Adverse reactions : תופעות לוואי

4.8         Undesirable effects

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 section 4.4).

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 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 of intravenous infliximab

Infections and infestations
Very common:              Viral infection (e.g. influenza, herpes virus infection).
Common:                   Bacterial infections (e.g. sepsis, cellulitis, abscess).
Uncommon:                 Tuberculosis, fungal infections (e.g. candidiasis, onychomycosis).
Rare:                     Meningitis, opportunistic infections (such as invasive fungal infections [pneumocystosis, histoplasmosis, aspergillosis, coccidioidomycosis,
cryptococcosis, blastomycosis], bacterial infections [atypical mycobacterial, listeriosis, salmonellosis], and viral infections
[cytomegalovirus]), parasitic infections, hepatitis B reactivation.
Not known:            Vaccine breakthrough infection (after in utero exposure to infliximab)*.
Neoplasms benign, malignant and unspecified (including cysts and polyps) Rare:                  Lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, leukaemia, melanoma, cervical cancer.
Not known:             Hepatosplenic T-cell lymphoma (primarily in adolescents and young adult males with Crohn’s disease and ulcerative colitis), Merkel cell carcinoma, Kaposi’s sarcoma.
Blood and lymphatic system disorders
Common:                Neutropenia, leukopenia, anaemia, lymphadenopathy.
Uncommon:              Thrombocytopenia, lymphopenia, lymphocytosis.
Rare:                  Agranulocytosis (including infants exposed in utero to infliximab), thrombotic thrombocytopenic purpura, pancytopenia, haemolytic anaemia, idiopathic thrombocytopenic purpura.
Immune system disorders
Common:                Allergic respiratory symptom.
Uncommon:              Anaphylactic reaction, lupus-like syndrome, serum sickness or serum sickness-like reaction.
Rare                   Anaphylactic shock, vasculitis, sarcoid-like reaction Metabolism and nutrition disorders
Uncommon:              Dyslipidaemia.
Psychiatric disorders
Common:                Depression, insomnia.
Uncommon:              Amnesia, agitation, confusion, somnolence, nervousness.
Rare:                  Apathy.
Nervous system disorders
Very common:              Headache.
Common:                   Vertigo, dizziness, hypoaesthesia, paraesthesia.
Uncommon:                 Seizure, neuropathy.



Rare:                    Transverse myelitis, central nervous system demyelinating disorders (multiple sclerosis-like disease and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy).
Not known:               Cerebrovascular accidents in close temporal association with infusion.
Eye disorders
Common                   Conjunctivitis
Uncommon                 Keratitis, periorbital oedema, hordeolum
Rare                     Endophthalmitis
Not known                Transient visual loss occurring during or within 2 hours of infusion Cardiac disorders
Common                   Tachycardia, palpitation
Uncommon                 Cardiac failure (new onset or worsening), arrhythmia, syncope, bradycardia
Rare                     Cyanosis, pericardial effusion
Not known                Myocardial ischaemia/myocardial infarction

Vascular disorders
Common                   Hypotension, hypertension, ecchymosis, hot flush, flushing Uncommon                 Peripheral ischaemia, thrombophlebitis, haematoma Rare                     Circulatory failure, petechia, vasospasm
Respiratory, thoracic and mediastinal disorders
Very common            Upper respiratory tract infection, sinusitis
Common                 Lower respiratory tract infection (e.g. bronchitis, pneumonia), dyspnoea, epistaxis
Uncommon               Pulmonary oedema, bronchospasm, pleurisy, pleural effusion Rare                   Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis)
Gastrointestinal disorders
Very common:           Abdominal pain, nausea
Common:                Gastrointestinal haemorrhage, diarrhoea, dyspepsia, gastroesophageal reflux, constipation
Uncommon               Intestinal perforation, intestinal stenosis, diverticulitis, pancreatitis, cheilitis
Hepatobiliary disorders
Common:                Hepatic function abnormal, transaminases increased.
Uncommon:              Hepatitis, hepatocellular damage, cholecystitis.
Rare:                  Autoimmune hepatitis, jaundice.
Not known:             Liver failure.
Skin and subcutaneous tissue disorders
Common:                New onset or worsening psoriasis including pustular psoriasis (primarily palm & soles), urticaria, rash, pruritus, hyperhidrosis, dry skin, fungal dermatitis, eczema, alopecia.
Uncommon:              Bullous eruption, seborrhoea, rosacea, skin papilloma, hyperkeratosis, abnormal skin pigmentation.

