ADALIMUMAB Drug Interactions: What You Need to Know

INTERACTIONS

• Abatacept: Increased risk of serious infection ( 5.1 , 5.11 , 7.2 )
• Anakinra: Increased risk of serious infection ( 5.1 , 5.7 , 7.2 )
• Live vaccines: Avoid use with Adalimumab-adaz ( 5.10 , 7.3 ) * Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of Adalimumab-adaz has been demonstrated for the condition(s) of use (e.g. indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

7.1 Methotrexate Adalimumab has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent clearance of adalimumab, the data do not suggest the need for dose adjustment of either Adalimumab-adaz or MTX <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.2 Biological Products In clinical studies in patients with RA, an increased risk of serious infections has been observed with the combination of TNF-blockers with anakinra or abatacept, with no added benefit; therefore, use of Adalimumab-adaz with abatacept or anakinra is not recommended in patients with RA <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 , 5.11 )]</span> . A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information regarding the concomitant use of Adalimumab-adaz and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of Adalimumab-adaz with other biologic DMARDs (e.g., anakinra and abatacept) or other TNF-blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

7.3 Live Vaccines Avoid the use of live vaccines with Adalimumab-adaz <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10) ]</span>.

7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of Adalimumab-adaz in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

None. None ( 4 )

AND PRECAUTIONS

• Serious infections: Do not start Adalimumab-bwwd during an active infection. If an infection develops, monitor carefully, and stop Adalimumab-bwwd if infection becomes serious ( 5.1 )
• Invasive fungal infections: For patients who develop a systemic illness on Adalimumab-bwwd, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic ( 5.1 )
• Malignancies: Incidence of malignancies was greater in adalimumab-treated patients than in controls ( 5.2 )
• Anaphylaxis or serious hypersensitivity reactions may occur ( 5.3 )
• Hepatitis B virus reactivation: Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop Adalimumab-bwwd and begin anti- viral therapy ( 5.4 )
• Demyelinating disease: Exacerbation or new onset, may occur ( 5.5 )
• Cytopenias, pancytopenia: Advise patients to seek immediate medical attention if symptoms develop, and consider stopping Adalimumab-bwwd ( 5.6 )
• Heart failure: Worsening or new onset, may occur ( 5.8 )
• Autoimmunity: Stop Adalimumab-bwwd if lupus-like syndrome or autoimmune hepatitis develop ( 5.9 )

5.1 Serious Infections Patients treated with adalimumab products, including Adalimumab-bwwd, are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of Adalimumab-bwwd and these biologic products is not recommended in the treatment of patients with RA <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.7 , 5.11 ) and Drug Interactions ( 7.2 )]</span> . Treatment with Adalimumab-bwwd should not be initiated in patients with an active infection, including localized infections.

Patients

65 years of age and older, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. Consider the risks and benefits of treatment prior to initiating therapy in patients:

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
• with underlying conditions that may predispose them to infection.

Tuberculosis

Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving adalimumab products, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Adalimumab-bwwd and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating Adalimumab-bwwd, assess if treatment for latent tuberculosis is needed; and consider an induration of ≥ 5 mm a positive tuberculin skin test result, even for patients previously vaccinated with Bacille Calmette- Guerin (BCG). Consider anti-tuberculosis therapy prior to initiation of Adalimumab-bwwd in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with adalimumab products. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti- tuberculosis therapy is appropriate for an individual patient. Strongly consider tuberculosis in the differential diagnosis in patients who develop a new infection during Adalimumab-bwwd treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

Monitoring

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Adalimumab-bwwd, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with Adalimumab-bwwd.

Discontinue

Adalimumab-bwwd if a patient develops a serious infection or sepsis. For a patient who develops a new infection during treatment with Adalimumab-bwwd, closely monitor them, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and initiate appropriate antimicrobial therapy.

Invasive Fungal

Infections If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider appropriate empiric antifungal therapy, taking into account both the risk for severe fungal infection and the risks of antifungal therapy, while a diagnostic workup is being performed. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.

5.2 Malignancies Consider the risks and benefits of TNF-blocker treatment including Adalimumab-bwwd prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult subjects compared to control-treated adult subjects. During the controlled portions of 39 global adalimumab clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS), and uveitis (UV), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated subjects versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated subjects (median duration of treatment of 4 months for adalimumab-treated subjects and 4 months for control-treated subjects).

In

52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in adalimumab-treated subjects in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). 1 In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., subjects with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group. Non-Melanoma Skin Cancer During the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated subjects and 0.2 (0.10, 0.59) per 100 patient-years among control-treated subjects. Examine all patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment for the presence of NMSC prior to and during treatment with Adalimumab-bwwd. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF-blocker-treated subjects compared to control-treated subjects. In the controlled portions of 39 global adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV, 2 lymphomas occurred among 7973 adalimumab-treated subjects versus 1 among 4848 control-treated subjects.

In

52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS, and UV with a median duration of approximately 0.7 years, including 24,605 subjects and over 40,215 patient- years of adalimumab, the observed rate of lymphomas was approximately 0.11 per 100 patient- years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). 1 Rates of lymphoma in clinical trials of adalimumab cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those 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 blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. 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. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy ≤ 18 years of age), of which Adalimumab-bwwd is a member. 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 and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). 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. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including adalimumab products. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6- mercaptopurine and Adalimumab-bwwd should be carefully considered.

5.3 Hypersensitivity Reactions Anaphylaxis and angioneurotic edema have been reported following administration of adalimumab products. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue administration of Adalimumab-bwwd and institute appropriate therapy. In clinical trials of adalimumab, hypersensitivity reactions (e.g., rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed.

5.4 Hepatitis B Virus Reactivation Use of TNF blockers, including Adalimumab-bwwd, may increase the risk of 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. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. 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. For patients who are carriers of HBV and require treatment with TNF blockers, closely monitor such patients for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop Adalimumab-bwwd and initiate effective anti-viral therapy with appropriate supportive treatment. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of Adalimumab-bwwd therapy in this situation and monitor patients closely.

5.5 Neurologic Reactions Use of TNF blocking agents, including adalimumab products, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Exercise caution in considering the use of Adalimumab-bwwd in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders; discontinuation of Adalimumab-bwwd should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

5.6 Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with adalimumab products. The causal relationship of these reports to adalimumab products remains unclear. Advise all patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on Adalimumab-bwwd. Consider discontinuation of Adalimumab-bwwd therapy in patients with confirmed significant hematologic abnormalities.

5.7 Increased Risk of Infection When Used with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of Adalimumab-bwwd and anakinra is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.8 Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab products. Adalimumab products have not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using Adalimumab-bwwd in patients who have heart failure and monitor them carefully.

5.9 Autoimmunity Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 , 6.3 )]</span>. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Adalimumab-bwwd, discontinue treatment and evaluate the patient.

5.10 Immunizations In a placebo-controlled clinical trial of patients with RA, no difference was detected in anti- pneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of subjects developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown. Patients on Adalimumab-bwwd 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 products. 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 Adalimumab-bwwd therapy. Patients on Adalimumab-bwwd may receive concurrent vaccinations, except for live vaccines. The safety of administering live or live-attenuated vaccines in infants exposed to adalimumab products in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live- attenuated) exposed infants <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.4 )]</span> .

5.11 Increased Risk of Infection When Used with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including Adalimumab-bwwd is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .