to re-treatment with infliximab 10 mg/kg every 8 weeks.

There was no significant difference between placebo and infliximab for the proportion of patients with sustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscesses and urinary tract infection or for number of newly developed fistulas during treatment.

Maintenance therapy with infliximab every 8 weeks significantly reduced disease-related hospitalisations and surgeries compared with placebo. Furthermore, a reduction in corticosteroid use and improvements in quality of life were observed.

Adult ulcerative colitis

The safety and efficacy of infliximab were assessed in two (ACT 1 and ACT 2) randomised, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore >2) with an inadequate response to conventional therapies [oral corticosteroids, aminosalicylates and/or immunomodulators (6-MP, AZA)]. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. In both studies, patients were randomised to receive either placebo, 5 mg/kg infliximab, or 10 mg/kg infliximab at weeks 0, 2, 6, 14 and 22, and in ACT 1 at weeks 30, 38 and 46. Corticosteroid taper was permitted after week 8.

Table 8

Effects on clinical response, clinical remission and mucosal healing at Weeks 8 and 30. Combined data from ACT 1 & 2

Pharmacokinetic properties

In adults, single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. Pharmacokinetic results for single doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis, 5 mg/kg in Crohn’s disease, and 3 mg/kg to 5 mg/kg in plaque psoriasis indicate that the median terminal half-life of infliximab is 7.7 to 9.5 days.

Following an initial dose of Фламмэгис, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4-or 8 week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of Фламмэгис, median infliximab serum concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximab concentrations were not detectable (<0.1 mcg/mL) in patients who became positive for antibodies to infliximab. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.

Infliximab pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients with Crohn’s disease or ulcerative colitis following the administration of 5 mg/kg infliximab.

Population pharmacokinetic analysis showed that in children with juvenile rheumatoid arthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg Фламмэгис and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg Фламмэгис, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of Фламмэгис.

Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose proportional increases in the maximum serum concentration (Cmax) and area under the concentration-time curve (AUC). The volume of distribution at steady state (median Vd of 3.0 to 4.1 litres) was not dependent on the administered dose and indicated that infliximab is predominantly distributed within the vascular compartment. No time-dependency of the Pharmacokinetics was observed. The elimination pathways for infliximab have not been characterised. Unchanged infliximab was not detected in urine. No major age- or weight-related differences in clearance or volume of distribution were observed in rheumatoid arthritis patients. The pharmacokinetics of infliximab in elderly patients has not been studied. Studies have not been performed in patients with liver or renal disease.

At single doses of 3, 5, or 10 mg/kg, the median Cmax values were 77, 118 and 277 micrograms/mL, respectively. The median terminal half-life at these doses ranged from 8 to 9.5 days. In most patients, infliximab could be detected in the serum for at least 8 weeks after the recommended single dose of 5 mg/kg for Crohn's disease and the rheumatoid arthritis maintenance dose of 3 mg/kg every 8 weeks.

Repeated administration of infliximab (5 mg/kg at 0, 2 and 6 weeks in fistulising Crohn´s disease, 3 or 10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in serum after the second dose. No further clinically relevant accumulation was observed. In most fistulising Crohn's disease patients, infliximab was detected in serum for 12 weeks (range 4-28 weeks) after administration of the regimen.

Paediatric population

Population pharmacokinetic analysis based on data obtained from patients with ulcerative colitis (N=60), Crohn's disease (N=112), juvenile rheumatoid arthritis (N=117) and Kawasaki disease (N=16) with an overall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on body weight in a non-linear way. Following administration of 5 mg/kg infliximab every 8 weeks, the predicted median steady-state infliximab exposure (area under concentration-time curve at steady state, AUCss) in paediatric patients aged 6 years to 17 years was approximately 20% lower than the predicted median steady-state drug exposure in adults. The median AUCss in paediatric patients aged 2 years to less than 6 years was predicted to be approximately 40% lower than that in adults, although the number of patients supporting this estimate is limited.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the "PRECAUTIONS" Section

Patients treated with Фламмэгис are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.

Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease.

Treatment with Фламмэгис should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients:

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
• with underlying conditions that may predispose them to infection.

Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving Фламмэгис, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with Фламмэгис during treatment for latent tuberculosis.

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating Фламмэгис and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating Фламмэгис, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG).

Anti-tuberculosis therapy should also be considered prior to initiation of Фламмэгис in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Tuberculosis should be strongly considered in patients who develop a new infection during Фламмэгис treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Фламмэгис, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with Фламмэгис.

Фламмэгис should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Фламмэгис should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤18 years of age), including Фламмэгис. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of Фламмэгис clinical trials, 5 patients developed lymphomas among 5707 patients treated with Фламмэгис (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In rheumatoid arthritis patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with Crohn’s disease, rheumatoid arthritis or plaque psoriasis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including Фламмэгис. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with the immunosuppressants azathioprine or 6mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported Фламмэгис cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF-blockers or TNF-blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use Фламмэгис alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with Фламмэгис monotherapy from the clinical trial data.

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including Фламмэгис. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naive patients or the general population, particularly those over 60 years of age. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with Фламмэгис.

In the controlled portions of clinical trials of some TNF-blocking agents including Фламмэгис, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients. During the controlled portions of Фламмэгис trials in patients with moderately to severely active rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 Фламмэгис-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among Фламмэгис-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for Фламмэгис-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among Фламмэгис-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected.

In a clinical trial exploring the use of Фламмэгис in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in Фламмэгис-treated patients compared with control patients. All patients had a history of heavy smoking. Prescribers should exercise caution when considering the use of Фламмэгис in patients with moderate to severe COPD.

Psoriasis patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for Фламмэгис, NMSCs were more common in patients with previous phototherapy.

The potential role of TNF-blocking therapy in the development of malignancies is not known. Rates in clinical trials for Фламмэгис cannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering Фламмэгис treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving Фламмэгис.

Use of TNF blockers, including Фламмэгис, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including Фламмэгис. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.

Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving Фламмэгис. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of Фламмэгис; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, Фламмэгис should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving Фламмэгис without progression to severe hepatic injury.

Фламмэгис has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of Фламмэгис in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg Фламмэгис, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking Фламмэгис. There have also been post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer Фламмэгис to patients with heart failure, they should be closely monitored during therapy, and Фламмэгис should be discontinued if new or worsening symptoms of heart failure appear.

Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving Фламмэгис. The causal relationship to Фламмэгис therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with Фламмэгис who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on Фламмэгис. Discontinuation of Фламмэгис therapy should be considered in patients who develop significant hematologic abnormalities.

Фламмэгис has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include anaphylaxis, urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of Фламмэгис infusion.

However, in some cases, serum sickness-like reactions have been observed in patients after initial Фламмэгис therapy (i.e., as early as after the second dose), and when Фламмэгис therapy was reinstituted following an extended period without Фламмэгис treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.

Фламмэгис should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction.

In rheumatoid arthritis, Crohn’s disease and psoriasis clinical trials, re-administration of Фламмэгис after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment. In general, the benefit-risk of re-administration of Фламмэгис after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where Фламмэгис maintenance therapy for psoriasis is interrupted, Фламмэгис should be reinitiated as a single dose followed by maintenance therapy.

Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of Фламмэгис infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of Фламмэгис. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms.

Фламмэгис and other agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barre syndrome. Prescribers should exercise caution in considering the use of Фламмэгис in patients with these neurologic disorders and should consider discontinuation of Фламмэгис if these disorders develop.

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of Фламмэгис and anakinra is not recommended.

In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of Фламмэгис and abatacept is not recommended.

There is insufficient information regarding the concomitant use of Фламмэгис with other biological therapeutics used to treat the same conditions as Фламмэгис. The concomitant use of Фламмэгис with these biologics is not recommended because of the possibility of an increased risk of infection.

Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

Treatment with Фламмэгис may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Фламмэгис, treatment should be discontinued.

