Abrilada

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABRILADA (ABRILADA®)

Composition:

Active substance: adalimumab;

One pre-filled pen contains 40 mg adalimumab in 0.8 mL of solution;

Excipients: L-histidine, L-histidine hydrochloride monohydrate, sucrose, disodium edetate dihydrate, L-methionine, polysorbate 80, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless to slightly light brown solution.

Pharmacotherapeutic group

Immunosuppressants. Tumor necrosis factor-alpha (TNF-α) inhibitors.

ATC Code L04A B04.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Adalimumab specifically binds to TNF and neutralizes the biological effects of TNF, blocking its interaction with the p55 and p75 TNF receptors on the cell surface.

Adalimumab also modulates biological responses induced or regulated by TNF, including changes in levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 at IC50 0.1–0.2 nM).

Pharmacodynamic Effects

In patients with rheumatoid arthritis, adalimumab caused a rapid reduction, compared to baseline values, in markers of acute-phase inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], and serum cytokine levels [IL-6]). Following adalimumab administration, a reduction in serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which mediate tissue remodeling underlying cartilage destruction, was also observed. Patients receiving adalimumab typically showed a reduction in hematological signs of chronic inflammation.

Following adalimumab treatment, rapid reduction in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), ulcerative colitis (UC), and hidradenitis suppurativa (HS). Concurrently, in patients with Crohn’s disease, a significant reduction in TNF-α expression was associated with decreased numbers of cells expressing inflammatory markers in the colon. Endoscopic evaluations of intestinal mucosa in patients receiving adalimumab demonstrated signs of mucosal healing.

Pharmacokinetics

Absorption and Distribution

After a single subcutaneous dose of 40 mg, absorption and distribution of adalimumab were slow, with mean peak serum concentrations reached approximately 5 days after administration. The mean absolute bioavailability of adalimumab, calculated from three studies, following a single 40 mg subcutaneous dose, was 64%.

After a single intravenous dose ranging from 0.25 to 10 mg/kg, concentrations were dose-proportional. Following a 0.5 mg/kg dose (approximately 40 mg), clearance ranged from 11–15 mL/hour, the volume of distribution (Vss) was 5 to 6 L, and the mean terminal half-life was approximately 2 weeks. Adalimumab concentrations in synovial fluid in patients with rheumatoid arthritis were 31–96% of serum levels.

After subcutaneous administration of 40 mg every 2 weeks in patients with rheumatoid arthritis (RA), steady-state concentrations ranged from 5 µg/mL (without concomitant methotrexate) to 8–9 µg/mL (with methotrexate). Serum adalimumab concentrations at steady state increased nearly proportionally with subcutaneously administered doses of 20, 40, and 80 mg every 2 weeks or weekly.

After subcutaneous administration of 24 mg/m² (maximum 40 mg) every 2 weeks in patients with polyarticular juvenile idiopathic arthritis aged 4 to 17 years, steady-state concentrations (measured from week 20 to week 48) were 5.6 ± 5.6 µg/mL (102% CV – coefficient of variation) without concomitant methotrexate and 10.9 ± 5.2 µg/mL (47.7% CV) with methotrexate.

In children with polyarticular JIA aged 2–4 years and in children aged ≥4 years with body weight <15 kg, after administration of adalimumab at 24 mg/m² without concomitant methotrexate, mean steady-state concentrations were 6.0 ± 6.1 mg/mL (101% CV) and 7.9 ± 5.6 µg/mL (71.2% CV) with methotrexate, respectively.

After subcutaneous administration of 24 mg/m² (maximum 40 mg) every 2 weeks in patients aged 6 to 17 years with enthesitis-related arthritis, steady-state concentrations (measured at week 24) were 8.8 ± 6.6 µg/mL without concomitant methotrexate and 11.8 ± 4.3 µg/mL with methotrexate.

After subcutaneous administration of 40 mg every 2 weeks in adult patients with non-radiographic axial spondyloarthritis, the mean (± standard deviation) steady-state concentration at week 68 was 8.0 ± 4.6 µg/mL.

In adult patients with psoriasis, the mean steady-state serum concentration was 5 µg/mL with adalimumab monotherapy at 40 mg every 2 weeks.

After administration of adalimumab at 0.8 mg/kg (maximum 40 mg) subcutaneously every 2 weeks in children with chronic plaque psoriasis, the mean (± standard deviation) steady-state concentration was approximately 7.4 ± 5.8 µg/mL (79% CV).

In adult patients with hidradenitis suppurativa, serum adalimumab concentrations after administration of 160 mg at week 0 followed by 80 mg at week 2 were approximately 7 to 8 µg/mL at weeks 2 and 4. The mean steady-state concentration from week 12 to week 36 was approximately 8 to 10 µg/mL when adalimumab was administered at 40 mg weekly. The effect of adalimumab in children with HS was determined using pharmacokinetic modeling and simulation based on pharmacokinetics from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis, Crohn’s disease, and enthesitis-related arthritis). The recommended dosing regimen for children with HS is 40 mg every 2 weeks. Since adalimumab exposure may depend on patient body weight, children with higher body weight and inadequate response to treatment may receive the recommended adult dose of 40 mg weekly.

