Article Contents
- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4 . Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBER(S)
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1.NAME OF THE MEDICINAL PRODUCT
Inflectra 100 mg powder for concentrate for solution for infusion
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
One vial contains 100 mg of infliximab*. After reconstitution each mL contains 10 mg of infliximab.
* Infliximab is a chimeric
For the full list of excipients, see section 6.1.
3.PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion
The powder is white.
4. Clinical particulars
4.1Therapeutic indications
Rheumatoid arthritis
Inflectra, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in:
adult patients with active disease when the response to
adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.
In these patient populations, a reduction in the rate of the progression of joint damage, as measured by
Adult Crohn’s disease
Inflectra 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.
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).
Paediatric Crohn’s disease
Inflectra is indicated for treatment of severe, active Crohn’s disease in children and adolescents aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. Infliximab has been studied only in combination with conventional immunosuppressive therapy.
Ulcerative colitis
Inflectra 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
Paediatric ulcerative colitis
Inflectra is indicated for treatment of severely active ulcerative colitis in children and adolescents aged 6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroids and
Ankylosing spondylitis
Inflectra is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy.
Psoriatic arthritis
Inflectra is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate.
Inflectra should be administered
in combination with methotrexate
or alone in patients who show intolerance to methotrexate or for whom methotrexate is
contraindicated.
Infliximab has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by
Psoriasis
Inflectra is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or psoralen
4.2Posology and method of administration
Inflectra treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, inflammatory bowel diseases, ankylosing spondylitis, psoriatic arthritis or psoriasis. Inflectra should be administered intravenously. Inflectra infusions should be administered by qualified healthcare professionals trained to detect any
During Inflectra treatment, other concomitant therapies, e.g. corticosteroids and immunosuppressants should be optimised.
Posology
Adults (≥18 years)
Rheumatoid arthritis
3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
Inflectra must be given concomitantly with methotrexate.
Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a patient has an inadequate response or loses response after this period, consideration may be given to increase the dose
8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If
adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.
Moderately to severely active Crohn’s disease
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. Available data do not support further infliximab treatment, in patients not responding within 6 weeks of the initial infusion.
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
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 (see
section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
Fistulising, active Crohn’s disease
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
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 (see
section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
In Crohn’s disease, experience with
Ulcerative colitis
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.
Ankylosing spondylitis
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 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2 doses), no additional treatment with infliximab should be given.
Psoriatic arthritis
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.
Psoriasis
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. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.
If the signs and symptoms of disease recur, infliximab can be
The safety and efficacy of
The safety and efficacy of
The safety and efficacy of
Limited experience from
Limited experience from
In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a
Elderly patients (≥65 years)
Specific studies of Inflectra in elderly patients have not been conducted. No major
Impaired renal and/or hepatic function
Inflectra has not been studied in these patient populations. No dose recommendations can be made (see section 5.2).
Paediatric population
Crohn’s disease (6 to 17 years)
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 do not support further infliximab treatment in children and adolescents not responding within the first 10 weeks of treatment (see section 5.1).
Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeks may be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefully considered in those patients who show no evidence of additional therapeutic benefit after a change in dosing interval.
The safety and efficacy of Inflectra have not been studied in children with Crohn’s disease below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.
Ulcerative colitis (6 to 17 years)
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 do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1).
The safety and efficacy of Inflectra have not been studied in children with ulcerative colitis below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.
Psoriasis
The safety and efficacy of Inflectra in children and adolescents younger than 18 years in the indication psoriasis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis
The safety and efficacy of Inflectra in children and adolescents younger than 18 years in the indications juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Juvenile rheumatoid arthritis
The safety and efficacy of Inflectra in children and adolescents younger than 18 years in the indication juvenile rheumatoid arthritis have not been established. Currently available data are described in sections 4.8 and 5.2 but no recommendation on a posology can be made.
Impaired renal and/or hepatic function
Inflectra has not been studied in these patient populations. No dose recommendations can be made (see section 5.2).
Method of administration
Inflectra should be administered intravenously over a 2 hour period. All patients administered Inflectra are to be observed for at least
Shortened infusions across adult indications
In carefully selected adult patients who have tolerated at least 3 initial
For preparation and administration instructions, see section 6.6.
4.3Contraindications
Patients with a history of hypersensitivity to infliximab (see section 4.8), to other murine proteins, or to any of the excipients listed in section 6.1.
Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections (see section 4.4).
Patients with moderate or severe heart failure (NYHA class III/IV) (see sections 4.4 and 4.8).
4.4Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the trademark and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Infusion reactions and hypersensitivity
Infliximab has been associated with acute
Acute infusion reactions including anaphylactic reactions may develop during (within seconds) or within a few hours following infusion. If acute infusion reactions occur, the infusion must be interrupted immediately. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be
Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions. A low proportion of the infusion reactions was serious allergic reactions. An association between development of antibodies to infliximab and reduced duration of response has also been observed. Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant immunomodulator therapy was more profound in
In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing
Infections
- Remicade - infliximab
- Flixabi - infliximab
- Remsima - infliximab
Prescription drugs listed. Substance: "Infliximab"
Patients must be monitored closely for infections including tuberculosis before, during and after treatment with Inflectra. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with Inflectra must not be given if a patient develops a serious infection or sepsis.
Caution should be exercised when considering the use of Inflectra in patients with chronic infection or a history of recurrent infections, including concomitant immunosuppressive therapy. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.
Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data show that TNFα is essential for the clearing of intracellular infections. Clinical experience shows that host defence against infection is compromised in some patients treated with infliximab.