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with Фламмэгис is not recommended.

Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab. Infliximab is known to cross the placenta and has been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Фламмэгис.

It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating Фламмэгис therapy. The interval between vaccination and initiation of Фламмэгис therapy should be in accordance with current vaccination guidelines.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Patients or their caregivers should be advised of the potential benefits and risks of Фламмэгис. Physicians should instruct their patients to read the Medication Guide before starting Фламмэгис therapy and to reread it each time they receive an infusion. It is important that the patient’s overall health be assessed at each treatment visit and that any questions resulting from the patient’s or their caregiver’s reading of the Medication Guide be discussed.

Inform patients that Фламмэгис may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctors if they develop any symptoms of an infection, including tuberculosis and reactivation of hepatitis B virus infections. Patients should be counseled about the risk of lymphoma and other malignancies while receiving Фламмэгис.

Advise patients to report any signs of new or worsening medical conditions such as heart disease, neurological disease, or autoimmune disorders. Advise patients to report any symptoms of a cytopenia such as bruising, bleeding or persistent fever.

The significance of the results of nonclinical studies for human risk is unknown. A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFα to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn’s disease. Results indicated that cV1q did not cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.

It is not known whether Фламмэгис can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Фламмэгис should be given to a pregnant woman only if clearly needed. Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with Фламмэгис. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies.

As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants. Cases of agranulocytosis in infants exposed in utero have also been reported.

It is not known whether Фламмэгис is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from Фламмэгис, women should not breastfeed their infants while taking Фламмэгис. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of Фламмэгис have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn’s disease or ulcerative colitis. However, Фламмэгис has not been studied in children with Crohn’s disease or ulcerative colitis <6 years of age.

Фламмэгис is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.

Фламмэгис has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn’s disease. The longer term (greater than 1 year) safety and effectiveness of Фламмэгис in pediatric Crohn’s disease patients have not been established in clinical trials.

The safety and effectiveness of Фламмэгис for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of Фламмэгис in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older. The effectiveness of Фламмэгис in inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.

In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when Фламмэгис is used in combination with other immunosuppressants.

The longer term (greater than 1 year) safety and effectiveness of Фламмэгис in pediatric ulcerative colitis patients have not been established in clinical trials.

The safety and efficacy of Фламмэгис in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.

Doses of 3 mg/kg Фламмэгис or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg Фламмэгис at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with Фламмэгис for up to 2 years in a companion extension study.

The study failed to establish the efficacy of Фламмэгис in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults.

A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg Фламмэгис was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg Фламмэгис group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg Фламмэгис group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received Фламмэгис by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg Фламмэгис compared with 12% (6/49) of patients who received 6 mg/kg.

A total of 68% (41/60) of patients who received 3 mg/kg Фламмэгис in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg Фламмэгис in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.

In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received Фламмэгис, compared to younger patients-although the incidence of serious adverse reactions in patients aged 65 or older was higher in both Фламмэгис and control groups compared to younger patients. In Crohn’s disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections

In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.

Infusion reactions and hypersensitivity

Infliximab has been associated with acute infusion-related reactions, including anaphylactic shock, and delayed hypersensitivity reactions.

Acute infusion reactions including anaphylactic reactions may develop during (within seconds) or within a few hours following infusion. If acute infusion reactions occur, the infusion must be interrupted immediately. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects.

Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions. A low proportion of the infusion reactions was serious allergic reactions. An association between development of antibodies to infliximab and reduced duration of response has also been observed. Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant immunomodulator therapy was more profound in episodically-treated patients than in patients given maintenance therapy. Patients who discontinue immunosuppressants prior to or during infliximab treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given and further Фламмэгис infusions must not be administered.

In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Фламмэгис-free interval. Patients should be advised to seek immediate medical advice if they experience any delayed adverse event. If patients are re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.

Infections

Patients must be monitored closely for infections including tuberculosis before, during and after treatment with Фламмэгис. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with Фламмэгис must not be given if a patient develops a serious infection or sepsis.

