ABRILADA 7 Warnings And Precautions

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

Concurrent Administration of Biologic DMARDs or TNF-Antagonists

Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocking agent, etanercept, with no added benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. Therefore, the combination of Abrilada and anakinra is not recommended. See (9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions injection).

Concomitant administration of Abrilada with other biologic DMARDs (e.g., anakinra and abatacept) or other TNF antagonists is not recommended based upon the increased risk for infections and other potential pharmacological interactions. See (9 DRUG INTERACTIONS, 9.4 Drug-Drug Interactions).

Switching Between Biological DMARDs

When switching from one biologic to another, patients should continue to be monitored for signs of infection.

Surgery

There is limited safety experience of surgical procedures in patients treated with adalimumab. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Abrilada should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving adalimumab.

Carcinogenesis and Mutagenesis

Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. See (16 NON-CLINICAL TOXICOLOGY, TOXICOLOGY, Mutagenicity and Carcinogenicity, In vitro Genotoxicity).

Cardiovascular

Patients with Congestive 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. Adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF-blocker, a higher rate of serious CHF-related adverse events was observed. Physicians should exercise caution when using Abrilada in patients who have heart failure and monitor them carefully. Abrilada is contraindicated in moderate to severe heart failure (see 2 CONTRAINDICATIONS).

Gastrointestinal

Small Bowel Obstruction

Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that adalimumab does not worsen or cause strictures.

Hematologic

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 infrequently 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 Abrilada. Discontinuation of Abrilada therapy should be considered in patients with confirmed significant hematologic abnormalities.

Hypersensitivity Reactions

Allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients receiving adalimumab in clinical trials. See (8 ADVERSE REACTIONS). Reports of serious allergic reactions, including anaphylaxis, have been received following adalimumab administration. If an anaphylactic reaction or other serious allergic reactions occur, administration of Abrilada should be discontinued immediately and appropriate therapy initiated.

Immune

Autoimmunity

Treatment with adalimumab may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Abrilada, treatment should be discontinued. See (8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview, Autoantibodies).

Immunosuppression

The possibility exists for TNF-blocking agents, including adalimumab, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis who 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. The impact of treatment with adalimumab on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. See (7 WARNINGS AND PRECAUTIONS, Infections and Malignancies) and (8 ADVERSE REACTIONS, 8.1 Adverse Reaction Overview, Infections and Malignancies).

Immunizations

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 patients and 40% of placebo-treated patients achieved at least a 2-fold increase in antibody titer to at least three out of five 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 patients and 63% of placebo-treated patients achieved at least a 4-fold increase in antibody titer to at least two out of three 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 Abrilada therapy.

Patients on Abrilada 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 five months following the mother’s last Abrilada injection during pregnancy. See (7 WARNINGS AND PRECAUTIONS, 7.1 Special Populations, 7.1.1 Pregnant Women).

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) tuberculosis. Before initiation, during and after treatment with Abrilada, patients should be evaluated for active and inactive (“latent”) tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infections should be initiated prior to therapy with Abrilada. 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-Guérin (BCG).

If active tuberculosis is diagnosed, Abrilada therapy must not be initiated.

The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or travelled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis. If latent infection is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylactic treatment, in accordance with the Canadian Tuberculosis Standards and Centers for Disease Control and Prevention guidelines, before the initiation of Abrilada. Use of anti-tuberculosis prophylactic treatment should also be considered before the initiation of Abrilada 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.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients receiving adalimumab. Also, active tuberculosis has developed in patients receiving adalimumab 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 Abrilada 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, listlessness) occur during or after therapy with Abrilada, and physicians should monitor for signs and symptoms of active tuberculosis, including patients who are tuberculosis skin test negative.