It should be noted that suppression of TNFα may mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections and of typical clinical presentation of rare and unusual infections is critical in order to minimise delays in diagnosis and treatment.
Patients taking
Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients treated with 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.
Patients who develop a new infection while undergoing treatment with Inflectra, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Inflectra should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled.
Tuberculosis
There have been reports of active tuberculosis in patients receiving infliximab. It should be noted that in the majority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease.
Before starting treatment with Inflectra, all patients must be evaluated for both active and inactive (‘latent’) tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e. tuberculin skin test and chest
If active tuberculosis is diagnosed, Inflectra therapy must not be initiated (see section 4.3).
If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Inflectra therapy should be very carefully considered.
If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with antituberculosis therapy before the initiation of Inflectra, and in accordance with local recommendations.
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 Inflectra.
Use of
Some cases of active tuberculosis have been reported in patients treated with infliximab during and after treatment for latent tuberculosis.
All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g. persistent cough, wasting/weight loss,
Invasive fungal infections
In patients treated with Inflectra, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness, and a physician with expertise in the diagnosis and treatment of invasive fungal infections should be consulted at an early stage when investigating these patients.
Invasive fungal infections may present as disseminated rather than localised disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed taking into account both the risk for severe fungal infection and the risks of antifungal therapy.
For patients who have resided in or travelled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of Inflectra treatment should be carefully considered before initiation of Inflectra therapy.
Fistulising Crohn’s disease
Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate Inflectra therapy until a source for possible infection, specifically abscess, has been excluded (see section 4.3).
Hepatitis B (HBV) reactivation
Reactivation of hepatitis B has occurred in patients receiving a
Patients should be tested for HBV infection before initiating treatment with Inflectra. 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 Inflectra 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
Hepatobiliary events
Cases of jaundice and
Concurrent administration of
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another
Concurrent administration of
In clinical studies concurrent administration of
Concurrent administration with other biological therapeutics
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.
Switching between biological DMARDs
Care should be taken and patients should continue to be monitored when switching from one biologic to another, since overlapping biological activity may further increase the risk for adverse events, including infection.
Live Vaccines/therapeutic infectious agents
In patients receiving
In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus
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 Inflectra.
Autoimmune processes
The relative deficiency of TNFα caused by
Neurological events
Use of
Malignancies and lymphoproliferative disorders
In the controlled portions of clinical studies of
In an exploratory clinical study evaluating the use of infliximab in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in infliximab- treated patients compared with control patients. All patients had a history of heavy smoking. Caution should be exercised in considering treatment of patients with increased risk for malignancy due to heavy smoking.
With the current knowledge, a risk for the development of lymphomas or other malignancies in patients treated with a
Caution should also be exercised in patients with psoriasis and a medical history of extensive immunosuppressant therapy or prolonged PUVA treatment.
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in patients treated with
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
A
60 years of age. Periodic screening should continue in women treated with Inflectra, including those over 60 years of age.
All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with
Since the possibility of increased risk of cancer development in patients with newly diagnosed dysplasia treated with infliximab is not established, the risk and benefits to the individual patients must be carefully reviewed and consideration should be given to discontinuation of therapy.
Heart failure
Inflectra should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Inflectra must not be continued in patients who develop new or worsening symptoms of heart failure (see sections 4.3 and 4.8).
Haematologic reactions
There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients receiving
Others
There is limited safety experience of infliximab treatment in patients who have undergone surgical procedures, including arthroplasty. The long
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 patients (≥65 years)
The incidence of serious infections in
Paediatric population
Infections
In clinical studies, infections have been reported in a higher proportion of paediatric patients compared to adult patients (see section 4.8).
Vaccinations
It is recommended that paediatric patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating Inflectra therapy.
Malignancies and lymphoproliferative disorders
Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with
cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with
4.5Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
In rheumatoid arthritis, psoriatic arthritis and Crohn's disease patients, there are indications that concomitant use of methotrexate and other immunomodulators reduces the formation of antibodies against infliximab and increases the plasma concentrations of infliximab. However, the results are uncertain due to limitations in the methods used for serum analyses of infliximab and antibodies against infliximab.
Corticosteroids do not appear to affect the pharmacokinetics of infliximab to a clinically relevant extent.
The combination of Inflectra with other biological therapeutics used to treat the same conditions as Inflectra, including anakinra and abatacept, is not recommended (see section 4.4).
It is recommended that live vaccines not be given concurrently with Inflectra. 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 (see section 4.4).
It is recommended that therapeutic infectious agents not be given concurrently with Inflectra (see section 4.4).
4.6Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last Inflectra treatment.
Pregnancy
The moderate number (approximately 450) of prospectively collected pregnancies exposed to infliximab with known outcomes, including a limited number (approximately 230) exposed during the first trimester, does not indicate unexpected effects on pregnancy outcome. Due to its inhibition of TNFα, 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 TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity (see section 5.3).
The available clinical experience is too limited to exclude a risk, and administration of infliximab is therefore not recommended during pregnancy.
Infliximab crosses the placenta and has been detected in the serum of infants up to 6 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 at least 6 months after birth (see sections 4.4 and 4.5). Cases of agranulocytosis have also been reported (see section 4.8).
It is unknown whether infliximab is excreted in human milk or absorbed systemically after ingestion. Because human immunoglobulins are excreted in milk, women must not breast feed for at least
6 months after Inflectra treatment.
Fertility
There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function (see section 5.3).
4.7Effects on ability to drive and use machines
Inflectra may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of Inflectra (see section 4.8).
