Infliximab

It is recommended that patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating infliximab therapy. Patients on infliximab may receive concurrent vaccinations, except for live vaccines.

In a subset of 90 adult patients with rheumatoid arthritis from the ASPIRE study a similar proportion of patients in each treatment group (methotrexate plus: placebo [n=17], 3 mg/kg [n=27] or 6 mg/kg infliximab [n=46]) mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine, indicating that infliximab did not interfere with T-cell independent humoral immune responses. However, studies from the published literature in various indications (e.g. rheumatoid arthritis, psoriasis, Crohn's disease) suggest that non-live vaccinations received during treatment with anti-TNF therapies, including infliximab, may elicit a lower immune response than in patients not receiving anti-TNF therapy.

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 infliximab is not recommended.

Infant exposure in utero

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. A twelve month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab. If infant infliximab serum levels are undetectable or infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clear clinical benefit for the individual infant.

Infant exposure via breast milk

Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable.

Therapeutic infectious agents

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 infliximab.

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

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.

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 infliximab and abatacept is not recommended.

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

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 infliximab therapy. Discontinuation of infliximab should be considered if these disorders develop.

The long half-life of infliximab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on infliximab should be closely monitored for infectious and non-infectious complications, and appropriate actions should be taken.

Patients should be tested for HBV infection before initiating treatment with infliximab. 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 infliximab 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, infliximab should be stopped and effective antiviral therapy with appropriate supportive treatment should be initiated.

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 infliximab.

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

The moderate number of prospectively collected pregnancies exposed to infliximab resulting in live birth with known outcomes, including approximately 1,100 exposed during the first trimester, does not indicate an increase in the rate of malformation in the newborn.

Based on an observational study from Northern Europe, an increased risk (OR, 95% CI; p-value) for C-section (1.50, 1.14-1.96; p=0.0032), preterm birth (1.48, 1.05-2.09; p=0.024), small for gestational age (2.79, 1.54-5.04; p=0.0007), and low birth weight (2.03, 1.41-2.94; p=0.0002) was observed in women exposed during pregnancy to infliximab (with or without immunomodulators/corticosteroids, 270 pregnancies) as compared to women exposed to immunomodulators and/or corticosteroids only (6,460 pregnancies). The potential contribution of exposure to infliximab and/or the severity of the underlying disease in these outcomes remains unclear.

Due to its inhibition of TNF_α, infliximab administered during pregnancy could affect normal immune responses in the newborn. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNF_α, there was no indication of maternal toxicity, embryotoxicity or teratogenicity.

The available clinical experience is limited. Infliximab should only be used during pregnancy if clearly needed.

Infliximab crosses the placenta and has been detected in the serum of infants up to 12 months following birth. After in utero exposure to infliximab, infants may be at increased risk of infection, including serious disseminated infection that can become fatal. Administration of live vaccines (e.g., BCG vaccine) to infants exposed to infliximab in utero is not recommended for 12 months after birth. If infant infliximab serum levels are undetectable or infliximab administration was limited to the first trimester of pregnancy, administration of a live vaccine might be considered at an earlier timepoint if there is a clear clinical benefit for the individual infant. Cases of agranulocytosis have also been reported.

Limited data from published literature indicate infliximab has been detected at low levels in human milk at concentrations up to 5% of the maternal serum level. Infliximab has also been detected in infant serum after exposure to infliximab via breast milk. While systemic exposure in a breastfed infant is expected to be low because infliximab is largely degraded in the gastrointestinal tract, the administration of live vaccines to a breastfed infant when the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable. Infliximab could be considered for use during breast-feeding.

Women of childbearing potential

Women of childbearing potential should consider the use of adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last infliximab treatment.

Fertility

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

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

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.

The safety profile of infliximab 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 297, 38 and 105 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) and active ulcerative colitis patients (evaluated in 334, 40 and 140 patients for the subcutaneous infliximab group, the intravenous infliximab group and the placebo group, respectively) was overall similar to the safety profile of the intravenous formulation.

Tabulated list of adverse reactions

Table 1 lists 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 of infliximab:

^* COVID-19 was seen with the SC administered infliximab
^** including bovine tuberculosis (disseminated BCG infection)
¹ At month 12 of the controlled period for adult clinical trials across all indications, the median weight increase was 3.50 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects. The median weight increase for inflammatory bowel disease indications was 4.14 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects, and the median weight increase for rheumatology indications was 3.40 kg for infliximab-treated subjects vs. 3.00 kg for placebo-treated subjects

Description of selected adverse drug reactions

Systemic injection reaction and localised injection site reaction in adult patients administered with infliximab subcutaneous formulation

The safety profile of infliximab 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 infliximab subcutaneous group and 175 patients in the infliximab intravenous group.

The incidence rate of systemic injection reactions (e.g. rash, pruritus, flushing and oedema) was 1.2 patients per 100 patient-years in the infliximab subcutaneous group (from Week 6) and 2.1 patients per 100 patient-years in the infliximab intravenous group who switched to infliximab subcutaneous administration (from Week 30). All systemic injection reactions were mild to moderate.

The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus and swelling) was 17.6 patients per 100 patient-years in the infliximab subcutaneous group (from Week 6) and 21.4 patients per 100 patient-years in those who switched to infliximab subcutaneous administration (from Week 30). Most of these reactions were mild to moderate and resolved spontaneously without any treatment within a day.

In the integrated analysis including a Phase I study conducted in patients with active Crohn's disease and active ulcerative colitis, a Phase III study conducted in patients with active Crohn's disease and a Phase III study conducted in patients with active ulcerative colitis, the safety population consisted of 631 patients in the infliximab subcutaneous group (297 patients with active Crohn's disease and 334 patients with active ulcerative colitis) and 245 patients in the Placebo group (105 patients with active Crohn's disease and 140 patients with active ulcerative colitis).

The incidence rate of systemic injection reactions (e.g. nausea and dizziness) was 3.56 patients per 100 patient-years in the infliximab subcutaneous group.

The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus, bruising) was 8.68 patients per 100 patient-years in the infliximab subcutaneous group. Most 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. 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 been reported, some in close temporal association with infusion of infliximab; cerebrovascular accidents have also been reported 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.

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

Intravenous formulation

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. In rheumatoid arthritis patients who received the recommended repeated treatment dose regimens with methotrexate, 8% of patients developed antibodies to 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 Crohn's disease patients who received maintenance treatment, antibodies to infliximab occurred overall in 3.3% of patients receiving immunosuppressants and in 13.3% of patients not receiving immunosuppressants. The antibody incidence was 2-3 fold higher for patients treated episodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodies to infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reduced efficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab

Because immunogenicity analyses are assay-specific, comparison of the incidence of antibodies to infliximab reported in this section with the incidence of antibodies in other studies may be misleading.

Subcutaneous formulation

In rheumatoid arthritis patients on maintenance treatment, the incidence of anti-infliximab antibodies following the subcutaneous infliximab was demonstrated to be not higher than that of the intravenous infliximab and anti-infliximab antibodies 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 on maintenance treatment, the incidence of anti-infliximab antibodies was not higher in patients who received subcutaneous infliximab in comparison to those who received intravenous infliximab. In Crohn's disease and ulcerative colitis patients, there was a correlation between loss of response and anti-infliximab antibodies, while anti-infliximab antibodies had no significant impact on the safety profile.

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 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.

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 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 using intravenous infliximab:

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.

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.