In patients with Crohn’s disease, after administration of adalimumab at 80 mg at week 0 followed by 40 mg at week 2, serum concentrations were approximately 5.5 µg/mL during induction therapy. After administration of 160 mg at week 0 followed by 80 mg at week 2, serum concentrations were approximately 12 µg/mL during induction. The mean steady-state concentration in patients with Crohn’s disease was approximately 7 µg/mL when adalimumab was administered at the maintenance dose of 40 mg every 2 weeks.

In children with moderate to severe Crohn’s disease, the initial dose of adalimumab in an open-label study was 160/80 mg or 80/40 mg at weeks 0 and 2, depending on body weight. At week 4, patients were randomized 1:1 to receive, based on body weight, either standard dose (40/20 mg every 2 weeks) or low dose (20/10 mg every 2 weeks) for maintenance therapy. The mean (± standard deviation) steady-state concentration was approximately 15.7 ± 6.6 µg/mL at week 4 in patients with body weight ≥40 kg (160/80 mg) and 10.6 ± 6.1 µg/mL in patients with body weight <40 kg (80/40 mg).

In patients who continued treatment in their assigned group, mean (± standard deviation) adalimumab concentrations at week 52 were 9.5 ± 5.6 µg/mL in the standard-dose group and 3.5 ± 2.2 µg/mL in the low-dose group. Mean concentrations remained stable in patients who continued adalimumab treatment over 52 weeks. In patients whose dose was increased from once every 2 weeks to once weekly, mean (± standard deviation) serum adalimumab concentrations at week 52 were 15.3 ± 11.4 µg/mL (40/20 mg weekly) and 6.7 ± 3.5 µg/mL (20/10 mg weekly).

In patients with ulcerative colitis, after administration of adalimumab at an initial dose of 160 mg at week 0 followed by 80 mg at week 2, serum concentrations were approximately 12 µg/mL during induction therapy. The mean steady-state concentration in patients with ulcerative colitis was approximately 8 µg/mL during maintenance therapy with 40 mg every 2 weeks.

In children with ulcerative colitis, the mean steady-state serum concentration of adalimumab at week 52 after subcutaneous administration of a body weight-based dose of 0.6 mg/kg (maximum 40 mg) every 2 weeks was 5.01 ± 3.28 µg/mL. In patients who received 0.6 mg/kg (maximum 40 mg) weekly, the mean (± standard deviation) steady-state serum concentration at week 52 was 15.7 ± 5.60 µg/mL.

In patients with uveitis, after administration of adalimumab at an initial dose of 80 mg at week 0 followed by 40 mg every 2 weeks starting at week 1, the mean steady-state concentration was approximately 8 to 10 µg/mL.

The effect of adalimumab in children with uveitis was determined using pharmacokinetic modeling and simulation based on pharmacokinetics from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis, Crohn’s disease, and enthesitis-related arthritis). There are no clinical data on initial dosing in children under 6 years of age. In the absence of methotrexate, the initial dose is predicted to lead to increased systemic exposure.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and simulation predicted comparable exposure and efficacy of adalimumab in patients receiving 80 mg every 2 weeks versus 40 mg weekly (including adult patients with RA, HS, UC, CD, or psoriasis, children with HS, and children with body weight ≥40 kg with CD or UC).

Exposure–Response Relationship in Children

Based on clinical trial data in patients with JIA (pJIA and ERA), an exposure–response relationship was established between plasma concentration and response according to the PedACR 50 criterion. The apparent plasma concentration of adalimumab associated with half-maximal probability of PedACR 50 response (EC50) was 3 µg/mL (95% CI 1–6 µg/mL). The exposure–response relationship between adalimumab concentration and efficacy in children with moderate to severe chronic plaque psoriasis was established for responses based on PASI 75 and PGA (‘clear’ or ‘minimal’). PASI 75 and PGA ‘clear’ or ‘minimal’ responses increased with increasing adalimumab concentration, with both endpoints showing a similar apparent EC50 of approximately 4.5 µg/mL (95% CI 0.4–47.6 and 1.9–10.5, respectively).

Elimination

Population pharmacokinetic analysis of data from over 1300 patients with rheumatoid arthritis revealed a trend toward increased apparent clearance of adalimumab with increasing body weight. After adjusting for body weight differences, patient sex and age were found to have minimal impact on adalimumab clearance. Serum levels of free adalimumab (not bound to anti-adalimumab antibodies [AAA]) were lower in patients who tested positive for AAA.

Hepatic or Renal Impairment

Adalimumab has not been studied in patients with hepatic or renal impairment.

Clinical characteristics

Indications

Rheumatoid arthritis

Adalimumab in combination with methotrexate is indicated for:

• treatment of moderate to severe active rheumatoid arthritis in adult patients when an adequate response has not been achieved with disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• treatment of severe active and progressive rheumatoid arthritis in adult patients who have not previously been treated with methotrexate.

Adalimumab may be used as monotherapy in cases of methotrexate intolerance or when continuation of methotrexate therapy is considered inappropriate.

Adalimumab has demonstrated slowing of radiographically confirmed structural joint damage progression and improvement in functional status when used concomitantly with methotrexate.