Rare:                     Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, furunculosis, linear IgA bullous dermatosis (LABD),
acute generalised exanthematous pustulosis (AGEP), lichenoid reactions.
Not known:                Worsening of symptoms of dermatomyositis.
Musculoskeletal and connective tissue disorders
Common:               Arthralgia, myalgia, back pain.
Renal and urinary disorders
Common:                  Urinary tract infection.
Uncommon:                Pyelonephritis.
Reproductive system and breast disorders
Uncommon:             Vaginitis.
General disorders and administration site conditions
Very common:           Infusion-related reaction, pain.
Common:                Chest pain, fatigue, fever, injection site reaction, chills, oedema.
Uncommon:              Impaired healing.
Rare:                  Granulomatous lesion.
Investigations
Uncommon:                 Autoantibody positive.
Rare:                     Complement factor abnormal.
* including bovine tuberculosis (disseminated BCG infection), see section 4.4 
Description of selected adverse drug reactions

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 Section 5.1.

The incidence rate of systemic injection reactions (e.g. rash, pruritus, flushing and oedema) was 1.2 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 2.1 patients 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 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 Remsima subcutaneous group (from Week 6) and 21.4 patients 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) from Part 1 and Part 2 of the study. For study details, see Section 5.1.

The incidence rate of systemic injection reactions (e.g. nausea and dizziness) was 2.3 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and there were no systemic injection reactions reported in the Remsima intravenous group who switched to Remsima subcutaneous administration (from Week 30).

The incidence rate of localised injection site reactions (e.g. injection site erythema, pain, pruritus, bruising) was 23.3 patients per 100 patient-years in the Remsima subcutaneous group (from Week 6) and 7.5 patients per 100 patient-years in the Remsima intravenous group who switched to Remsima subcutaneous administration (from Week 30). 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 section 4.4). 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 (see section 4.4).

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 (see section 4.4: "Systemic injection reaction/ localised injection site reaction/ hypersensitivity").

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 and anti-infliximab antibodies had no significant impact on efficacy (determined by clinical response and clinical remission according to CDAI score for Crohn's disease patients or partial Mayo score for ulcerative colitis patients) and 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 (see section 4.4).

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 section 4.4).
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 section 4.4).

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 section 4.4).

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 section 4.4).

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 section 4.4).

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 (see section 4.4).

Table 2
Proportion of patients with increased ALT activity in clinical studies using intravenous infliximab
Number of patients3    Median follow-up          ≥ 3 x ULN              ≥ 5 x ULN Indication                                  (wks)4 placebo infliximab placebo infliximab placebo infliximab placebo infliximab Rheumatoid
375       1,087       58.1        58.3      3.2%       3.9%        0.8%      0.9% arthritis1
Crohn’s
324       1,034       53.7        54.0      2.2%       4.9%        0.0%      1.5% disease2
Ulcerative
242        482        30.1        30.8      1.2%       2.5%        0.4%      0.6% colitis
Ankylosing
76        275        24.1       101.9      0.0%       9.5%        0.0%      3.6% spondylitis
Psoriatic
98        191        18.1        39.1      0.0%       6.8%        0.0%      2.1% arthritis
Plaque
281       1,175       16.1        50.1      0.4%       7.7%        0.0%      3.4% psoriasis

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 (see section 4.4).

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 section 4.4).

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at https://sideeffects.health.gov.il.
In addition, you can report to Padagis via the following address: Padagis.co.il