Caution should be exercised when considering the use of Фламмэгис in patients with chronic infection or a history of recurrent infections, including concomitant immunosuppressive therapy. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.

Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data show that TNFα is essential for the clearing of intracellular infections. Clinical experience shows that host defence against infection is compromised in some patients treated with infliximab.

It should be noted that suppression of TNFα may mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections and of typical clinical presentation of rare and unusual infections is critical in order to minimise delays in diagnosis and treatment.

Patients taking TNF-blockers are more susceptible to serious infections.

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

Patients who develop a new infection while undergoing treatment with Фламмэгис, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Фламмэгис should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled.

Tuberculosis

There have been reports of active tuberculosis in patients receiving infliximab. It should be noted that in the majority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease.

Before starting treatment with Фламмэгис, all patients must be evaluated for both active and inactive ('latent') tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e. tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

If active tuberculosis is diagnosed, Фламмэгис therapy must not be initiated.

If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Фламмэгис therapy should be very carefully considered.

If inactive ('latent') tuberculosis is diagnosed, treatment for latent tuberculosis must be started with antituberculosis therapy before the initiation of Фламмэгис, and in accordance with local recommendations.

In patients who have several or significant risk factors for tuberculosis and have a negative test for latent tuberculosis, antituberculosis therapy should be considered before the initiation of Фламмэгис.

Use of anti-tuberculosis therapy should also be considered before the initiation of Фламмэгис in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.

Some cases of active tuberculosis have been reported in patients treated with infliximab during and after treatment for latent tuberculosis.

All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after Фламмэгис treatment.

Invasive fungal infections

In patients treated with Фламмэгис, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness, and a physician with expertise in the diagnosis and treatment of invasive fungal infections should be consulted at an early stage when investigating these patients.

Invasive fungal infections may present as disseminated rather than localised disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed taking into account both the risk for severe fungal infection and the risks of antifungal therapy.

For patients who have resided in or travelled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of Фламмэгис treatment should be carefully considered before initiation of Фламмэгис therapy.

Fistulising Crohn's disease

Patients with fistulising Crohn's disease with acute suppurative fistulas must not initiate Фламмэгис therapy until a source for possible infection, specifically abscess, has been excluded.

Hepatitis B (HBV) reactivation

Reactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab, who are chronic carriers of this virus. Some cases have had fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Фламмэгис. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Carriers of HBV who require treatment with Фламмэгис should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Фламмэгис should be stopped and effective antiviral therapy with appropriate supportive treatment should be initiated.

Hepatobiliary events

Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience of infliximab. Isolated cases of liver failure resulting in liver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations >5 times the upper limit of normal develop(s), Фламмэгис should be discontinued, and a thorough investigation of the abnormality should be undertaken.

Concurrent administration of TNF-alpha inhibitor and anakinra

Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of Фламмэгис and anakinra is not recommended.

Concurrent administration of TNF-alpha inhibitor and abatacept

In clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-antagonists alone, without increased clinical benefit. The combination of Фламмэгис and abatacept is not recommended.

Concurrent administration with other biological therapeutics

There is insufficient information regarding the concomitant use of infliximab with other biological therapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab with these biologics is not recommended because of the possibility of an increased risk of infection, and other potential pharmacological interactions.

Switching between biological DMARDs

Care should be taken and patients should continue to be monitored when switching from one biologic to another, since overlapping biological activity may further increase the risk for adverse events, including infection.

Live vaccines/therapeutic infectious agents

In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with Фламмэгис is not recommended.

In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus Calmette-Guérin (BCG) infection has been reported following administration of BCG vaccine after birth. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab.

Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with Фламмэгис.

Autoimmune processes

The relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of an autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Фламмэгис and is positive for antibodies against double-stranded DNA, further treatment with Фламмэгис must not be given.

Neurological events

Use of TNF-blocking agents, including infliximab, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiation of Фламмэгис therapy. Discontinuation of Фламмэгис should be considered if these disorders develop.