Juvenile idiopathic arthritis

Polyarticular juvenile idiopathic arthritis

Adalimumab in combination with methotrexate is indicated for treatment of active polyarticular juvenile idiopathic arthritis in patients with body weight ≥ 30 kg who have had an inadequate response to one or more DMARDs. Adalimumab may be used as monotherapy in cases of methotrexate intolerance or when continuation of methotrexate therapy is considered inappropriate (see section "Pharmacodynamics" regarding efficacy in monotherapy). No studies have been conducted with adalimumab in patients under 2 years of age.

Enthesitis-related arthritis

Adalimumab is indicated for treatment of active enthesitis-related arthritis in patients with body weight ≥ 30 kg who have had an inadequate response to conventional therapy, or in whom such therapies are contraindicated or not tolerated (see section "Pharmacodynamics").

Axial spondyloarthritis

Ankylosing spondylitis (AS)

Adalimumab is indicated for treatment of adult patients with severe active ankylosing spondylitis who have not responded to conventional therapy.

Axial spondyloarthritis without radiographic confirmation of AS

Adalimumab is indicated for treatment of adult patients with active axial spondyloarthritis without radiographic confirmation of AS but with evidence of inflammation based on elevated CRP levels and/or MRI findings, who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) or who are intolerant to these drugs.

Psoriatic arthritis

Adalimumab is indicated for treatment of active and progressive psoriatic arthritis in adult patients who have had an inadequate response to prior DMARD therapy. Adalimumab has demonstrated slowing of radiographic progression of peripheral joint damage in patients with symmetric polyarticular disease (see section "Pharmacodynamics") and improvement in functional status.

Psoriasis

Adalimumab is indicated for treatment of adult patients with moderate to severe chronic plaque psoriasis who require systemic therapy.

Plaque psoriasis in children

Adalimumab is indicated for treatment of severe chronic plaque psoriasis in children with body weight ≥ 30 kg who have had an inadequate response to, or contraindications to/intolerance of, topical therapy and/or phototherapy.

Hidradenitis suppurativa

Adalimumab is indicated for treatment of moderate to severe active hidradenitis suppurativa (HS) (acne inversa) in adult patients and children aged 12 years and older who have not responded to conventional systemic HS therapy (see sections "Pharmacodynamics" and "Pharmacokinetics").

Crohn's disease

Adalimumab is indicated for treatment of moderate to severe Crohn's disease in adult patients who have not responded to a full course of corticosteroid and/or immunosuppressant therapy, or in whom such therapies are contraindicated or not tolerated.

Crohn's disease in children

Adalimumab is indicated for treatment of moderate to severe Crohn's disease in children (with body weight ≥ 40 kg) who have not responded to conventional therapy, including primary nutritional therapy, corticosteroids and/or immunomodulators, or in whom such therapies are contraindicated or not tolerated.

Ulcerative colitis

Adalimumab is indicated for treatment of moderate to severe active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy, including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or in whom such therapies are contraindicated or not tolerated.

Ulcerative colitis in children

Adalimumab is indicated for treatment of moderate to severe active ulcerative colitis in children (aged 6 years and older) who have had an inadequate response to conventional therapy, including corticosteroids and/or 6-mercaptopurine (6-MP) or azathioprine (AZA), or in whom such therapies are contraindicated or not tolerated.

Uveitis

Adalimumab is indicated for treatment of non-infectious intermediate, posterior, and panuveitis in adult patients who have not responded to corticosteroid therapy, who require corticosteroid dose reduction, or in whom corticosteroid therapy is contraindicated or not tolerated.

Uveitis in children

Adalimumab is indicated for treatment of chronic non-infectious anterior uveitis in children with body weight ≥ 30 kg who have not responded to, are intolerant to, or for whom conventional therapy is contraindicated.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Active tuberculosis or other serious infections such as sepsis and opportunistic infections (see section "Special precautions").

Moderate to severe heart failure (NYHA class III/IV) (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction

Adalimumab has been studied in patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriatic arthritis receiving the drug as monotherapy and in combination with methotrexate. The rate of antibody formation was lower when adalimumab was used concomitantly with methotrexate compared to monotherapy. Use of adalimumab without methotrexate resulted in increased antibody formation, increased clearance, and reduced efficacy of adalimumab (see section "Pharmacodynamics").

Concomitant use of Adalimumab with anakinra is not recommended (see below "Concomitant use with biologic DMARDs or TNF antagonists").

Concomitant use of Adalimumab with abatacept is not recommended (see below "Concomitant use with biologic DMARDs or TNF antagonists").

Special precautions for use

Traceability

To improve the monitoring of biological medicinal products, it is necessary to clearly record in the documentation the trade name and batch number of the administered medicinal product.

Infections

The risk of developing severe infections increases in patients receiving TNF antagonists. Impaired lung function may increase the risk of developing infections. Therefore, patients should be closely monitored before, during, and after treatment with the medicinal product Abrilada due to the possibility of developing infections (including tuberculosis). Since elimination of adalimumab may last up to four months, monitoring of patients should continue throughout this period.

Abrilada should not be administered to patients with active infectious processes, including chronic or localized infections, until the infection is controlled. In patients who have had contact with individuals with tuberculosis or who have returned from countries with a high incidence of tuberculosis or from endemic areas for fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis), the benefit-risk ratio should be assessed before initiating Abrilada therapy (see below "Other opportunistic infections").