4.8Undesirable effects
Summary of the safety profile
Upper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical trials, occurring in 25.3% of
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
< 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
Infections and infestations | Viral infection (e.g. influenza, herpes virus infection). |
Very common: | |
Common: | Bacterial infections (e.g. sepsis, cellulitis, abscess). |
Uncommon: | Tuberculosis, fungal infections (e.g. candidiasis). |
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, |
| melanoma, cervical cancer. |
Not known: | Hepatosplenic |
| adults with Crohn’s disease and 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, |
| |
Rare | Anaphylactic shock, vasculitis, |
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 |
| demyelinating disorders (such as |
| 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 |
Uncommon: | skin, fungal dermatitis, eczema, alopecia. |
Bullous eruption, onychomycosis, seborrhoea, rosacea, skin papilloma, | |
| hyperkeratosis, abnormal skin pigmentation. |
Rare: | Toxic epidermal necrolysis, |
| multiforme, furunculosis. |
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: | |
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
An
In a clinical study of patients with rheumatoid arthritis (ASPIRE), 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
In a clinical study of patients with Crohn’s disease (SONIC),
In
Infusion reactions following
A clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safety of
Delayed hypersensitivity
In clinical studies delayed hypersensitivity reactions have been uncommon and have occurred after
There are insufficient data on the incidence of delayed hypersensitivity reactions after
In a
Immunogenicity
Patientswho developed antibodies to infliximab were more likely (approximately
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
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
In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was higher in infliximab plus
In
Malignancies and lymphoproliferative disorders
- Retacrit - Hospira UK Limited
- Levetiracetam hospira - Hospira UK Limited
- Zoledronic acid hospira - Hospira UK Limited
- Taxespira (docetaxel hospira uk limited ) - Hospira UK Limited
- Palonosetron hospira - Hospira UK Limited
- Pemetrexed hospira - Hospira UK Limited
Prescription drugs listed. Manufacturer: "Hospira UK Limited"
In clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patient years, 5 cases of lymphomas and 26
941 patient years.
In
Cases of malignancies, including lymphoma, have also been reported in the
In an exploratory clinical study involving patients with moderate to severe COPD who were either current smokers or
A
In addition,
Heart failure
In a Phase II study aimed at evaluating infliximab in congestive heart failure (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
49 patients on placebo.
There have been
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
Table 2
Proportion of patients with increased ALT activity in clinical studies
|
| Median |
|
|
|
| |||
Indication | Number of patients |
| (wks)4 | ≥3 x ULN | ≥5 x ULN | ||||
| placebo | infliximab | placebo |
| infliximab | placebo | infliximab | placebo | infliximab |
Rheumatoid | 1,087 | 58.1 |
| 58.3 | 3.2% | 3.9% | 0.8% | 0.9% | |
arthritis1 |
| ||||||||
Crohn’s | 1,034 | 53.7 |
| 54.0 | 2.2% | 4.9% | 0.0% | 1.5% | |
disease2 |
| ||||||||
Paediatric |
|
|
|
|
|
|
|
|
|
Crohn’s | N/A | N/A |
| 53.0 | N/A | 4.4% | N/A | 1.5% | |
disease |
|
|
|
|
|
|
|
|
|
Ulcerative | 30.1 |
| 30.8 | 1.2% | 2.5% | 0.4% | 0.6% | ||
colitis |
| ||||||||
|
|
|
|
|
|
|
|
| |
Paediatric | N/A | N/A |
| 49.4 | N/A | 6.7% | N/A | 1.7% | |
Ulcerative |
|
|
|
|
|
|
|
|
|
colitis |
|
|
|
|
|
|
|
|
|
Ankylosing | 24.1 |
| 101.9 | 0.0% | 9.5% | 0.0% | 3.6% | ||
spondylitis |
| ||||||||
|
|
|
|
|
|
|
|
| |
Psoriatic | 18.1 |
| 39.1 | 0.0% | 6.8% | 0.0% | 2.1% | ||
arthritis |
| ||||||||
|
|
|
|
|
|
|
|
| |
Plaque | 1,175 | 16.1 |
| 50.1 | 0.4% | 7.7% | 0.0% | 3.4% | |
psoriasis |
| ||||||||
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|
1Placebo patients received methotrexate while infliximab patients received both infliximab and methotrexate.
2Placebo 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.
3Number of patients evaluated for ALT.
4Median
Antinuclear antibodies
Approximately half of
Paediatric population
Juvenile rheumatoid arthritis patients
Infliximab was studied in a clinical study in 120 patients (age range:
Infusion reactions
Infusion reactions occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kg compared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg infliximab group, 4 out of
60 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg group, 2 out of 57 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction (see section 4.4).
Immunogenicity
Antibodies to infliximab developed in 38% of patients receiving 3 mg/kg compared with 12% of patients receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6 mg/kg group.
Infections
Infections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of children receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 weeks (see section 4.4).
Paediatric Crohn’s disease patients
The following adverse events were reported more commonly in paediatric Crohn’s disease patients in the REACH study (see section 5.1) than in adult Crohn’s disease patients: anaemia (10.7%), blood in stool (9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). Other special considerations are discussed below.
In REACH, 17.5% of randomised patients experienced 1 or more infusion reactions. There were no serious infusion reactions, and 2 subjects in REACH had
Immunogenicity
Antibodies to infliximab were detected in 3 (2.9%) paediatric patients.
Infections
In the REACH study, infections were reported in 56.3% of randomised subjects treated with infliximab. Infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for
3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both
Paediatric ulcerative colitis patients
Overall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse event was worsening of ulcerative colitis, the incidence of which was higher in patients on the q12 week vs. the q8 week dosing regimen.
Overall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.
