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In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
AMGEVITA is a biosimilar product of HUMIRA and interchangeability or auto‐substitution between AMGEVITA and HUMIRA is not allowed.
Infections: Serious infections, due to bacterial, mycobacterial, invasive fungal (disseminated or extrapulmonary histoplasmosis, aspergillosis, coccidioidomycosis) viral, parasitic or other opportunistic infections have been reported in patients receiving TNF-blocking agents. Sepsis, rare cases of tuberculosis, candidiasis, listeriosis, Legionellosis and pneumocystis have also been reported with the use of TNF-antagonists, including adalimumab. Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicemia. Hospitalization or fatal outcomes associated with infections have been reported. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease could predispose them to infections.
Treatment with AMGEVITA should not be initiated in patients with active infections including chronic or localized infections until infections are controlled. In patients who have been exposed to tuberculosis, and patients who have traveled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with AMGEVITA should be considered prior to initiating therapy (see Other Opportunistic Infections as follows).
As with other TNF-antagonists, patients should be monitored closely for infections, including tuberculosis before, during and after treatment with AMGEVITA.
Patients who develop a new infection while undergoing treatment with AMGEVITA should be monitored closely and undergo a complete diagnostic evaluation. Administration of AMGEVITA should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until infections are controlled.
Physicians should exercise caution when considering the use of AMGEVITA in patients with a history of recurring infection or with underlying conditions, which may predispose patients to infections.
Tuberculosis: Tuberculosis including reactivation and new onset of tuberculosis, has been reported in patients receiving Adalimumab. Reports included cases of pulmonary and extrapulmonary (i.e. disseminated).
Before initiation of therapy with AMGEVITA, all patients should be evaluated for both active and inactive ("latent") tuberculosis infection. This evaluation should include a detailed medical assessment of patient history of tuberculosis or possible previous exposure to people with active tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests (e.g. chest x-ray and tuberculin skin test) should be performed in accordance with local recommendations. Treatment of latent tuberculosis infections should be initiated prior to therapy with AMGEVITA. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG)+.
+as permitted by local regulations.
The possibility of undetected latent tuberculosis should be considered especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis.
If active tuberculosis is diagnosed, AMGEVITA therapy must not be initiated.
If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylactic treatment before the initiation of AMGEVITA and in accordance with local recommendations. Use of anti-tuberculosis prophylactic treatment should also be considered in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis.
Anti-tuberculosis treatment of patients with latent tuberculosis infection reduces the risk of reactivation in patients receiving treatment with AMGEVITA. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with AMGEVITA. Also, active tuberculosis has developed in patients receiving AMGEVITA whose screening for latent tuberculosis infection was negative, and some patients who have been successfully treated for active tuberculosis have redeveloped active tuberculosis while being treated with TNF-blocking agents.
Patients receiving AMGEVITA should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered especially in patients who are severely ill or immunocompromised.
Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g., persistent cough, wasting/weight loss, low grade fever) occur during or after therapy with AMGEVITA.
Other Opportunistic Infections: Opportunistic infections, including invasive fungal infections, have been observed in patients receiving Adalimumab. These infections are not consistently recognized in patients taking TNF-blockers and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.
Patients taking TNF-blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Those who develop fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock should promptly seek medical attention for a diagnostic evaluation.
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection. Patients are at risk of histoplasmosis and other invasive fungal infections and hence clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made 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. Patients who develop a severe fungal infection are also advised to stop the TNF-blocker until infections are controlled.
Hepatitis B Reactivation: Use of TNF-blockers has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. Prescribers should exercise caution in prescribing TNF-blockers for patients identified as carriers of HBV. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, AMGEVITA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated.
Neurologic Events: TNF-antagonists, including Adalimumab, have been associated in rare cases with new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis, and optic neuritis, and peripheral demyelinating disease, including Guillain Barré syndrome. Prescribers should exercise caution in considering the use of AMGEVITA in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of AMGEVITA should be considered if any of these disorders develop.
There is a known association between intermediate uveitis and central demyelinating disorders. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to the initiation of AMGEVITA therapy and regularly during treatment to assess for pre-existing central demyelinating disorders.