Malignancies and lymphoproliferative disorders

In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies including lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During clinical studies of infliximab across all approved indications the incidence of lymphoma in infliximab-treated patients was higher than expected in the general population, but the occurrence of lymphoma was rare. In the post-marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.

In an exploratory clinical study evaluating the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in infliximab-treated patients compared with control patients. All patients had a history of heavy smoking. Caution should be exercised in considering treatment of patients with increased risk for malignancy due to heavy smoking.

With the current knowledge, a risk for the development of lymphomas or other malignancies in patients treated with a TNF-blocking agent cannot be excluded. Caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.

Caution should also be exercised in patients with psoriasis and a medical history of extensive immunosuppressant therapy or prolonged PUVA treatment.

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in patients treated with TNF-blockers cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. The potential risk with the combination of AZA or 6-MP and infliximab should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Фламмэгис cannot be excluded.

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab. Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.

A population-based retrospective cohort study using data from Swedish national health registries found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age. Periodic screening should continue in women treated with Фламмэгис, including those over 60 years of age.

All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. With current data it is not known if infliximab treatment influences the risk for developing dysplasia or colon cancer.

Since the possibility of increased risk of cancer development in patients with newly diagnosed dysplasia treated with infliximab is not established, the risk and benefits to the individual patients must be carefully reviewed and consideration should be given to discontinuation of therapy.

Heart failure

Фламмэгис should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Фламмэгис must not be continued in patients who develop new or worsening symptoms of heart failure.

Haematologic reactions

There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including infliximab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of Фламмэгис therapy should be considered in patients with confirmed significant haematologic abnormalities.

Others

There is limited safety experience of infliximab treatment in patients who have undergone surgical procedures, including arthroplasty. The long half-life of infliximab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Фламмэгис should be closely monitored for infections, and appropriate actions should be taken.

Failure to respond to treatment for Crohn's disease may indicate the presence of a fixed fibrotic stricture that may require surgical treatment. There is no evidence to suggest that infliximab worsens or causes fibrotic strictures.

Special populations

Elderly (>65 years)

The incidence of serious infections in infliximab-treated patients 65 years and older was greater than in those under 65 years of age. Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly.

Paediatric population

Infections

In clinical studies, infections have been reported in a higher proportion of paediatric patients compared to adult patients.

Vaccinations

It is recommended that paediatric patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating Фламмэгис therapy.

Malignancies and lymphoproliferative disorders

Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-blockers cannot be excluded.

Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. The potential risk with the combination of AZA or 6-MP and infliximab should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Фламмэгис cannot be excluded.

Effects on ability to drive and use machines

Фламмэгис may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of Фламмэгис.

Dosage (Posology) and method of administration

The recommended dose of Фламмэгис is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active Crohn’s disease or fistulizing Crohn’s disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue Фламмэгис in these patients.

The recommended dose of Фламмэгис for pediatric patients 6 years and older with moderately to severely active Crohn’s disease is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.

The recommended dose of Фламмэгис is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active ulcerative colitis.

The recommended dose of Фламмэгис for pediatric patients 6 years and older with moderately to severely active ulcerative colitis is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.

The recommended dose of Фламмэгис is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active rheumatoid arthritis. Фламмэгис should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses.

The recommended dose of Фламмэгис is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active ankylosing spondylitis.

The recommended dose of Фламмэгис is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of psoriatic arthritis. Фламмэгис can be used with or without methotrexate.

The recommended dose of Фламмэгис is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) plaque psoriasis.

Prior to initiating Фламмэгис and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.

Adverse effects during administration of Фламмэгис have included flu-like symptoms, headache, dyspnea, hypotension, transient fever, chills, gastrointestinal symptoms, and skin rashes. Anaphylaxis might occur at any time during Фламмэгис infusion. Approximately 20% of Фламмэгис-treated patients in all clinical trials experienced an infusion reaction compared with 10% of placebo-treated patients. Prior to infusion with Фламмэгис, premedication may be administered at the physician’s discretion. Premedication could include antihistamines (anti-H1 +/-anti-H2), acetaminophen and/or corticosteroids.

