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IXIFI is a biosimilar medicinal product. The prescribing physician should be involved in any decision regarding its interchangeability. 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.
Before starting treatment with IXIFI, patients must be evaluated for both active and inactive ('latent') tuberculosis (see Infections as follows).
IXIFI should be used with caution in patients with mild heart failure (NYHA Class I/II) (see Heart Failure as follows).
Infusion Reactions and Hypersensitivity: Infliximab has been associated with acute infusion-related reactions, including, anaphylactic shock, and delayed hypersensitivity reactions (see Adverse Reactions). To minimize the incidence of hypersensitivity reactions, including infusion reactions and serum sickness-like reactions, IXIFI should be administered as regular maintenance therapy after an induction regimen at weeks 0, 2 and 6 (see Dosage & Administration).
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 (see Dosage & Administration). Patients may be pretreated 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 were serious allergic reactions. In Crohn's disease patients, 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 IXIFI 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 IXIFI infusions must not be administered (see Immunogenicity under Adverse Reactions).
In clinical trials, delayed hypersensitivity reaction has been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing drug-free interval. Advise patients to seek immediate medical advice if they experience any delayed adverse event (see Delayed Hypersensitivity under Adverse Reactions). If patients are retreated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.
Infusion Reactions Following Re-administration of IXIFI: In a psoriasis clinical trial, a 3-dose re-induction of infliximab after a period of no treatment resulted in a higher incidence of serious infusion reactions during the re-induction regimen (see Adverse Reactions) than had been observed in rheumatoid arthritis, psoriasis, and Crohn's disease trials in which a period of no drug treatment was followed by regular maintenance therapy without re-induction.
In the case where IXIFI maintenance therapy for psoriasis is interrupted, IXIFI should be reinitiated as a single dose followed by maintenance therapy.
In general, the benefit-risk of re-administration of IXIFI after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2, and 6, should be carefully considered.
Infections: Patients must be monitored closely for infections including tuberculosis before, during and after treatment with IXIFI. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with IXIFI must not be given if a patient develops a serious infection or sepsis.
IXIFI should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of IXIFI in patients with chronic infection or a history of recurrent infections, including use of concomitant immunosuppressive medications. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.
Tumor 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 defense against infection is compromised in some patients treated with infliximab.
It should be noted that suppression of TNFα may also mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections is critical in order to minimize delays in diagnosis and treatment.
Patients taking TNF blockers are more susceptible to serious infections. Mycobacterial (including tuberculosis [frequently disseminated or extrapulmonary at clinical presentation]), viral infections, bacterial infections, including sepsis and pneumonia, invasive fungal infections, and other opportunistic infections have been observed in patients treated with infliximab. Some of these infections have been fatal. Opportunistic infections reported in patients on infliximab have included, but are not limited to pneumocystosis, histoplasmosis, cytomegalovirus infection, atypical mycobacterial infections, listeriosis and aspergillosis. In clinical trials, infections have been reported more frequently in pediatric patient populations than in adult populations (see Adverse Reactions).
Tuberculosis: Before starting treatment with IXIFI, 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). 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, IXIFI therapy must not be initiated (see Contraindications).
If inactive ('latent') tuberculosis is diagnosed, prophylactic anti-tuberculosis therapy must be started before the initiation of IXIFI, and in accordance with local recommendations. In this situation, the benefit/risk balance of IXIFI therapy should be very carefully considered.
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 IXIFI. Use of anti-tuberculosis therapy should also be considered before the initiation of IXIFI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Use of anti-tuberculosis therapy should be considered before the initiation of IXIFI in patients who have several or highly significant risk factors for tuberculosis infection and have a negative test for latent tuberculosis.
The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a physician with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy.
Cases of active tuberculosis have occurred in patients treated with infliximab during and after treatment for latent tuberculosis. Cases of active tuberculosis including miliary tuberculosis and tuberculosis with extrapulmonary location have been reported in patients treated with infliximab.
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 IXIFI treatment.
Invasive Fungal Infections: For patients who have resided in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of IXIFI treatment should be carefully considered before initiation or continuation of IXIFI therapy.
