Inflectra 100 mg powder for concentrate for solution for infusion
One vial contains 100 mg of infliximab*. After reconstitution each mL contains 10 mg of infliximab.
* Infliximab is a chimeric human-murine IgG1 monoclonal antibody produced in murine hybridoma cells by recombinant DNA technology.
For the full list of excipients, see section 6.1.
Powder for concentrate for solution for infusion
The powder is white.
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 disease-modifying antirheumatic drugs (DMARDs), including methotrexate, has been inadequate.
• 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 X-ray, has been demonstrated (see section 5.1).
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 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
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 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.
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 X-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1).
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 ultra-violet A (PUVA) (see section 5.1).
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 infusion-related issues. Patients treated with Inflectra should be given the package leaflet and the special Alert card.
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 step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 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
• Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see 'Re-administration' below and section 4.4).
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
• 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 (see 'Re-administration' below and section 4.4).
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 re-administration if signs and symptoms of disease recur is limited and comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking.
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.
Re-administration for Crohn's disease and rheumatoid arthritis
If the signs and symptoms of disease recur, infliximab can be re-administered within 16 weeks following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after infliximab-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-administration after an infliximab-free interval of more than 16 weeks has not been established. This applies to both Crohn's disease patients and rheumatoid arthritis patients.
Re-administration for ulcerative colitis
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).
Re-administration for ankylosing spondylitis
The safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established (see sections 4.4 and 4.8).
Re-administration for psoriatic arthritis
The safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).
Re-administration for psoriasis
Limited experience from re-treatment with one single infliximab dose in psoriasis after an interval of 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared to the initial induction regimen (see section 5.1).
Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher incidence of infusion reactions, including serious ones, when compared to 8-weekly maintenance treatment (see section 4.8).
Re-administration across indications
In case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-induction regimen is not recommended (see section 4.8). In this situation, Inflectra should be re-initiated as a single dose followed by the maintenance dose recommendations described above.
Elderly patients (≥65 years)
Specific studies of Inflectra in elderly patients have not been conducted. No major age-related differences in clearance or volume of distribution were observed in clinical studies. No dose adjustment is required (see section 5.2). For more information about the safety of Inflectra in elderly patients see sections 4.4 and 4.8.
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 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have occurred previously (see section 4.4).
Shortened infusions across adult indications
In carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of Inflectra (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. If an infusion reaction occurs in association with a shortened infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. Shortened infusions at doses >6 mg/kg have not been studied (see section 4.8).
For preparation and administration instructions, see section 6.6.
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).
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 infusion-related reactions, including anaphylactic shock, and delayed hypersensitivity reactions (see section 4.8).
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 pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects.
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 episodically-treated patients than in patients given maintenance therapy. Patients who discontinue immunosuppressants prior to or during infliximab treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given and further Inflectra infusions must not be administered (see section 4.8).
In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Inflectra-free interval. Patients should be advised to seek immediate medical advice if they experience any delayed adverse event (see section 4.8). If patients are re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.
Infections
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 TNF-blockers are more susceptible to serious infections.
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 eva luation. 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 eva luated for both active and inactive ('latent') tuberculosis. This eva luation 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 X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.
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 anti-tuberculosis therapy should also be considered before the initiation of Inflectra in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
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, low-grade fever) appear during or after Inflectra treatment.
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 TNF-antagonist including infliximab, who are chronic carriers of this virus. Some cases have had fatal outcome.
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 TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Inflectra should be stopped and effective antiviral therapy with appropriate supportive treatment should be initiated.
Hepatobiliary events
Very rare cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience of infliximab. Isolated cases of liver failure resulting in liver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should be eva luated for evidence of liver injury. If jaundice and/or ALT elevations ≥5 times the upper limit of normal develop(s), Inflectra should be discontinued, and a thorough investigation of the abnormality should be undertaken.
Concurrent administration of TNF-alpha inhibitor and anakinra
Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of Inflectra and anakinra is not recommended.
Concurrent administration of TNF-alpha inhibitor and abatacept
In clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-antagonists alone, without increased clinical benefit. The combination of Inflectra and abatacept is not recommended.
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 anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent adminstration of live vaccines with Inflectra is not recommended.
In infants exposed in utero to infliximab, fatal outcome due to disseminated Bacillus Calmette-Guérin (BCG) infection has been reported following administration of BCG vaccine after birth. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab (see section 4.6).
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 anti-TNF therapy may result in the initiation of an autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Inflectra and is positive for antibodies against double-stranded DNA, further treatment with Inflectra must not be given (see section 4.8).
Neurological events
Use of TNF-blocking agents, including infliximab, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiation of Inflectra therapy. Discontinuation of Inflectra should be considered if these disorders develop.
Malignancies and lymphoproliferative disorders
In the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies including lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During clinical studies of infliximab across all approved indications the incidence of lymphoma in infliximab-treated patients was higher than expected in the general population, but the occurrence of lymphoma was rare. In the post-marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.
In an exploratory clinical study eva luating 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 TNF-blocking agent cannot be excluded (see section 4.8). Caution shou
