Remsima 120 mg Adverse Reactions

Summary of the safety profile: Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical trials with infliximab, 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 (congestive heart failure), 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, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn's disease) and serious infusion reactions (see Precautions).
The safety profile of Remsima subcutaneous formulation from active rheumatoid arthritis (evaluated in 168 and 175 patients for the subcutaneous infliximab group and the intravenous infliximab group, respectively), active Crohn's disease (evaluated in 59 and 38 patients for the subcutaneous infliximab group and the intravenous infliximab group, respectively) and active ulcerative colitis patients (evaluated in 38 and 40 patients for the subcutaneous infliximab group and the intravenous infliximab group, respectively) was overall similar to the safety profile of the intravenous formulation.
Tabulated list of adverse reactions: Table 16 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. (See Table 16.)

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Systemic injection reaction and localised injection site reaction in adult patients administered with Remsima subcutaneous formulation: The safety profile of Remsima subcutaneous formulation in combination with methotrexate was evaluated in a Phase I/III parallel group study in patients with active rheumatoid arthritis. The safety population consisted of 168 patients in the Remsima subcutaneous group and 175 patients in the Remsima intravenous group. For study details, see Pharmacology: Pharmacodynamics under Actions.
The incidence of systemic injection reactions (e.g. rash, pruritus, flushing and oedema) was 1.2 per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 2.1 per 100 patient-years in the Remsima intravenous group who switched to Remsima subcutaneous administration (from Week 30). All systemic injection reactions were mild to moderate.
The incidence of localised injection site reactions (e.g. injection site erythema, pain, pruritus and swelling) was 17.6 per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 21.4 per 100 patient-years in those who switched to Remsima subcutaneous administration (from Week 30). Most of these reactions were mild to moderate and resolved spontaneously without any treatment within a day.
In a Phase I study conducted in patients with active Crohn's disease and active ulcerative colitis, the safety population consisted of 97 patients in the Remsima subcutaneous group (59 patients with active Crohn's disease and 38 patients with active ulcerative colitis) and 78 patients in the Remsima intravenous group (38 patients with active Crohn's disease and 40 patients with active ulcerative colitis). For study details, see Pharmacology: Pharmacodynamics under Actions.
There was no incidence of systemic injection reactions reported during this study. The incidence of localised injection site reactions (e.g. injection site erythema, pain, pruritus, bruising) was 28.1 per 100 patient-years in the Remsima subcutaneous group (from Week 6).
All of these reactions were mild to moderate and mostly resolved spontaneously without any treatment within a few days.
In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema and severe bronchospasm, and seizure have been associated with infliximab intravenous administration (see Precautions). 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.
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 with intravenous infliximab, 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 (see Precautions).
In a 1-year clinical study with repeated infusions of IV infliximab in patients with Crohn's disease (ACCENT I study), the incidence of serum sickness-like reactions was 2.4%.
Immunogenicity: In rheumatoid arthritis patients, the incidence of anti-infliximab antibodies following the subcutaneous infliximab was demonstrated to be not higher than that of the intravenous infliximab and had no significant impact on efficacy (determined by disease activity score in 28 joints [DAS28] and American College of Rheumatology criteria 20 [ACR20]) and the safety profile.
In Crohn's disease and ulcerative colitis patients who received maintenance treatment of subcutaneous infliximab, the antibody incidence was not higher in patients who received subcutaneous infliximab in comparison to those who received intravenous infliximab.
In psoriatic arthritis patients who received 5 mg/kg with and without methotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% of patients receiving methotrexate and in 26% of patients not receiving methotrexate at baseline).
In psoriasis patients treated with intravenous infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab (see Precautions).
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 (see Precautions).
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 (see Precautions).
In post-marketing spontaneous reporting, infections are the most common serious adverse reaction. 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 (see Precautions).
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 (see Precautions).
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 (see Precautions).
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 (see Precautions).
Heart failure: In a Phase II study aimed at evaluating infliximab in 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 17). 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 (see Precautions). (See Table 17.)

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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 (see Precautions).
Other special populations: Elderly: In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab plus methotrexate-treated patients 65 years and older (11.3%) than in those under 65 years of age (4.6%). In patients treated with methotrexate alone, the incidence of serious infections was 5.2% in patients 65 years and older compared to 2.7% in patients under 65 (see Precautions).
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.