In patients treated with IXIFI, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness. Invasive fungal infections may present as disseminated rather than localized 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. The decision to administer empiric antifungal therapy should be made, if feasible, in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
Fistulizing Crohn's Disease: Patients with fistulizing Crohn's disease with acute suppurative fistulas must not initiate IXIFI therapy until a source for possible infection, specifically abscess, has been excluded (see Contraindications).
Hepatitis B Reactivation: Reactivation of hepatitis B has occurred in patients receiving a TNF blocker including infliximab, who are chronic carriers of this virus. Some cases have had fatal outcome. Patients at risk for Hepatitis B Virus (HBV) infection should be evaluated for prior evidence of HBV infection before initiating IXIFI therapy. Carriers of HBV who require treatment with IXIFI 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 anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, IXIFI should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. Patients should be tested for HBV infection before initiating treatment with immunosuppressants, including IXIFI. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended.
Hepatobiliary Events: 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. A causal relationship between infliximab and these events has not been established. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or alanine aminotransferase (ALT) elevations ≥ 5 times the upper limit of normal develops, IXIFI should be discontinued, and a thorough investigation of the abnormality should be undertaken.
Concurrent Administration with Other Biological Therapeutics: Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers. Therefore, the concurrent use of IXIFI and anakinra is not recommended.
In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit. Because of the nature of the adverse events seen with the concurrent use of TNF blockers and abatacept therapy, the concurrent use of infliximab and abatacept is not recommended.
There is insufficient information regarding the concurrent use of infliximab products with other biological products used to treat the same conditions as IXIFI. The concurrent use of IXIFI with these biological products is not recommended because of the possibility of an increased risk of infection and other potential pharmacological interactions.
Switching Between Biological DMARDs: When switching from one biologic to another, patients should continue to be monitored, since overlapping biological activity may further increase the risk of infection.
Vaccinations: Prior to initiating IXIFI in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines.
Live Vaccines/Therapeutic Infectious Agents: In patients receiving TNF blockers, 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 administration of live vaccines with IXIFI is not recommended.
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 IXIFI.
Infants Exposure in Utero: Fatal outcome due to disseminated Bacille Calmette-Guérin (BCG) infection has been reported in an infant who received BCG vaccine after in utero exposure to infliximab. A 12-month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab, unless infliximab exposure was limited to the first trimester or if infant infliximab serum levels are undetectable. Administration of a live vaccine prior to 12 months of age might be considered if the benefit of the vaccination clearly outweighs the theoretical risk of administration of live vaccines to the infants (see Use in Pregnancy & Lactation).
Infants Exposure Via Breast Milk: Administration of a live vaccine to a breastfed infant while the mother is receiving infliximab is not recommended unless infant infliximab serum levels are undetectable (see Use in Pregnancy & Lactation).
Non-live Vaccines: In a subset of patients from the ASPIRE study, a similar proportion of patients in each treatment group mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine, indicating that infliximab did not interfere with T-cell independent humoral immune responses.
Autoimmune Processes: The relative deficiency of TNFα caused by TNF blocker therapy may result in the initiation of an autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with IXIFI and is positive for antibodies against double-stranded DNA, further treatment with IXIFI must not be given (see Antinuclear Antibodies (ANA)/Anti-double-stranded DNA (dsDNA) Antibodies under Adverse Reactions).
Neurological Events: Infliximab and other agents that inhibit TNFα have been associated with seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome (see Adverse Reactions). Prescribers should exercise caution in considering the use of IXIFI in patients with these neurologic disorders and should consider discontinuation of IXIFI if these disorders develop.
Malignancies and Lymphoproliferative Disorders: In the controlled portions of clinical trials of all the TNF blockers, more cases of malignancies including lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During clinical trials of infliximab across all approved indications, the incidence of lymphoma in infliximab-treated subjects was higher than expected in the general population, but the occurrence of lymphoma was rare. Patients with Crohn's disease or rheumatoid arthritis, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blocker therapy.