A complete evaluation and careful monitoring are required for patients who develop a new infection during treatment with Abrilada. Treatment with Abrilada should be discontinued in the event of severe infection or sepsis, and appropriate antimicrobial or antifungal agents should be administered until the infection is controlled. Abrilada should be used with particular caution in patients with recurrent infections or pre-existing conditions that increase susceptibility to infections, including concomitant use of immunosuppressive agents.

Severe infections

Severe infections, such as sepsis caused by bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections (listeriosis, legionellosis, and pneumocystosis), have been observed in patients receiving adalimumab.

Other severe infections, including pneumonia, pyelonephritis, septic arthritis, and septicemia, were observed in clinical trials. Cases of hospitalization due to infections (including fatal outcomes) have been reported.

Tuberculosis

Cases of reactivation and development of new tuberculosis infections have been reported in patients receiving adalimumab therapy. Reports included both pulmonary and extrapulmonary forms (i.e., disseminated tuberculosis).

Before initiating therapy with Abrilada, patients should be thoroughly evaluated for active and inactive (latent) tuberculosis. The evaluation should include a thorough assessment of the patient's history of tuberculosis or exposure to individuals with active tuberculosis, as well as previous and/or concomitant immunosuppressive therapy. All patients should undergo a tuberculin skin test (Mantoux test) and chest X-ray before starting therapy (local recommendations may apply). The performance and results of these tests should be documented in the patient's medical record. Physicians should be aware of the risk of false-negative tuberculin skin test results, particularly in severely ill or immunocompromised patients.

Abrilada therapy should not be initiated if active tuberculosis is diagnosed (see section "Contraindications").

In all situations described below, the benefit-risk ratio of therapy should be carefully considered.

The decision to treat patients with suspected latent tuberculosis should be made after consultation with a pulmonologist.

In cases of latent tuberculosis, specific anti-tuberculosis treatment should be initiated before starting Abrilada therapy, in accordance with local recommendations.

Consideration should be given to initiating anti-tuberculosis treatment before starting Abrilada therapy in patients with risk factors for tuberculosis infection who have a negative latent tuberculosis test result, and in patients with a history of latent or active tuberculosis for whom adequate treatment cannot be confirmed.

Despite prophylactic anti-tuberculosis treatment, cases of tuberculosis reactivation have occurred in patients receiving adalimumab. In some patients who previously received successful treatment for active tuberculosis, recurrent tuberculosis has developed during adalimumab therapy.

All patients should be advised to consult a physician if symptoms suggestive of tuberculosis (e.g., persistent cough, fatigue/weight loss, low-grade fever, lethargy) develop during or after Abrilada therapy.

Other opportunistic infections

Opportunistic infections, including invasive fungal infections, have been reported during adalimumab therapy. Such infections have sometimes not been diagnosed promptly in patients receiving TNF antagonists, leading to delayed treatment initiation and occasionally resulting in death.

In the event of fever, malaise, weight loss, increased sweating, cough, dyspnea, and/or pulmonary infiltrates or other signs of serious systemic illness (with or without shock), patients should undergo immediate evaluation for invasive fungal infection and Abrilada administration should be discontinued immediately. The decision to initiate empirical antifungal therapy in such patients should be made after consultation with an expert in the diagnosis and treatment of invasive fungal infections.

Hepatitis B virus reactivation

The use of TNF blockers, including adalimumab, has been associated with reactivation of hepatitis B virus in chronic carriers (i.e., those with a positive surface antigen). Cases of hepatitis B virus reactivation have sometimes been fatal. Before initiating Abrilada therapy, patients at risk should be screened for hepatitis B virus. If the screening result is positive, the decision to treat should be made after consultation with a hepatologist.

Abrilada should be used with caution in patients who are hepatitis B virus carriers, and if prescribed, such patients should be closely monitored for signs of hepatitis B virus reactivation during therapy and for several months after discontinuation of treatment. There are no data on the efficacy and safety of antiviral agents for preventing hepatitis B virus reactivation in carriers receiving TNF antagonists to prevent reactivation. In the event of hepatitis B virus reactivation, Abrilada therapy should be discontinued and effective antiviral treatment and appropriate supportive therapy should be initiated.

Neurological disorders

Rare cases of onset or exacerbation of clinical and/or radiological signs of demyelinating disorders of the central nervous system, including multiple sclerosis, optic neuritis, and demyelinating disorders of the peripheral nervous system, including Guillain-Barré syndrome, have been reported during treatment with TNF blockers, including adalimumab. Careful assessment of the benefit-risk ratio of using Abrilada is recommended in patients with demyelinating disorders of the central or peripheral nervous system. Therapy with Abrilada should be discontinued if such disorders occur. An association between non-infectious intermediate uveitis and demyelinating disorders of the central nervous system is known. Neurological evaluation should be performed in patients with non-infectious intermediate uveitis before initiating Abrilada therapy and regularly during therapy to monitor for the development of central nervous system demyelinating disorders.

Allergic reactions

Serious allergic reactions associated with adalimumab occurred rarely during clinical trials. Non-serious allergic reactions associated with adalimumab occurred infrequently during clinical trials. Serious allergic reactions, including anaphylaxis, have been reported after adalimumab administration. In the event of an anaphylactic reaction or other serious allergic reaction, Abrilada administration should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

During clinical trials in 64 patients with rheumatoid arthritis receiving adalimumab, no cases of suppression of delayed-type hypersensitivity, reduction in immunoglobulin levels, or quantitative changes in effector T- and B-cells, as well as NK cells, monocytes/macrophages, and neutrophils were observed.