Immunogenicity
Antibodies to infliximab were detected in 4 (7.7%) patients through week 54.
Infections
Infections were reported in 31 (51.7%) of 60 treated patients in C0168T72 and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 was similar to that in the paediatric Crohn’s disease study (REACH) but higher than the proportion in the adults ulcerative colitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72 was 13/22 (59%) in the every 8 week maintenance treatment group and 14/23 (60.9%) in the every
12 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age

group than in the older age group. While the proportion of patients with infections was also higher in the younger age group, for serious infections, the proportions were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.
Additional information on special populations
Elderly patients (≥65 years)
In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab plus
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9Overdose
No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic effects.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressants, tumour necrosis factor alpha (TNFα) inhibitors, ATC code: L04AB02.
Inflectra is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Mechanism of action
Infliximab is a chimeric
Pharmacodynamic effects
Infliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximab prevented disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity.
Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients and correlate with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction and tissue degradation. After infliximab treatment, patients exhibited decreased levels of serum interleukin 6
number or in proliferative responses to in vitro mitogenic stimulation when compared with untreated patients’ cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermal inflammation and normalization of keratinocyte differentiation in psoriatic plaques. In psoriatic arthritis, short term treatment with infliximab reduced the number of
Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration of infliximab, revealed a substantial reduction in detectable TNFα. Infliximab treatment of Crohn’s disease patients was also associated with a substantial reduction of the commonly elevated serum inflammatory marker, CRP. Total peripheral white blood cell counts were minimally affected in
Clinical efficacy and safety
Adult rheumatoid arthritis
The efficacy of infliximab was assessed in two multicentre, randomised,
The primary endpoints were the reduction of signs and symptoms as assessed by the American College of Rheumatology criteria (ACR20 for ATTRACT, landmark
The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a
Results from week 54 (ACR20, total van der
A reduction in the rate of the progression of structural joint damage (erosions and joint space narrowing) was observed in all infliximab groups at 54 weeks (Table 3).
The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatment withdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone group cannot be defined.

Table 3
Effects on ACR20, Structural Joint Damage and Physical Function at week 54, ATTRACT
| Controla |
|
| Infliximabb |
|
|
| 3 mg/kg | 3 mg/kg | 10 mg/kg | 10 mg/kg | All | |
|
| q 8 wks | q 4 wks | q 8 wks | q 4 wks | infliximabb |
Patients with ACR20 | 15/88 | 36/86 | 41/86 | 51/87 | 48/81 | 176/340 |
response/Patients evaluated | (17%) | (42%) | (48%) | (59%) | (59%) | (52%) |
(%) |
|
|
|
|
|
|
Total scored (van der |
|
|
|
| ||
Change from baseline | 7.0±10.3 | 1.3 ± 6.0 | 1.6 ± 8.5 | 0.2 ± 3.6 | 0.6 ± 5.9 | |
(Mean ± SDc) | 4.0 | 0.5 | 0.1 | 0.5 | 0.0 | |
Median | ||||||
(Interquartile range) | (0.5,9.7) | |||||
Patients with no | 13/64 | 34/71 | 35/71 | 37/77 | 44/66 | 150/285 |
deterioration/patients | (20%) | (48%) | (49%) | (48%) | (67%) | (53%) |
evaluated (%)c |
|
|
|
|
|
|
HAQ change from baseline | ||||||
over timee (patients |
|
|
|
|
|
|
evaluated) |
|
|
|
|
|
|
Mean ± SDc | 0.2 ± 0.3 | 0.4 ± 0.3 | 0.5 ± 0.4 | 0.5 ± 0.5 | 0.4 ± 0.4 | 0.4 ± 0.4 |
acontrol = All patients had active RA despite treatment with stable methotrexate doses for 6 months prior to enrolment and were to remain on stable doses throughout the study. Concurrent use of stable doses of oral corticosteroids (≤10 mg/day) and/or NSAIDs was permitted, and folate supplementation was given.
ball infliximab doses given in combination with methotrexate and folate with some on corticosteroids and/or NSAIDs
cp <0.001, for each infliximab treatment group vs. control
dgreater values indicate more joint damage.
eHAQ = Health Assessment Questionnaire; greater values indicate less disability.
The ASPIRE study evaluated responses at 54 weeks in 1,004 methotrexate naive patients with early (≤3 years disease duration, median 0.6 years) active rheumatoid arthritis (median swollen and tender joint count of 19 and 31, respectively). All patients received methotrexate (optimised to 20 mg/wk by week 8) and either placebo, 3 mg/kg or 6 mg/kg infliximab at weeks 0, 2, and 6 and every 8 weeks thereafter. Results from week 54 are shown in Table 4.
After 54 weeks of treatment, both doses of infliximab + methotrexate resulted in statistically significantly greater improvement in signs and symptoms compared to methotrexate alone as measured by the proportion of patients achieving ACR20, 50 and 70 responses.
In ASPIRE, more than 90% of patients had at least two evaluable
Table 4
Effects on ACRn, Structural Joint Damage and Physical Function at week 54, ASPIRE
| Placebo |
| Infliximab + MTX |
|
| 3 mg/kg | 6 mg/kg | Combined | |
| + MTX |
|
|
|
Subjects randomised | ||||
Percentage ACR improvement |
|
|
|
|
Mean ± SDa | 24.8 ± 59.7 | 37.3 ± 52.8 | 42.0 ± 47.3 | 39.6 ± 50.1 |
Change from baseline in total van der |
|
| ||
Mean ± SDa | 3.70±9.61 | 0.42±5.82 | 0.51±5.55 | 0.46±5.68 |
Median | 0.43 | 0.00 | 0.00 | 0.00 |
Improvement from baseline in HAQ averaged over time from week 30 to week 54c |
| |||
Mean ± SDd | 0.68 ± 0.63 | 0.80 ± 0.65 | 0.88 ± 0.65 | 0.84 ± 0.65 |
ap <0.001, for each infliximab treatment group vs control
bgreater values indicate more joint damage.
cHAQ = Health Assessment Questionnaire; greater values indicate less disability.
dp = 0.030 and <0.001 for the 3 mg/kg and 6 mg/kg treatment groups respectively vs. placebo + MTX.