During infusion, mild to moderate infusion reactions may improve following slowing or suspension of the infusion, and upon resolution of the reaction, reinitiation at a lower infusion rate and/or therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these interventions, Фламмэгис should be discontinued.

During or following infusion, patients who have severe infusion-related hypersensitivity reactions should be discontinued from further Фламмэгис treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of the reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs.

Фламмэгис is intended for use under the guidance and supervision of a physician. The reconstituted infusion solution should be prepared by a trained medical professional using aseptic technique by the following procedure:

1. Calculate the dose, total volume of reconstituted Фламмэгис solution required and the number of Фламмэгис vials needed. Each Фламмэгис vial contains 100 mg of the infliximab antibody.
2. Reconstitute each Фламмэгис vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present.
3. Dilute the total volume of the reconstituted Фламмэгис solution dose to 250 mL with sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted Фламмэгис from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Do not dilute the reconstituted Фламмэгис solution with any other diluent. Slowly add the total volume of reconstituted Фламмэгис solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL.
4. The Фламмэгис infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 £gm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored for reuse.
5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of Фламмэгис with other agents. Фламмэгис should not be infused concomitantly in the same intravenous line with other agents.
6. Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.

Фламмэгис treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. Фламмэгис should be administered intravenously. Фламмэгис infusions should be administered by qualified healthcare professionals trained to detect any infusion-related issues. Patients treated with Фламмэгис should be given the package leaflet and the patient alert card.

During Фламмэгис treatment, other concomitant therapies, e.g. corticosteroids and immunosuppressants should be optimised.

Posology

Adults (>18 years)

Rheumatoid arthritis

3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Фламмэгис must be given concomitantly with methotrexate.

Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a patient has an inadequate response or loses response after this period, consideration may be given to increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.

Moderately to severely active Crohn's disease

5 mg/kg given as an intravenous infusion followed by an additional 5 mg/kg infusion 2 weeks after the first infusion. If a patient does not respond after 2 doses, no additional treatment with infliximab should be given. Available data do not support further infliximab treatment, in patients not responding within 6 weeks of the initial infusion.

In responding patients, the alternative strategies for continued treatment are:

- Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed by infusions every 8 weeks or

- Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see 'Re-administration' below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

Fistulising, active Crohn's disease

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusions at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given.

In responding patients, the alternative strategies for continued treatment are:

- Maintenance: Additional infusions of 5 mg/kg every 8 weeks or

- Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed by infusions of 5 mg/kg every 8 weeks (see 'Re-administration' below and section 4.4).

Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

In Crohn's disease, experience with re-administration if signs and symptoms of disease recur is limited and comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking.

Ulcerative colitis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.

Ankylosing spondylitis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2 doses), no additional treatment with infliximab should be given.

Psoriatic arthritis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.

Psoriasis

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.

Re-administration for Crohn's disease and rheumatoid arthritis

If the signs and symptoms of disease recur, infliximab can be re-administered within 16 weeks following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after infliximab-free intervals of less than 1 year. The safety and efficacy of re-administration after an infliximab-free interval of more than 16 weeks has not been established. This applies to both Crohn's disease patients and rheumatoid arthritis patients.

Re-administration for ulcerative colitis

The safety and efficacy of re-administration, other than every 8 weeks, has not been established.

Re-administration for ankylosing spondylitis

The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established.

Re-administration for psoriatic arthritis

The safety and efficacy of re-administration, other than every 8 weeks, has not been established.

Re-administration for psoriasis

Limited experience from re-treatment with one single infliximab dose in psoriasis after an interval of 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared to the initial induction regimen.

Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher incidence of infusion reactions, including serious ones, when compared to 8-weekly maintenance treatment.

Re-administration across indications

In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-induction regimen is not recommended. In this situation, Фламмэгис should be re-initiated as a single dose followed by the maintenance dose recommendations described above.