Malignancies and lymphoproliferative disorders

In controlled clinical trials of TNF antagonists, malignancies, including lymphoma, were reported more frequently in patients receiving a TNF antagonist than in control group patients. However, these cases were rare. In post-marketing experience, cases of leukemia associated with the use of TNF antagonists have been reported. Moreover, patients with long-standing, highly active rheumatoid arthritis have an increased background risk of developing lymphoma and leukemia, which complicates risk assessment. Based on available data, a possible risk of developing lymphoma, leukemia, or other malignancies in patients treated with TNF antagonists cannot be excluded.

Post-marketing experience has reported cases of malignancies (including fatal cases) in children and adults (up to 22 years of age) who received treatment with TNF antagonists (age at initiation of therapy ≤ 18 years), including adalimumab. Lymphomas accounted for approximately half of these cases. The remainder included various malignancies, including rare malignancies typically associated with immunosuppression. The risk of developing malignancies in children receiving TNF antagonist therapy cannot be excluded.

In post-marketing experience, hepatosplenic T-cell lymphoma has been very rarely reported in patients receiving adalimumab. This is a rare type of lymphoma characterized by a highly aggressive course and is usually fatal. Some cases of hepatosplenic T-cell lymphoma during adalimumab therapy occurred in young people who had previously received therapy with infliximab in combination with azathioprine or 6-mercaptopurine for the treatment of inflammatory bowel diseases. The potential risk of concomitant use of azathioprine or 6-mercaptopurine with adalimumab should be carefully evaluated. The risk of developing hepatosplenic T-cell lymphoma in patients receiving Abrilada therapy cannot be excluded (see section "Adverse reactions").

Studies on the use of adalimumab in patients with a history of malignancies or continuation of therapy in patients who develop malignancies have not been conducted. Therefore, this should be taken into account, and decisions on using adalimumab in such patients should be made with caution (see section "Adverse reactions").

In all patients, especially those with a history of intensive immunosuppressive therapy, or in patients with psoriasis who have received PUVA therapy (psoralens with UVA), non-melanoma skin cancer should be excluded before and during the period of Abrilada use. Melanoma and Merkel cell carcinoma have also been reported in patients receiving TNF antagonists, including adalimumab (see section "Adverse reactions").

In a prospective clinical trial evaluating the use of another TNF antagonist (infliximab) in patients with chronic obstructive pulmonary disease, more frequent cases of malignancies, mostly in the lungs, head, and neck area, were reported compared to the control group. All patients were long-term smokers. Therefore, TNF antagonists should be used with caution in patients with chronic obstructive pulmonary disease and in patients with an increased risk of malignancies due to smoking. Currently, it is unknown whether adalimumab use affects the risk of developing dysplasia or colorectal cancer. All patients with ulcerative colitis who are at increased risk of developing dysplasia or colorectal cancer (including patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or those with a history of dysplasia or colorectal cancer, should undergo regular screening for dysplasia before starting therapy and throughout the course of the disease. Screening should include colonoscopy and biopsy according to local recommendations.

Hematological disorders

Rarely, pancytopenia and aplastic anemia have been reported with the use of TNF antagonists. Cytopenia (thrombocytopenia, leukopenia) of clinical significance has been reported with adalimumab use. All patients should be advised to seek immediate medical consultation if symptoms characteristic of blood disorders (such as persistent fever, bruising, bleeding, pallor of skin and mucous membranes) occur during Abrilada use. Discontinuation of Abrilada should be considered if serious blood disorders are confirmed in the patient.

Vaccination

Similar antibody responses to the standard 23-valent pneumococcal vaccine and trivalent influenza vaccine were observed in a study involving 226 adult patients with rheumatoid arthritis receiving adalimumab or placebo. There are no data on secondary transmission of infection from live vaccines in patients receiving adalimumab.

Children of vaccination age are recommended to receive all necessary vaccinations according to the vaccination schedule before starting adalimumab therapy, if possible.

Patients receiving adalimumab may be vaccinated, except for live vaccines. Live vaccines (e.g., BCG vaccine) should not be administered to infants exposed to adalimumab in utero within 5 months after the last adalimumab injection to the mother during pregnancy.

Heart failure

In a clinical trial with another TNF antagonist, worsening of heart failure and increased mortality associated with heart failure were observed. Cases of worsening heart failure have also been reported in patients receiving adalimumab. Abrilada should be used with caution in patients with mild heart failure (NYHA class I/II). Abrilada is contraindicated in moderate to severe heart failure (see section "Contraindications"). Abrilada therapy should be discontinued if new symptoms of heart failure develop or if heart failure worsens.

Autoimmune processes

Treatment with Abrilada may lead to the development of autoantibodies. The impact of long-term adalimumab use on the development of autoimmune diseases is unknown. If symptoms suggestive of lupus-like syndrome develop during Abrilada therapy and antibodies to double-stranded DNA are detected, further treatment with Abrilada should be discontinued (see section "Adverse reactions").