Non-lymphoma Malignancy: In an exploratory clinical trial 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 of malignancy due to heavy smoking.
Caution should also be exercised in patients with psoriasis and a medical history of extensive immunosuppressant therapy or prolonged PUVA treatment.
Psoriasis patients should be monitored for non-melanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment.
Pediatric Malignancy: Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) who received TNF blockers (initiation of therapy ≤ 18 years of age), including infliximab, to treat Juvenile Idiopathic Arthritis (JIA), Crohn's disease or other conditions. Approximately half the reports were lymphomas. The other cases represented a variety of different malignancies and included malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants, such as methotrexate, azathioprine or 6-mercaptopurine. The role of TNF blockers in the development of malignancies in children and adolescents remains unclear.
Hepatosplenic T-cell Lymphoma (HSTCL): Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF blockers 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 azathioprine or 6-mercaptopurine concomitantly with or immediately prior to a TNF blocker. The vast majority of infliximab cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. Cases of HSTCL have also occurred in Crohn's disease patients and ulcerative colitis patients receiving azathioprine or 6-mercaptopurine who were not treated with infliximab. Before initiating or continuing IXIFI therapy in a patient who is receiving an immunosuppressant such as azathioprine or 6-mercaptopurine, the need for continuing the immunosuppressant therapy should be carefully assessed in light of the potential risks of concomitant therapy. The causal relationship of HSTCL to infliximab therapy remains unclear.
A risk for the development for HSTCL in patients treated with IXIFI cannot be excluded (see Dosage & Administration and Adverse Reactions).
All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before the therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. With current data, it is not known if infliximab treatment influences the risk for developing dysplasia or colon cancer (see Adverse Reactions).
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.
Leukemia: Cases of acute and chronic leukemia have been reported with post-marketing TNF blocker use in RA and other diseases. Even in the absence of TNF blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.
Skin Cancers: Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including infliximab products (see Adverse Reactions). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Cervical Cancer: A population-based retrospective cohort study using data from Swedish national health registries found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab compared to biologics-naïve patients or the general population, including those over 60 years of age. A causal relationship between infliximab and cervical cancer cannot be excluded. Periodic screening should continue in women treated with IXIFI, including those over 60 years of age.
The potential role of TNF blocker therapy in the development of malignancies is not known. With the current knowledge, a risk for the development of lymphomas or other malignancies in patients treated with a TNF blocker cannot be excluded (see Adverse Reactions). Caution should be exercised when considering TNF blocker therapy for patients with history of malignancy or when considering continuing treatment in patients who develop a malignancy.
Congestive Heart Failure: IXIFI should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and IXIFI must not be continued in patients who develop new or worsening symptoms of heart failure (see Contraindications and Adverse Reactions).
Hematologic Events: Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab products. The causal relationship to infliximab therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with IXIFI who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on IXIFI. Discontinuation of IXIFI therapy should be considered in patients who develop significant hematologic abnormalities.
Others: Studies have not been performed in patients with liver or renal disease (see Pharmacology: Pharmacokinetics under Actions).
There are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function (see Pharmacology: Toxicology: Preclinical safety data under Actions).
There is limited safety experience of surgical procedures in infliximab-treated patients. The long half-life of IXIFI should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on IXIFI should be closely monitored for infections, and appropriate actions should be taken.
There is limited safety experience of infliximab treatment in patients who have undergone arthroplasty.
Treatment of patients with intestinal strictures due to Crohn's disease is not recommended since the risk/benefit relationship in this patient population has not been established.
Effects on ability to drive and use machines: Caution should be taken when driving or using machinery following administration of IXIFI (see Adverse Reactions).
Use in Children: IXIFI has not been studied in patients with Crohn's disease or ulcerative colitis below the age of 6 years.
Use in the Elderly: The pharmacokinetics of infliximab in elderly patients has not been studied. The incidence of serious infections in infliximab-treated geriatric patients was greater than in infliximab-treated younger adult patients; therefore, close monitoring of geriatric patients for development of serious infections is recommended.