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 Virus (HBV) Reactivation

Very rare cases of hepatitis B virus (HBV) reactivation have been associated with anti-TNF therapy. Clinically active HBV infection occurred following a latency period ranging from 3 to 20 months after initiation of therapy. In the majority of cases, patients were also taking other immunosuppressive drugs, including methotrexate, azathioprine, and/or corticosteroids. Hence, establishing a causal relationship to anti-TNF agents is confounded by the presence of these other medications. Where outcome information was provided, most patients were reported to have improved after antiviral treatment and/or discontinuation of the anti-TNF agent. However, fatal outcomes have also occurred in reported cases. Patients at risk of HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy. Those identified as chronic carriers (i.e., surface antigen positive) should be monitored for signs and symptoms of active HBV infection throughout the course of therapy and for several months following discontinuation of therapy. Reactivation of HBV is not unique to anti-TNF-alpha agents and has been reported with other immunosuppressive drugs.

Malignancies

In the controlled portions of clinical trials of some TNF-blocking agents, including adalimumab, more cases of malignancies have been observed among patients receiving those TNF-blockers compared to control patients.

In the controlled and uncontrolled open-label portions of clinical trials of adalimumab, the more frequently observed malignancies, other than lymphoma and non-melanoma skin cancer, were breast, colon, prostate, lung, and melanoma.

Cases of acute and chronic leukemia have been reported in association with post-marketing 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.

Malignancies in Pediatric Patients and Young Adults

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (i.e., including adalimumab). 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 post-marketing reports.

Post-marketing 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. 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 Abrilada should be carefully considered.

No malignancies were observed in the indicated pediatric patient population with Crohn’s disease treated with adalimumab (n=102) for 52 weeks in a clinical trial.

No malignancies were observed in pediatric patients aged 3 to 17 years with active JIA-associated chronic non-infectious anterior uveitis who were treated with adalimumab (n=90, randomized 2:1 to adalimumab:placebo) for up to18 months in a clinical trial.

Treatment-emergent malignancies occurred in 2/480 adalimumab-treated UC patients in the double-blind controlled portion of two clinical trials (range of treatment duration from Weeks 0 to 52). The malignancies were squamous cell carcinoma and gastric cancer. Gastric cancer was considered serious and the patient discontinued as a result.

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 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.

Lymphoma

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving TNF-blockers compared to control patients.

However, for adalimumab, the occurrence of lymphoma was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. 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.

In combining the controlled and uncontrolled open-label portions of the 23 clinical trials in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis, with a median duration of approximately 2.4 years, including 8764 patients and 27,196 patient-years of therapy, the observed rate of lymphomas (95% CI) is 1.2 [0.9, 1.7] per 1000 patient-years. This is approximately 3-fold higher than expected in the general population.

During the controlled and open-label periods of 14 trials with adalimumab, the overall standard incidence ratio (SIR) of malignancies was 0.99 [95% confidence interval (CI), 0.81 to 1.20]. With current knowledge in this area, a possible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.

No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving adalimumab. Additional caution should be exercised when considering Abrilada treatment in these patients.

Non-Lymphoma Malignancy

During the controlled portions of 21 adalimumab trials in adult patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% CI) of 6.9 (4.4, 10.6) per 1,000 patient-years among 5196 adalimumab-treated patients versus a rate of 6.4 (3.5, 11.9) per 1,000 patient-years among 3347 control patients (median duration of treatment of 4.0 months for adalimumab-treated patients and 3.9 months for control-treated patients).

During the controlled portions of 21 adalimumab rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, psoriasis, and uveitis trials, the rate (95% CI) of non-melanoma skin cancers was 8.9 (6.1, 13.1) per 1,000 patient-years among adalimumab-treated patients and 3.2 (1.3, 7.7) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% CI) of 2.7 (1.4, 5.5) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.6) per 1,000 patient-years among control patients. The rate (95% CI) of lymphomas was 0.7 (0.2, 2.7) per 1,000 patient-years among adalimumab-treated patients and 0.6 (0.1, 4.6) per 1,000 patient-years among control patients.