Concomitant use with biological disease-modifying antirheumatic drugs or other TNF antagonists

Severe infections were observed during clinical trials of concomitant use of anakinra and another TNF antagonist (etanercept), without therapeutic advantage compared to etanercept monotherapy. Given the nature of adverse events observed during combination therapy with etanercept and anakinra, similar toxicity may develop with the combination of anakinra and another TNF antagonist. Therefore, the combination of adalimumab and anakinra is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of adalimumab with other biological agents (e.g., anakinra and abatacept) or with other TNF antagonists is not recommended due to the potential increased risk of severe infections and other potential pharmacological interactions (see section "Interaction with other medicinal products and other forms of interaction").

Surgical procedures

Limited data are available on the safety of surgical procedures in patients receiving adalimumab. The long half-life of adalimumab should be taken into account when planning surgical procedures. A patient requiring surgery and receiving Abrilada therapy should be carefully evaluated for infections. Appropriate measures should be taken if necessary. Limited data are available on the safety of use in patients who underwent arthroplasty during adalimumab therapy.

Small bowel obstruction

Lack of response to Crohn's disease treatment may indicate the presence of a fixed fibrotic stricture requiring surgical treatment. Available data suggest that Abrilada therapy does not cause the development or progression of strictures.

Elderly patients

The frequency of severe infections in patients aged 65 years and older receiving adalimumab (3.7%) is higher than in younger patients (1.5%). Some cases were fatal. Due to the higher frequency of infections in elderly patients, Abrilada should be used with caution in this age group.

Excipients

Polysorbate

This medicinal product contains polysorbate 80, which may cause hypersensitivity reactions.

Sodium

This medicinal product contains less than 1 mmol of sodium (23 mg) per 0.8 mL, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should use reliable contraception methods during treatment and for at least five months after the last dose of Abrilada.

Pregnancy

A prospective analysis of data on adalimumab use during pregnancy (approximately 2100 pregnancies resulting in live births with known outcomes, including over 1500 cases of use in the first trimester) did not show an increased frequency of congenital malformations in newborns.

A prospective cohort registry included 257 women with rheumatoid arthritis (RA) or Crohn's disease (CD) who received adalimumab for at least the first trimester, and 120 women with RA or CD who did not receive adalimumab. The primary endpoint was the frequency of major congenital malformations in newborns. The frequency of pregnancies resulting in the birth of at least one live infant with a major congenital malformation was 6 out of 69 (8.7%) in the group of women with RA receiving adalimumab and 5 out of 74 (6.8%) in the group of women with RA not receiving the drug (unadjusted odds ratio [OR] 1.31, 95% confidence interval [CI] 0.38–4.52). In the group of women with CD receiving adalimumab, the frequency was 16 out of 152 (10.5%), and in the group of women with CD not receiving the drug, 3 out of 32 (9.4%) (unadjusted OR 1.14, 95% CI 0.31–4.16). In the combined group of women with RA and CD, the adjusted OR (adjusted for baseline differences) was 1.10 (95% CI 0.45–2.73). No clear differences were observed between women who used and did not use adalimumab regarding secondary endpoints such as spontaneous abortions, minor congenital malformations, preterm births, birth weight and length, and serious or opportunistic infections, and no cases of stillbirth or development of malignancies were recorded. Interpretation of the data may have been influenced by methodological limitations of the study, including small sample size and non-randomized study design.

In a developmental toxicity study in monkeys, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. Preclinical data on postnatal toxicity of adalimumab are lacking.

Since adalimumab inhibits TNF-α, its use during pregnancy may disrupt normal immune responses in the newborn. Adalimumab should be used in pregnant women only if clearly necessary.

Adalimumab can cross the placenta and be detected in the serum of newborns whose mothers received adalimumab during pregnancy. Therefore, these newborns may have an increased risk of infection. Live vaccines (e.g., BCG vaccine) should not be administered to infants exposed to adalimumab in utero within 5 months after the last adalimumab injection to the mother during pregnancy.

Breastfeeding

Limited published data indicate that adalimumab is excreted in breast milk in very low concentrations—ranging from 0.1% to 1% of the maternal serum level. Given that immunoglobulin G proteins undergo proteolysis in the gastrointestinal tract and have low bioavailability, systemic effects of adalimumab on breastfed infants are unlikely. Therefore, Abrilada may be used during breastfeeding.

Fertility

Preclinical data on the effect of adalimumab on fertility are lacking.

Ability to influence reaction speed when driving or operating machinery

Adalimumab may have a minor influence on reaction speed when driving or operating machinery. Abrilada use may cause vertigo and visual acuity disturbances (see section "Adverse reactions").

Method of Administration and Dosage

Treatment with the medicinal product Abrilada must be initiated and supervised by a physician experienced in the diagnosis and management of diseases for which Abrilada is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiating treatment with Abrilada (see section "Special Precautions"). Patients receiving Abrilada should be provided with a patient alert card. After appropriate training in injection technique, patients may self-administer Abrilada if their physician confirms that this is appropriate. If necessary, the patient should remain under continued clinical monitoring.

During treatment with Abrilada, concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be re-evaluated.

Abrilada at a dose of 40 mg should not be used to provide doses less than 40 mg.

Dosage

Rheumatoid Arthritis

The recommended dose of Abrilada for adult patients with rheumatoid arthritis is 40 mg of adalimumab administered subcutaneously every two weeks. Treatment with methotrexate should be continued during therapy with Abrilada.