Malignancies: In the controlled portions of clinical trials of TNF-antagonist, more cases of malignancies including lymphoma have been observed among patients receiving a TNF-antagonist compared with control patients. The size of the control group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation. During the long-term open label trials with Adalimumab, the overall rate of malignancies was similar to what would be expected for an age, gender and race matched general population. With the current knowledge, a possible risk for the development of lymphomas, or other malignancies in patients treated with a TNF-antagonist cannot be excluded.
Malignancies, some fatal, have been reported among children and adolescents who received treatment with TNF-blocking agents. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. The malignancies occurred after a median of 30 months of therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.
Very rare postmarketing reports of hepatosplenic T-cell lymphoma (HSTCL), a rare aggressive lymphoma that is often fatal, have been identified in patients treated with adalimumab. Most of the patients had prior infliximab therapy as well as concomitant azathioprine or 6-mercaptopurine use for inflammatory bowel disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and AMGEVITA should be carefully considered. The causal association of HSTCL with adalimumab is not clear.
No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving AMGEVITA. Thus additional caution should be exercised in considering AMGEVITA treatment of these patients.
All patients, and in particular patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with AMGEVITA.
Cases of acute and chronic leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Patients with rheumatoid arthritis may be at a higher risk (up to 2-fold) than the general population for the development of leukemia, even in the absence of TNF-blocking therapy.
With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. 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 therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.
Allergic: Serious allergic reactions associated with Adalimumab were rare during clinical trials. Reports of serious allergic reactions including anaphylaxis have been received following Adalimumab administration. If an anaphylactic reaction or other serious allergic reaction occurs, administration of AMGEVITA should be discontinued immediately and appropriate therapy initiated.
The needle cover of the pre-filled autoinjector is made from dry natural rubber (latex) This may cause severe allergic reactions in patients sensitive to latex.
Hematologic Events: Rare reports of pancytopenia including aplastic anemia have been reported with TNF-blocking agents. Adverse events of the hematologic system, including medically significant cytopenia (e.g. thrombocytopenia, leukopenia) have been reported with Adalimumab. The causal relationship of these reports to Adalimumab remains unclear. 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) while on AMGEVITA. Discontinuation of AMGEVITA therapy should be considered in patients with confirmed significant hematologic abnormalities.
Concurrent administration of biologic DMARDS or TNF-antagonists: Serious infections were seen in clinical studies with concurrent use of anakinra and another TNF-antagonist, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNF-antagonists. Therefore, the combination of adalimumab and anakinra is not recommended.
Concomitant administration of adalimumab with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF-antagonists is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.
Immunosuppression: In a study of 64 patients with RA that were treated with Adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B-cells and NK-cells, monocyte/macrophages, and neutrophils.
Vaccinations: In a randomized, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with Adalimumab, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the Adalimumab group compared to 82% in the placebo group. A total of 37% of Adalimumab-treated subjects and 40% of placebo-treated subjects achieved at least a 2-fold increase in at least 3 out of 5 pneumococcal antigens. In the same study 98% of patients in the Adalimumab group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of Adalimumab-treated subjects and 63% of placebo-treated subjects achieved at least a 4-fold increase in at least 2 out of 3 influenza antigens.
It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating AMGEVITA therapy.
Patients on AMGEVITA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Adalimumab.
Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for 5 months following the mother's last adalimumab injection during pregnancy.
Congestive Heart Failure: Adalimumab has not been formally studied in patients with congestive heart failure (CHF), however, in clinical studies with another TNF-antagonist, a higher rate of serious CHF-related adverse events including worsening CHF and new onset CHF have been reported. Cases of worsening CHF have also been reported in patients receiving Adalimumab. Physicians should exercise caution when using AMGEVITA in patients who have heart failure and monitor them carefully.
Autoimmune Processes: Treatment with Adalimumab may result in the formation of autoimmune antibodies.
The impact of long-term treatment with Adalimumab on the development of autoimmune diseases is unknown.
If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with AMGEVITA, treatment should be discontinued (see Autoantibodies under Adverse Reactions).
Use in the Elderly: The frequency of serious infection among Adalimumab treated subjects over 65 years of age was higher than for those under 65 years of age. Of the total number of subjects in clinical studies of Adalimumab, 9.4% were 65 years and over, while approximately 2.0% were 75 and over. Because there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
