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Infliximab

Infliximab

The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC please click here: https://www.medicines.org.uk/emc/product/3831

Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11

Introduction and Mechanism of Action

Infliximab is a tumour necrosis factor alpha (TNFα) inhibitor. It is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of TNF α but not to lymphotoxin α (TNF ß). Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. In vivo, infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity. Infliximab is currently approved for the treatment of moderately to severely active and fistulising adult Crohn’s disease, severe active paediatric Crohn’s disease, ulcerative colitis.

Therapeutic indications

Ulcerative Colitis: Infliximab 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 mercaptopurine (MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.

 

Crohn's Disease: Infliximab 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. Infliximab is also indicated for 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).

Dosing, administration

Ulcerative Colitis: The recommended dose regiment of Infliximab is 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.

 

Crohn's Disease: The recommended dose regimen of infliximab to moderately to severely active Crohn’s disease is 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.

 

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

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

The recommended dose is 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. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.

Contraindications

Hypersensitivity to the active substance, to other murine proteins, or to any of the excipients listed in section 6.1 of the full SmPC

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)

Adverse effects

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, hepatosplenic T cell 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.

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.

Blood and lymphatic system disorders

Common:

Neutropenia, leucopenia, 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.

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).

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 of full SmPC

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 infliximab 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: 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 (see section 4.8 of full SmPC).

Laboratory parameters and Monitoring

Monitoring should be undertaken as per local and national guidelines

Interactions with other Drugs

No interaction studies have been performed.

The combination of infliximab with other biological therapeutics used to treat the same conditions, including anakinra and abatacept, is not recommended

It is recommended that live vaccines not be given concurrently with infliximab. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for at least 6 months following birth

It is recommended that therapeutic infectious agents not be given concurrently with infliximab

Special situations

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 treatment.

Pregnancy

Infliximab does not indicate an increase in the rate of malformation in the new born in the first trimester. The available clinical experience is limited. Infliximab should only be used during pregnancy if clearly needed. Infants that may have been exposed to infliximab in utero should not receive live vaccines for at least 6 months and up to 1-year post-partum.

Breast-feeding

It is unknown whether infliximab is excreted in human milk or absorbed systemically after ingestion.

Fertility

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