Concomitant therapy with glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, and analgesics may also be continued during Abrilada treatment. For information on the use of other disease-modifying antirheumatic drugs (DMARDs) besides methotrexate, see sections "Special Precautions" and "Pharmacodynamics".

In monotherapy, for some patients who exhibit a reduced response to Abrilada at a dose of 40 mg every two weeks, dose escalation to 40 mg of adalimumab weekly or 80 mg every two weeks may be justified.

Available data indicate that a clinical response is usually achieved within 12 weeks of treatment. The need for continued therapy should be reassessed in patients who do not respond to treatment within this timeframe.

Interruption of Therapy

Therapy may be interrupted if necessary (e.g., prior to surgery or in the case of severe infection). Available data indicate that clinical response and safety profile after resuming adalimumab therapy after 70 days or more are similar to those observed prior to the interruption.

Ankylosing Spondylitis, Non-Radiographic Axial Spondyloarthritis, and Psoriatic Arthritis

The recommended dose of Abrilada for patients with ankylosing spondylitis, non-radiographic axial spondyloarthritis, and psoriatic arthritis is 40 mg of adalimumab administered subcutaneously every two weeks.

Available data indicate that a clinical response is usually achieved within 12 weeks of treatment. The need for continued therapy should be reassessed in patients who do not respond to treatment within this timeframe.

Psoriasis

The recommended initial dose of Abrilada for adults is 80 mg administered subcutaneously; one week after the initial dose, 40 mg is administered subcutaneously every two weeks.

The need for continued therapy should be carefully reassessed after 16 weeks in patients who do not respond to treatment within this period.

For patients who do not achieve an adequate response to Abrilada at a dose of 40 mg every two weeks after 16 weeks of therapy, increasing the dose to 40 mg weekly or 80 mg every two weeks may be effective. The benefit-risk balance of continuing therapy at 40 mg weekly or 80 mg every two weeks should be carefully evaluated in patients who do not achieve an adequate response after dose escalation (see section "Pharmacodynamics"). If an adequate response is achieved after switching to 40 mg weekly or 80 mg every two weeks, the dose may subsequently be reduced to 40 mg every two weeks.

Hidradenitis Suppurativa

The recommended dosing regimen for adult patients with hidradenitis suppurativa (HS) is an initial dose of 160 mg on Day 1 (this dose may be administered as four 40 mg injections in one day or two 40 mg injections per day on two consecutive days), followed by 80 mg two weeks later on Day 15 (this dose should be administered as two 40 mg injections in one day). Two weeks later (Day 29), the recommended dose is 40 mg weekly or 80 mg every two weeks (two 40 mg injections in one day). Antibiotics may be continued during Abrilada therapy if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

The need for continued therapy should be carefully reassessed after 12 weeks in patients who do not show positive clinical progression within this timeframe.

If therapy is interrupted, resumption of Abrilada at a dose of 40 mg weekly or 80 mg every two weeks is possible (see section "Pharmacodynamics").

For long-term therapy, the benefit-risk ratio should be periodically evaluated (see section "Pharmacodynamics").

Crohn’s Disease

For induction of remission, the recommended initial dose of Abrilada for adult patients with moderate to severe Crohn’s disease is 80 mg at Week 0, followed by a reduced dose of 40 mg at Week 2. If a more rapid clinical response is required, an initial dose of 160 mg at Week 0 may be administered (this dose may be given as four 40 mg injections in one day or two 40 mg injections per day on two consecutive days), followed by 80 mg at Week 2 as two 40 mg injections in one day. It should be noted that in this case, the risk of adverse reactions is increased.

After induction therapy, the recommended dose is 40 mg administered subcutaneously every two weeks. Alternatively, if a patient has discontinued therapy and symptoms reappear, Abrilada therapy may be restarted. Limited data are available on re-initiating therapy after a treatment interruption of more than 8 weeks from the last dose.

During maintenance therapy, corticosteroid doses may be gradually tapered according to clinical practice.

In patients with a diminished clinical response after receiving Abrilada at 40 mg every two weeks, dose escalation to 40 mg weekly or 80 mg every two weeks may be required.

Some patients who do not achieve a clinical response by Week 4 of treatment may benefit from continuing maintenance therapy up to Week 12. The need for continued therapy should be carefully reassessed in patients who do not respond to treatment within this timeframe.

Ulcerative Colitis

The recommended initial dose for induction of remission in adult patients with moderate to severe ulcerative colitis is 160 mg at Week 0 (this dose may be administered as four 40 mg injections in one day or two 40 mg injections per day on two consecutive days) and 80 mg at Week 2 as two 40 mg injections in one day. After induction therapy, the recommended dose is 40 mg administered subcutaneously every two weeks.

During maintenance therapy, corticosteroid doses may be gradually tapered according to clinical practice.

In patients with a diminished clinical response after receiving Abrilada at 40 mg every two weeks, dose escalation to 40 mg weekly or 80 mg every two weeks may be required.

Available data indicate that clinical response is usually achieved within 2–8 weeks of treatment. Abrilada therapy should be continued only in patients who achieve a clinical response within this timeframe.

