Remicade

/ Janssen

Adults(18 years)
Rheumatoid arthritis: 3 mg/kg given as an intravenous infusion over a 2-hour period followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. In carefully selected patients with rheumatoid arthritis who have tolerated 3 initial 2-hour infusions of Remicade, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. Shortened infusions at doses > 6 mg/kg have not been studied. Remicade 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 over a 2-hour period 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 Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
Fistulising, active Crohn’s disease: 5 mg/kg given as an intravenous infusion over a 2-hour period 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.
Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment. 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 over a 2-hour period 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 over a 2-hour period 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 over a 2-hour period followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
See prescribing information for full details.

Adult: Crohn’s disease: Treatment of moderate to severe active Crohn’s disease in patients who have not responded despite of a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant.
Treatment of fistulising Crohn’s disease in patients who have not responded despite of a full and adequate course of therapy with conventional treatment.
Paediatric Crohn’s disease: REMICADE is indicated for: Treatment of severe active Crohn’s disease in paediatric patients 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. REMICADE has been studied only in combination with conventional immunosuppressive therapy.
Ankylosing spondylitis: REMICADE is indicated for: Treatment of ankylosing spondylitis in patients who have severe axial symptoms elevated serological markers of inflammatory activity and who have responded inadequately to conventional therapy.
Psoriatic arthritis: REMICADE is indicated for: Treatment of active and progressive psoriatic arthritis in adults when the response to previous DMARD therapy has been inadequate.
REMICADE should be administered: either in combination with methotrexate or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated.
REMICADE 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.
Rheumatoid arthritis: REMICADE in combination with methotrexate is indicated for the reduction of signs and symptoms as well as the improvement in physical function in: Patients with active disease when the response to disease-modifying drugs including methotrexate has been inadequate.
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.
Psoriasis: REMICADE is indicated for: Treatment of moderate to severe plaque psoriasis in adults who failed to respond to or who have a contraindication to or are intolerant to other systemic therapy including cyclosporine methotrexate or PUVA.
Ulcerative colitis: REMICADE is indicated for: Treatment of moderately to severely active ulcerative colitis in patients 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.
Paediatric ulcerative colitis: Remicade is indicated for treatment of severely active ulcerative colitis, in paediatric patients 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.

Patients with a history of hypersensitivity to infliximab, to other murine proteins, or to any of the excipients.
Patients with tuberculosis or other severe infections such as sepsis, abscesses, and opportunistic infections.
Patients with moderate or severe heart failure (NYHA class III/IV).

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. 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 Remicade 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 Remicade infusions must not be administered. In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Remicade-free interval. Patients should be advised to seek immediate medical advice if they experience any delayed adverse event. 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 Remicade. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with Remicade must not be given if a patient develops a serious infection or sepsis. Caution should be exercised when considering the use of Remicade 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 (TNF) mediates inflammation and modulates cellular immune responses. Experimental data show that TNF 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 TNF 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 minimize 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 Remicade, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Remicade 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 Remicade. 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 Remicade, 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 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, Remicade therapy must not be initiated. 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 Remicade therapy should be very carefully considered. If inactive (‘latent’) tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Remicade, 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, anti-tuberculosis therapy should be considered before the initiation of Remicade. Use of anti-tuberculosis therapy should also be considered before the initiation of Remicade in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. 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 Remicade treatment.
Invasive fungal infections: In patients treated with Remicade, 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 Remicade treatment should be carefully considered before initiation of Remicade therapy.
Fistulising Crohn’s disease: Patients with fistulising Crohn’s disease with acute suppurative fistulas must not initiate Remicade therapy until a source for possible infection, specifically abscess, has been excluded.
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 Remicade. 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 Remicade 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, Remicade 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 Remicade. Isolated cases of liver failure resulting in liver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5 times the upper limit of normal develop(s), Remicade 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 Remicade 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 Remicade and abatacept is not recommended. Concurrent Administration with other Biological Therapeutics There is insufficient information regarding the concomitant use with other biological therapeutics used to treat the same conditions as in this product. The concomitant use with these biologics is not recommended because of the possibility of an increased risk of infection, and other potential pharmacological interactions.
Switching between biological Therapeutics: When switching from one biologic to another, patients should continue to be monitored for since overlapping biological activity may further increase the risk of 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 could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with this product. 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 this product.
For full details see prescribing information.

Viral infection, fever, headache, vertigo/dizziness, hypertension, flushing, upper respiratory and lower respiratory tract infection, nausea, diarrhea, abdominal pain, dyspepsia, rash, pruritus, urticaria, increased sweating, dry skin, urinary tract infection, fatigue, chest pain.

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 this product with other biological therapeutics used to treat the same conditions, including anakinra and abatacept, is not recommended. Live Vaccines/Therapeutic Infectious Agents It is recommended that live vaccines not be given concurrently with Remicade. It is recommended that therapeutic infectious agents not be given concurrently with this product.
For full details see prescribing information.

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 Remicade 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. 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 up to 6 months in the serum of infants born to women treated with infliximab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to infliximab in utero is not recommended for 6 months following the mother’s last infliximab infusion during pregnancy.
Lactation: 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 Remicade treatment.
Fertility: There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function.
For full details see prescribing information.

No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic effects.