Disease modifying Antirheumatic Drugs
Drugs acting on colon and rectum
Psoriasis, seborrhea and ichthyosis
= Additional active ingredients
PRESENTATION AND DOSSAGE
VIAL (Pwdr. for concentr. for sol.for infus.): 20ml
Infliximab , 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.
Ankylosing spondylitis: Infliximab is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy.
Psoriatic arthritis: Infliximab is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate.
Infliximab should be administered: In combination with methotrexate. Or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated.
No interaction studies have been performed. In rheumatoid arthritis and psoriatic arthritis 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 Infliximab with other biological therapeutics used to treat the same conditions as Infliximab , including anakinra and abatacept, is not recommended. It is recommended that live vaccines not be given concurrently with Infliximab.
Patients with a history of hypersensitivity to infliximab or 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 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 Infliximab 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 Infliximab-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 Infliximab. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with Infliximab must not be given if a patient develops a serious infection or sepsis.
Caution should be exercised when considering the use of Infliximab 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 Infliximab, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Infliximab 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 Infliximab, 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, Infliximab 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 Infliximab 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 Infliximab, 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 Infliximab. Use of anti‑tuberculosis therapy should also be considered before the initiation of Infliximab 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 Infliximab treatment.
Invasive fungal infections: In patients treated with Infliximab, 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 Infliximab treatment should be carefully considered before initiation of Infliximab therapy.
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 Infliximab. 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 Infliximab 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, Infliximab 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 evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥5 times the upper limit of normal develop(s), Infliximab 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 Infliximab 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 Infliximab 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 could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with Infliximab. 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 Infliximab.
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 Infliximab and is positive for antibodies against double‑stranded DNA, further treatment with Infliximab must not be given.
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 Infliximab therapy. Discontinuation of Infliximab 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 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 TNF‑blocking agent cannot be excluded. Caution should be exercised when considering TNF‑blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy. 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 TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab in the post‑marketing setting. Approximately half the cases were lymphomas. The other 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 TNF‑blockers cannot be excluded.
Rare post‑marketing cases of hepatosplenic T‑cell lymphoma (HSTCL) have been reported in patients treated with TNF‑blocking agents including infliximab. This rare type of T‑cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The potential risk with the combination of AZA or 6‑MP and infliximab should be carefully considered. A risk for the development for hepatosplenic T‑cell lymphoma in patients treated with Infliximab cannot be excluded. Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab. Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.
Heart failure: Infliximab should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Infliximab must not be continued in patients who develop new or worsening symptoms of heart failure.
Haematologic reactions: There have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients receiving TNF‑blockers, including infliximab. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of Infliximab therapy should be considered in patients with confirmed significant haematologic abnormalities.
Others: There is limited safety experience of infliximab treatment in patients who have undergone surgical procedures, including arthroplasty. The long half‑life of infliximab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Infliximab should be closely monitored for infections, and appropriate actions should be taken.
Viral infection (e.g. influenza, herpes virus infection), Bacterial infections (e.g. sepsis, cellulitis, abscess), allergic respiratory symptom, depression, insomnia, headache.
See prescribing information for full details.
Infliximab is a chimeric human‑murine IgG1 monoclonal antibody produced in murine hybridoma cells by recombinant DNA technology.
This drug is a biosimilar medicinal product: The treatment is to be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or psoriasis. Infliximab should be administered intravenously. Infliximab infusions should be administered by qualified healthcare professionals trained to detect any infusion‑related issues. Patients treated with Infliximab should be given the package leaflet and the special Alert card. During the 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. Infliximab 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.
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 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. The safety and efficacy of re‑administration after an infliximab-free interval of more than 16 weeks has not been established. This applies to rheumatoid arthritis patients.
Re‑administration for ankylosing spondylitis: The safety and efficacy of re‑administration, other than every 6 to 8 weeks, has not been established.
Re‑administration for psoriatic arthritis: The safety and efficacy of re‑administration, other than every 8 weeks, has not been established.
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. 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.
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. In this situation, Infliximab should be re‑initiated as a single dose followed by the maintenance dose recommendations described above.
Older people (≥65 years): Specific studies of Infliximab 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.
Impaired renal and/or hepatic function: Infliximab has not been studied in these patient populations. No dose recommendations can be made.
Psoriasis: The safety and efficacy of Infliximab in children and adolescents younger than 18 years in the indication psoriasis have not been established.
Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis: The safety and efficacy of Infliximab in children and adolescents younger than 18 years in the indications juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established.
Juvenile rheumatoid arthritis: The safety and efficacy of Infliximab in children and adolescents younger than 18 years in the indication juvenile rheumatoid arthritis have not been established.
Impaired renal and/or hepatic function: Infliximab has not been studied in these patient populations. No dose recommendations can be made .
Method of administration: Infliximab should be administered intravenously over a 2 hour period. All patients administered Infliximab 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.
Shortened infusions across adult indications: In carefully selected adult patients who have tolerated at least 3 initial 2‑hour infusions of Infliximab (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.
For preparation and administration instructions- See prescribing information for full details.
No case of overdose has been reported. Single doses up to 20 mg/kg have been administered without toxic effects.
PREGNANCY & LACTATION
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.
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 Infliximab treatment.
Storage: Store in a refrigerator (2°C ‑ 8°C).
Shelf life: 36 months. For storage conditions after reconstitution of the medicinal product.
Compatibility: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
MANUFACTURER & DISTRIBUTER:
Manufacturer: Celltrion Inc, South Korea
License Holder: Perrigo Israel