The observed rate of malignancies, other than lymphoma and non-melanoma skin cancers, is approximately (95% CI) 8.5 (7.4, 9.7) per 1,000 patient years in the controlled portion of clinical trials and in ongoing and completed open-label extension studies. The observed rate of non- melanoma skin cancers is (95% CI) approximately 9.6 (8.5, 10.9) per 1,000 patient years, and the observed rate of lymphomas is (95% CI) approximately 1.3 (0.9, 1.8) per 1,000 patient years. The median duration of these studies is approximately 3.3 years and included 6276 adult patients who were on adalimumab for at least one year or who developed a malignancy within a year of starting therapy, representing over 26,044 patient years of therapy.

All patients, and in particular psoriasis patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of Psoralen Ultra-Violet A (PUVA) treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with Abrilada.

Monitoring and Laboratory Tests

There is no known interference between adalimumab and laboratory tests. 

Neurologic

Use of TNF-blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of 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 Abrilada in patients with preexisting or recent onset central nervous system demyelinating disorders; discontinuation of Abrilada 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 Abrilada therapy to assess for pre-existing central demyelinating disorders.

7.1 Special Populations

7.1.1 Pregnant Women

The extent of exposure in pregnancy during clinical trials is very limited, consisting only of individual cases.

An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human area under the curve (AUC) when given 40 mg adalimumab subcutaneously with methotrexate every week, or 373 times human AUC when given 40 mg adalimumab subcutaneously without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, Abrilada should be used during pregnancy only if clearly needed.

In a prospective cohort pregnancy exposure registry, conducted by the Organization of Teratology Information Specialists (OTIS)/MotherToBaby in the U.S. and Canada between 2004 and 2016, the risk of major birth defects in live-born infants was compared in 69 women with RA and 152 women with CD treated with adalimumab at least during the first trimester with 74 women with RA and 32 women with CD not treated with adalimumab during pregnancy. The proportion of major birth defects among live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD), respectively.

No pattern of major birth defects was observed. This study cannot reliably establish whether there is an association between adalimumab and the risk for major birth defects because of methodological limitations of the registry, including small sample size, the voluntary nature of the study, and the non-randomized design.

Adalimumab may cross the placenta into the serum of infants born to women treated with adalimumab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for five months following the mother’s last adalimumab injection during pregnancy.

Labor and Delivery

There are no known effects of adalimumab on labor or delivery.

7.1.2 Breast-feeding

Limited information from case reports in the published literature indicates the presence of adalimumab in human milk at concentrations of 0.1% to 1% of the maternal serum level. Published data suggest that the systemic exposure of adalimumab to a breastfed infant is expected to be low because adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects of local exposure in the gastrointestinal tract are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for adalimumab and any potential adverse effects on the breastfed child from adalimumab or from the underlying maternal condition.

7.1.3 Pediatrics

Polyarticular JIA

The efficacy and safety of adalimumab have been studied in pediatric patients aged 4 to 17 years (n=171) and 2 to 4 years (n=32). No overall differences were observed in the efficacy and safety between the two age groups. Adalimumab has not been studied in pediatric patients with polyarticular JIA less than 2 years of age or in pediatric patients with a weight below 10 kg.

Pediatric Crohn’s Disease

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Pediatric Uveitis

The efficacy and safety of adalimumab have been studied in pediatric patients with uveitis aged 2 to 17 years (n=90, randomized 2:1 to adalimumab: placebo). Very limited data are available for pediatric patients with uveitis between 2 and < 3 years of age. Serious adverse events were more frequent in children 4 years of age and younger.

Pediatric Ulcerative Colitis

The efficacy and safety of adalimumab has been studied in pediatric patients with ulcerative colitis aged 5 to 17 years (N = 93).

7.1.4 Geriatrics

A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years and older, received adalimumab in clinical Studies DE009, DE011, DE019 and DE031. No overall differences in effectiveness were observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab-treated patients over age 65 was higher than for those under the age of 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.