Data to support dose titration in rheumatoid arthritis come from ATTRACT, ASPIRE and the START study. START was a randomised, multicentre,
Adult Crohn’s disease
Induction treatment in moderately to severely active Crohn’s disease
The efficacy of a single dose treatment with infliximab was assessed in 108 patients with active Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥220 ≤400) in a randomised,
The primary endpoint was the proportion of patients who experienced a clinical response, defined as a decrease in CDAI by ≥70 points from baseline at the
At week 4, following administration of a single dose, 22/27 (81%) of
Maintenance treatment in moderately to severely active Crohn’s disease in adults
The efficacy of repeated infusions with infliximab was studied in a
Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients were classified as
The

Table 5
Effects on response and remission rate, data from ACCENT I
|
| ACCENT I |
|
|
| % of Patients |
|
| Placebo | Infliximab | Infliximab |
| Maintenance | Maintenance | Maintenance |
|
| 5 mg/kg | 10 mg/kg |
| (n=110) | (n=113) | (n=112) |
|
| (p value) | (p value) |
Median time to loss of response | 19 weeks | 38 weeks | >54 weeks |
through week 54 |
| (0.002) | (<0.001) |
Week 30 |
|
|
|
Clinical Responsea | 27.3 | 51.3 | 59.1 |
Clinical Remission | 20.9 | (<0.001) | (<0.001) |
38.9 | 45.5 | ||
10.7 (6/56) | (0.003) | (<0.001) | |
31.0 (18/58) | 36.8 (21/57) | ||
Week 54 |
| (0.008) | (0.001) |
|
|
| |
Clinical Responsea | 15.5 | 38.1 | 47.7 |
Clinical Remission | 13.6 | (<0.001) | (<0.001) |
28.3 | 38.4 | ||
Sustained | 5.7 (3/53) | (0.007) | (<0.001) |
17.9 (10/56) | 28.6 (16/56) | ||
|
| (0.075) | (0.002) |
aReduction in CDAI ≥25% and ≥70 points.
bCDAI <150 at both Week 30 and 54 and not receiving corticosteroids in the 3 months prior to Week 54 among patients who were receiving corticosteroids at baseline.
Beginning at week 14, patients who had responded to treatment, but subsequently lost their clinical benefit, were allowed to cross over to a dose of infliximab 5 mg/kg higher than the dose to which they were originally randomised. Eighty nine percent (50/56) of patients who lost clinical response on infliximab 5 mg/kg maintenance therapy after week 14 responded to treatment with infliximab
10 mg/kg.
Improvements in quality of life measures, a reduction in
Infliximab with or without AZA was assessed in a randomised,
The primary endpoint of the study was

Table 6
Percent of patients achieving
| AZA | Infliximab | Infliximab + AZA |
| Monotherapy | Monotherapy | Combination therapy |
Week 26 |
|
|
|
All randomised patients | 30.0% (51/170) | 44.4% (75/169) | 56.8% (96/169) |
|
| (p=0.006)* | (p=0.001)* |
*
Similar trends in the achievement of
Induction treatment in fistulising active Crohn’s disease
The efficacy was assessed in a randomised,
Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued to receive at least one of these therapies. Patients received three doses of either placebo or infliximab at weeks 0, 2 and 6. Patients were followed up to 26 weeks. The primary endpoint was the proportion of patients who experienced a clinical response, defined as ≥50% reduction from baseline in the number of fistulae draining upon gentle compression on at least two consecutive visits (4 weeks apart), without an increase in the use of medicinal products or surgery for Crohn’s disease.
Sixty eight percent (21/31) of
Maintenance treatment in fistulising active Crohn’s disease
The efficacy of repeated infusions with infliximab in patients with fistulising Crohn’s disease was studied in a
Table 7
- Flixabi - L04AB02
- Remsima - L04AB02
- Remicade - L04AB02
Prescription drugs listed. ATC Code: "L04AB02"
Effects on response rate, data from ACCENT II
| ACCENT II |
| |
| Placebo | Infliximab | |
| Maintenance | Maintenance |
|
| (n=99) | (5 mg/kg) |
|
|
| (n=96) |
|
Median time to loss of response | 14 weeks | >40 weeks | <0.001 |
through week 54 |
|
|
|
Week 54 |
|
|
|
Fistula Response (%)a | 23.5 | 46.2 | 0.001 |
Complete fistula response (%)b | 19.4 | 36.3 | 0.009 |
aA ≥50% reduction from baseline in the number of draining fistulas over a period of ≥4 weeks.
bAbsence of any draining fistulas.
Beginning at week 22, patients who initially responded to treatment and subsequently lost their response were eligible to cross over to active
infliximab 5 mg/kg group who crossed over because of loss of fistula response after week 22, 57% (12/21) responded to
There was no significant difference between placebo and infliximab for the proportion of patients with sustained closure of all fistulas through week 54, for symptoms such as proctalgia, abscesses and urinary tract infection or for number of newly developed fistulas during treatment.
Maintenance therapy with infliximab every 8 weeks significantly reduced
Adult ulcerative colitis
The safety and efficacy of infliximab were assessed in two (ACT 1 and ACT 2) randomised,
Table 8
Effects on clinical response, clinical remission and mucosal healing at Weeks 8 and 30. Combined data from ACT 1 & 2
|
| Placebo |
| Infliximab |
|
Subjects randomised | 5 mg/kg | 10 mg/kg | Combined | ||
Percentage of subjects in clinical response and in sustained clinical response |
|
| |||
Clinical response at Week 8a | 33.2% | 66.9% | 65.3% | 66.1% | |
Clinical response at Week 30a | 27.9% | 49.6% | 55.4% | 52.5% | |
Sustained response (clinical response |
|
|
|
| |
at both Week 8 and Week 30)a | 19.3% | 45.0% | 49.6% | 47.3% | |
Percentage of subjects in clinical remission and sustained remission |
|
| |||
Clinical remission at Week 8a | 10.2% | 36.4% | 29.8% | 33.1% | |
Clinical remission at Week 30a | 13.1% | 29.8% | 36.4% | 33.1% | |
Sustained remission(in remission at | 5.3% | 19.0% | 24.4% | 21.7% | |
both Week 8 and Week 30)a | |||||
Percentage of subjects with mucosal healing |
|
|
| ||
Mucosal healing at Week 8a | 32.4% | 61.2% | 60.3% | 60.7% | |
Mucosal healing at Week 30a | 27.5% | 48.3% | 52.9% | 50.6% | |
a | p <0.001, for each infliximab treatment group vs. placebo. |
|
|
|
The efficacy of infliximab through week 54 was assessed in the ACT 1 study.
At 54 weeks, 44.9% of patients in the combined infliximab treatment group were in clinical response compared to 19.8% in the placebo treatment group (p<0.001). Clinical remission and mucosal healing occurred in a greater proportion of patients in the combined infliximab treatment group compared to the placebo treatment group at week 54 (34.6% vs. 16.5%, p<0.001 and 46.1% vs. 18.2%, p<0.001, respectively). The proportions of patients in sustained response and sustained remission at week 54 were greater in the combined infliximab treatment group than in the placebo treatment group (37.9% vs. 14.0%, p<0.001; and 20.2% vs. 6.6%, p<0.001, respectively).
A greater proportion of patients in the combined infliximab treatment group were able to discontinue corticosteroids while remaining in clinical remission compared to the placebo treatment group at both week 30 (22.3% vs. 7.2%, p <0.001, pooled ACT 1 & ACT 2 data) and week 54 (21.0% vs. 8.9%, p=0.022, ACT 1 data).
The pooled data analysis from the ACT 1 and ACT 2 studies and their extensions, analysed from baseline through 54 weeks, demonstrated a reduction of ulcerative
The proportion of subjects who underwent colectomy at any time within 54 weeks following the first infusion of study agent were collected and pooled from the ACT 1 and ACT 2 studies and their extensions. Fewer subjects underwent colectomy in the 5 mg/kg infliximab group (28/242 or 11.6% [N.S.]) and the 10 mg/kg infliximab group (18/242 or 7.4% [p=0.011]) than in the placebo group (36/244; 14.8%).
The reduction in incidence of colectomy was also examined in another randomised,
In ACT 1 and ACT 2, infliximab improved quality of life, confirmed by statistically significant improvement in both a disease specific measure, IBDQ, and by improvement in the generic
Adult ankylosing spondylitis
Efficacy and safety of infliximab were assessed in two multicentre,
In the first study (P01522), which had a 3 month
patients were switched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of the study, 53 patients continued into an
In the second clinical study (ASSERT), 279 patients were randomised to receive either placebo (Group 1, n=78) or 5 mg/kg infliximab (Group 2, n=201) at 0, 2 and 6 weeks and every 6 weeks to week 24. Thereafter, all subjects continued on infliximab every 6 weeks to week 96. Group 1 received 5 mg/kg infliximab. In Group 2, starting with the week 36 infusion, patients who had a BASDAI ≥3 at 2 consecutive visits, received 7.5 mg/kg infliximab every 6 weeks thereafter through week 96.
In ASSERT, improvement in signs and symptoms was observed as early as week 2. At week 24, the number of ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the
5 mg/kg infliximab group (p<0.001). There were 95 subjects from group 2 who continued on 5 mg/kg every 6 weeks. At 102 weeks there were 80 subjects still on infliximab treatment and among those, 71 (89%) were ASAS 20 responders.
In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12, the number of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the 5 mg/kg group (p<0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At
102 weeks there were 49 subjects still on infliximab treatment and among those, 30 (61%) were BASDAI 50 responders.
