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 studies, 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, paediatric malignancy, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn’s disease), and serious infusion reactions (see section 4.4).

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, adverse reactions are presented in order of decreasing seriousness.

Table 1
Undesirable effects in clinical studies and from post-marketing experience 
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 or 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, hypoesthesia, 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, weight increased1.
Rare:                   Complement factor abnormal.
* including bovine tuberculosis (disseminated BCG infection), see section 4.4 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 reaction

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, 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, 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 (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.

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 (see section 4.4).


In a 1-year clinical study with repeated infusions in patients with Crohn's disease, 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. 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: “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 (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 

Indication              Number of patients3        Median follow-up          ≥ 3 x ULN                ≥ 5 x ULN (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
Paediatric Crohn’s      N/A        139          N/A       53.0        N/A         4.4%         N/A        1.5% disease
Ulcerative colitis      242        482          30.1      30.8        1.2%        2.5%         0.4%       0.6% Paediatric              N/A        60           N/A       49.4        N/A         6.7%         N/A        1.7% Ulcerative colitis
Ankylosing              76         275          24.1      101.9       0.0%        9.5%         0.0%       3.6% spondylitis
Psoriatic arthritis     98         191          18.1      39.1        0.0%        6.8%         0.0%       2.1% Plaque psoriasis   281          1,175   16.1      50.1        0.4%       7.7%        0.0%      3.4% 
1 Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate.
2 Placebo patients in the two Phase III studies in Crohn’s disease, 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, 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).

Additional information on 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 https://sideeffects.health.gov.il/