Elderly (>65 years)

Specific studies of Фламмэгис in elderly patients have not been conducted.8.

Renal and/or hepatic impairment

Фламмэгис has not been studied in these patient populations. No dose recommendations can be made.

Paediatric population

Crohn's disease (6 to 17 years)

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in children and adolescents not responding within the first 10 weeks of treatment.

Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeks may be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefully considered in those patients who show no evidence of additional therapeutic benefit after a change in dosing interval.

The safety and efficacy of Фламмэгис have not been studied in children with Crohn's disease below the age of 6 years.

Ulcerative colitis (6 to 17 years)

5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment.

The safety and efficacy of Фламмэгис have not been studied in children with ulcerative colitis below the age of 6 years.

Psoriasis

The safety and efficacy of Фламмэгис in children and adolescents younger than 18 years for the indication of psoriasis have not been established.

Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis

The safety and efficacy of Фламмэгис in children and adolescents younger than 18 years for the indications of juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established.

Juvenile rheumatoid arthritis

The safety and efficacy of Фламмэгис in children and adolescents younger than 18 years for the indication of juvenile rheumatoid arthritis have not been established.2 but no recommendation on a posology can be made.

Renal and/or hepatic impairment

Фламмэгис has not been studied in these patient populations. No dose recommendations can be made.

Method of administration

Фламмэгис should be administered intravenously over a 2 hour period. All patients administered Фламмэгис are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have occurred previously.

Shortened infusions across adult indications

In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of Фламмэгис (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. If an infusion reaction occurs in association with a shortened infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. Shortened infusions at doses >6 mg/kg have not been studied.

Special precautions for disposal and other handling

1. The dose and the number of Фламмэгис vials have to be calculated. Each Фламмэгис vial contains 100 mg infliximab. The required total volume of reconstituted Фламмэгис solution has to be calculated.

2. Under aseptic conditions, each Фламмэгис vial should be reconstituted with 10 mL of water for injections, using a syringe equipped with a 21-gauge (0.8 mm) or smaller needle. The flip-top from the vial has to be removed and the top has to be wiped with a 70% alcohol swab. The syringe needle should be inserted into the vial through the centre of the rubber stopper and the stream of water for injections directed to the glass wall of the vial. The solution has to be gently swirled by rotating the vial to dissolve the powder. Prolonged or vigorous agitation must be avoided. THE VIAL MUST NOT BE SHAKEN. Foaming of the solution on reconstitution may occur. The reconstituted solution should stand for 5 minutes. The solution should be colourless to light yellow and opalescent. The solution may develop a few fine translucent particles, as infliximab is a protein. The solution must not be used if opaque particles, discolouration, or other foreign particles are present.

3. The required volume of the reconstituted Фламмэгис solution should be diluted to 250 mL with sodium chloride 9 mg/mL (0.9%) solution for infusion. Do not dilute the reconstituted Фламмэгис solution with any other diluent. The dilution can be accomplished by withdrawing a volume of the sodium chloride 9 mg/mL (0.9%) solution for infusion from the 250-mL glass bottle or infusion bag equal to the volume of reconstituted Фламмэгис. The required volume of reconstituted Фламмэгис solution should slowly be added to the 250-mL infusion bottle or bag and gently be mixed.

4. The infusion solution has to be administered over a period of not less than the infusion time recommended. Only an infusion set with an in-line, sterile, non-pyrogenic, low protein-binding filter (pore size 1.2 micrometre or less) should be used. Since no preservative is present, it is recommended that the administration of the solution for infusion is to be started as soon as possible and within 3 hours of reconstitution and dilution. When reconstitution and dilution are performed under aseptic conditions, Фламмэгис infusion solution can be used within 24 hours if stored at 2°C to 8°C. Any unused portion of the infusion solution should not be stored for reuse.

5. Фламмэгис should be visually inspected for particulate matter or discolouration prior to administration. If visibly opaque particles, discolouration or foreign particles are observed it should not be used.

6. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.