In both studies, physical function and quality of life as measured by the BASFI and the physical component score of the

Adult psoriatic arthritis
Efficacy and safety were assessed in two multicentre,
In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patients with active polyarticular psoriatic arthritis. During the
In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in
200 patients with active psoriatic arthritis (≥5 swollen joints and ≥5 tender joints). Forty six percent of patients continued on stable doses of methotrexate (≤25 mg/week). During the
Key efficacy results for IMPACT and IMPACT 2 are shown in Table 9 below:
Table 9
Effects on ACR and PASI in IMPACT and IMPACT 2
|
| IMPACT |
|
|
| IMPACT 2* |
|
| Placebo | Infliximab | Infliximab | Placebo | Infliximab | Infliximab | |
Patients | (Week 16) | (Week 16) | (Week 98) | (Week 24) | (Week 24) | (Week 54) | |
N/Aa |
| ||||||
randomised |
|
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|
ACR response |
|
|
|
|
|
|
|
(% of patients) |
|
|
|
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|
N |
| ||||||
ACR 20 | 5(10%) | 34 (65%) | 48 (62%) | (16%) | 54 (54%) | 53 (53%) | |
response* |
|
|
|
|
|
|
|
ACR 50 | 0(0%) | 24 (46%) | 35 (45%) | (4%) | 41(41%) | 33 (33%) | |
response* |
|
|
|
|
|
|
|
ACR 70 | 0(0%) | 15 (29%) | 27 (35%) | (2%) | 27 (27%) | 20 (20%) | |
response* |
|
|
|
|
|
|
|
PASI response |
|
|
|
|
|
|
|
(% of patients)b |
|
|
|
|
|
|
|
N |
|
|
|
| |||
PASI 75 |
|
|
| (1%) | 50 (60%) | 40 (48.8%) | |
response** |
|
|
|
|
|
|
|
*
aWeek 98 data for IMPACT includes combined placebo crossover and infliximab patients who entered the
bBased on patients with PASI >2.5 at baseline for IMPACT, and patients with >3% BSA psoriasis skin involvement at baseline in IMPACT 2.
**PASI 75 response for IMPACT not included due to low N; p<0.001 for infliximab vs. placebo at week 24 for IMPACT 2.
In IMPACT and IMPACT 2, clinical responses were observed as early as week 2 and were maintained through week 98 and week 54 respectively. Efficacy has been demonstrated with or without concomitant use of methotrexate. Decreases in parameters of peripheral activity characteristic of psoriatic arthritis (such as number of swollen joints, number of painful/tender joints, dactylitis and presence of enthesopathy) were seen in the
Radiographic changes were assessed in IMPACT 2. Radiographs of hands and feet were collected at baseline, weeks 24 and 54. Infliximab treatment reduced the rate of progression of peripheral joint
damage compared with placebo treatment at the week 24 primary endpoint as measured by change from baseline in total modified
Adult psoriasis
The efficacy of infliximab was assessed in two multicentre, randomised,
SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasis that had previously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kg infliximab or placebo infusions at weeks 0, 2 and 6. Patients with a PGA score ≥3 were eligible to receive an additional infusion of the same treatment at week 26.
In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the 3 mg/kg infliximab group, 87.9% in the 5 mg/kg infliximab group, and 5.9% in the placebo group (p<0.001). By week 26, twenty weeks after the last induction dose, 30% of patients in the 5 mg/kg group and 13.8% of patients in the 3 mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptoms of psoriasis gradually returned with a median time to disease relapse of >20 weeks. No rebound was observed.
EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patients with plaque psoriasis. Patients received 5 mg/kg infliximab- or
Table 10
Summary of PASI response, PGA response and percent of patients with all nails cleared at Weeks 10, 24 and 50. EXPRESS
| Placebo → Infliximab | Infliximab | |
| 5 mg/kg | 5 mg/kg | |
| (at week 24) |
| |
Week 10 |
|
|
|
N |
| ||
≥90% improvement | (1.3%) | 172 (57.1%) a | |
≥75% improvement | (2.6%) | 242 (80.4%) a | |
≥50% improvement | (7.8%) | 274 (91.0%) | |
PGA of cleared (0) or minimal (1) | (3.9%) | 242 (82.9%) ab | |
PGA of cleared (0), minimal (1), or mild (2) | (18.2%) | 275 (94.2%) ab | |
Week 24 |
|
|
|
N |
| ||
≥90% improvement | (1.3%) | 161 (58.3%) a | |
≥75% improvement | (3.9%) | 227 (82.2%) a | |
≥50% improvement | (6.5%) | 248 (89.9%) | |
PGA of cleared (0) or minimal (1) | (2.6%) | 203 (73.6%) a | |
PGA of cleared (0), minimal (1), or mild (2) | (19.5%) | 246 (89.1%) a |

| Placebo → Infliximab | Infliximab | |
| 5 mg/kg | 5 mg/kg | |
| (at week 24) |
|
|
Week 50 |
|
|
|
N |
| ||
≥90% improvement | 34 (50.0%) | (45.2%) | |
≥75% improvement | 52 (76.5%) | (60.5%) | |
≥50% improvement | 61 (89.7%) | (68.7%) | |
PGA of cleared (0) or minimal (1) | 46 (67.6%) | (53.0%) | |
PGA of cleared (0), minimal (1), or mild (2) | 59 (86.8%) | (67.3%) | |
All nails clearedc |
|
|
|
Week 10 | 1/65 (1.5%) | 16/235 (6.8%) | |
Week 24 | 3/65 (4.6%) | 58/223 (26.0%) a | |
Week 50 | 27/64 (42.2%) | 92/226 (40.7%) |
ap <0.001, for each infliximab treatment group vs. control.
bn = 292.
cAnalysis was based on subjects with nail psoriasis at baseline (81.8% of subjects). Mean baseline NAPSI scores were 4.6 and 4.3 in infliximab and placebo group.
Significant improvements from baseline were demonstrated in DLQI (p<0.001) and the physical and mental component scores of the SF 36 (p<0.001 for each component comparison).
Paediatric population
Paediatric Crohn’s disease (6 to 17 years)
In the REACH study, 112 patients (6 to 17 years, median age 13.0 years) with moderate to severe, active Crohn’s disease (median paediatric CDAI of 40) and an inadequate response to conventional therapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. All patients were required to be on a stable dose of
5 mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty two (32) evaluable paediatric patients crossed over (9 subjects in the q8 weeks and 23 subjects in the q12 weeks maintenance groups). Twenty four of these patients (75.0%) regained clinical response after crossing over.
The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects achieving clinical remission at week 10 was 58.9% (66/112).
At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than the q12 week maintenance treatment group (35.3%, 18/51; p=0.013). At week 54, the figures were 55.8% (29/52) and 23.5% (12/51) in the q8 weeks and q12 weeks maintenance groups, respectively (p < 0.001).
Data about fistulas were derived from PCDAI scores. Of the 22 subjects that had fistulas at baseline, 63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) were in complete fistula response at week 10, 30 and 54, respectively, in the combined q8 weeks and q12 weeks maintenance groups.
In addition, statistically and clinically significant improvements in quality of life and height, as well as a significant reduction in corticosteroid use, were observed versus baseline.
Paediatric ulcerative colitis (6 to 17 years)
The safety and efficacy of infliximab were assessed in a multicentre, randomised,
All patients received an induction regimen of 5 mg/kg infliximab at weeks 0, 2, and 6. Patients who did not respond to infliximab at week 8 (n=15) received no further drug and returned for safety
q8 weeks or q12 weeks as a maintenance treatment regimen.
The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response at week 8 was similar between those with or without concomitant immunomodulator use at baseline. Clinical remission at week 8 was 33.3% (17/51) as measured by the Paediatric Ulcerative Colitis Activity Index (PUCAI) score.
At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was 38% (8/21) in the q8 week maintenance group and 18% (4/22) in the q12 week maintenance treatment group. For patients receiving corticosteroids at baseline, the proportion of patients in remission and not receiving corticosteroids at week 54 was 38.5% (5/13) for the q8 week and 0% (0/13) for the
q12 week maintenance treatment group.
In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 vs.15/60). While the numbers of patients in each subgroup are too small to draw definitive conclusions about the effect of age, there was a higher number of patients in the younger age group who stepped up in dose or discontinued treatment due to inadequate efficacy.
Other paediatric indications
The European Medicines Agency has waived the obligation to submit the results of studies with the reference medicinal product containing infliximab in all subsets of the paediatric population in rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and Crohn's disease (see section 4.2 for information on paediatric use).
5.2Pharmacokinetic properties
Single intravenous infusions of 1, 3, 5, 10 or 20 mg/kg of infliximab yielded dose proportional increases in the maximum serum concentration (Cmax) and area under the
At single doses of 3, 5, or 10 mg/kg, the median Cmax values were 77, 118 and 277 micrograms/mL, respectively. The median terminal
5 mg/kg for Crohn’s disease and the rheumatoid arthritis maintenance dose of 3 mg/kg every 8 weeks.
Repeated administration of infliximab (5 mg/kg at 0, 2 and 6 weeks in fistulising Crohn´s disease, 3 or 10 mg/kg every 4 or 8 weeks in rheumatoid arthritis) resulted in a slight accumulation of infliximab in serum after the second dose. No further clinically relevant accumulation was observed. In most fistulising Crohn’s disease patients, infliximab was detected in serum for 12 weeks (range
Paediatric population
Population pharmacokinetic analysis based on data obtained from patients with ulcerative colitis (N=60), Crohn’s disease (N=112), juvenile rheumatoid arthritis (N=117) and Kawasaki disease (N=16) with an overall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on body weight in a
5.3Preclinical safety data
Infliximab does not cross react with TNFα from species other than human and chimpanzees. Therefore, conventional preclinical safety data with infliximab are limited. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. In a fertility and general reproductive function study, the number of pregnant mice was reduced following administration of the same analogous antibody. It is not known whether this finding was due to effects on the males and/or the females. In a
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
Sucrose
Polysorbate 80
Sodium dihydrogen phosphate monohydrate
Disodium phosphate dihydrate
6.2Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3Shelf life
Before reconstitution:
60 months at 2 °C - 8 °C.
Inflectra may be stored at temperatures up to a maximum of 25°C for a single period of up to 6 months, but not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal from refrigerated storage, Inflectra must not be returned to refrigerated storage.
After reconstitution:
Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours at 25 C. From a microbiological point of view, the product should be used as soon as possible but within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at
2 to 8°C.
6.4Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions up to 25 °C before reconstitution of the medicinal product, see section 6.3.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5Nature and contents of container
Type 1 glass vial with a (butyl) rubber stopper and an aluminium seal with a
6.6Special precautions for disposal and other handling
1.The dose and the number of Inflectra vials have to be calculated. Each Inflectra vial contains 100 mg infliximab. The required total volume of reconstituted Inflectra solution has to be calculated.
2.Under aseptic conditions, each Inflectra vial should be reconstituted with 10 mL of water for injections, using a syringe equipped with a
3.The required volume of the reconstituted Inflectra solution should be diluted to 250 mL with sodium chloride 9 mg/mL (0.9%) solution for infusion. Do not dilute the reconstituted Inflectra solution with any other diluent. This can be accomplished by withdrawing a volume of the sodium chloride 9 mg/mL (0.9%) solution for infusion from the
4.The infusion solution has to be administered over a period of not less than the infusion time recommended (see section 4.2). Only an infusion set with an
5.Inflectra should be visually inspected for particulate matter or discolouration prior to administration. If visibly opaque particles, discolouration or foreign particles are observed it should not be used.
6.Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
Hospira UK Limited
Horizon
Honey Lane
Hurley
Maidenhead
SL6 6RJ
UK
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/13/854/001
EU/1/13/854/002
EU/1/13/854/003
EU/1/13/854/004
EU/1/13/854/005
- Victrelis
- Nexium control
- Riprazo
- Humalog
- Simponi
- Infanrix hexa
Prescription drugs listed:
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 10 September 2013
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu
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