Uveitis

The recommended initial dose of Abrilada for adult patients with uveitis is 80 mg; starting the first week after the initial dose, maintenance therapy should be initiated at 40 mg every two weeks. Limited data are available on using Abrilada alone as initial therapy. Abrilada therapy may be initiated in combination with corticosteroids and/or other non-biological immunomodulatory agents. Two weeks after starting Abrilada therapy, concomitantly administered corticosteroid doses may be gradually tapered according to clinical experience.

An annual assessment of the benefit-risk ratio of long-term therapy is recommended (see section "Pharmacodynamics").

Special Patient Populations

Elderly Patients

Dose adjustment is not required.

Patients with Hepatic and/or Renal Impairment

The use of adalimumab in these patients has not been studied; therefore, dosage recommendations are not available.

Children

Juvenile Idiopathic Arthritis

Polyarticular Juvenile Idiopathic Arthritis in Children

The recommended dose of Abrilada for children with polyarticular juvenile idiopathic arthritis depends on body weight (Table 1). Abrilada is administered subcutaneously every two weeks.

Table 1. Dosing of Abrilada for Patients with Polyarticular Juvenile Idiopathic Arthritis

Body weight of the patient	Dosage
30 kg and above	40 mg once every 2 weeks

Available data indicate that a clinical response is generally achieved within 12 weeks of treatment. The need for continuing therapy should be carefully reconsidered in patients who do not show a response to treatment within this period.

Adalimumab is not used for this indication in children under 2 years of age.

Enthesitis-related arthritis

The recommended dose of ABILLYA for children with enthesitis-related arthritis depends on body weight (Table 2). ABILLYA is administered subcutaneously once every 2 weeks.

Table 2. Dosage of ABILLYA for patients with enthesitis-related arthritis

Body weight of the patient	Dose
30 kg and above	40 mg once every 2 weeks

No studies have been conducted on the use of adalimumab in patients with enthesitis-related arthritis under 6 years of age.

Psoriatic arthritis and axial spondyloarthritis, including ankylosing spondylitis

Adalimumab is not administered to children for the indications of ankylosing spondylitis and psoriatic arthritis.

Plaque psoriasis in children

The recommended dose of ABRILADA for children with plaque psoriasis depends on body weight (Table 3). ABRILADA is administered subcutaneously.

Table 3. Dosage of ABRILADA for children with plaque psoriasis

Body weight of the patient	Dose
30 kg and above	Initial dose is 40 mg, then 40 mg once every 2 weeks, starting from week 1 after the initial dose

Careful reassessment of the need to continue therapy after 16 weeks is recommended for patients who have not shown a response to treatment during this period.

If retreatment with the medicinal product Abrilada is indicated, the treatment regimen specified above should be followed.

The safety of adalimumab use in children with plaque psoriasis has been studied for an average duration of 13 months.

Adalimumab is not administered for this indication in children under 4 years of age.

Pyoderma gangrenosum in children (aged 12 years and older)

There are no clinical studies on the use of adalimumab in children with PG. The dosing of adalimumab in these patients was determined by pharmacokinetic modeling and simulation (see section "Pharmacokinetics").

The recommended dose of Abrilada is 80 mg at week 0, followed by 40 mg once every 2 weeks starting at week 1, administered subcutaneously.

For children with an inadequate response to Abrilada 40 mg every 2 weeks, dose escalation to 40 mg once weekly or 80 mg every 2 weeks may be considered.

Antibiotics may be continued during therapy with Abrilada, if necessary. Daily topical cleansing of affected areas with antiseptics is also recommended.

Careful reassessment of the need to continue therapy after 12 weeks is recommended for patients who have not shown a positive response during this period.

Reinitiation of Abrilada therapy may be considered if necessary after treatment interruption.

For long-term therapy, the benefit-risk balance should be periodically evaluated (see adult data in section "Pharmacodynamics").

Adalimumab is not administered for this indication in children under 12 years of age.

Pediatric Crohn's disease

The recommended dose of Abrilada for patients with Crohn's disease depends on the patient's body weight (Table 4). Abrilada is administered subcutaneously.

Table 4. Dosing of the medicinal product Abrilada in children with Crohn's disease

Body weight of the patient	Induction dose	Maintenance therapy, starting from week 4
40 kg and above	80 mg at week 0 and 40 mg at week 2 If a more rapid response to therapy is required, the dose indicated below may be used. However, it should be noted that the risk of adverse events increases with the use of a higher induction dose. 160 mg at week 0 and 80 mg at week 2	40 mg once every 2 weeks

For patients with an inadequate response, dose escalation may be considered:

• patients with body weight ≥ 40 kg: 40 mg once weekly or 80 mg once every 2 weeks.

The need for continued therapy should be carefully re-evaluated in patients who do not show a clinical response within 12 weeks.

Adalimumab is not used for this indication in children under 6 years of age.

Ulcerative colitis in children

The recommended dose of Abrilada for children with ulcerative colitis aged 6 to 17 years inclusive depends on the patient's body weight (Table 5). Abrilada is administered subcutaneously.

Table 5. Dosing of Abrilada in children with ulcerative colitis

Body weight of patient	Induction dose	Maintenance therapy, starting from week 4*
Less than 40 kg	80 mg at week 0 (administered as two 40 mg injections on the same day) and 40 mg at week 2 (administered as one 40 mg injection)	40 mg once every 2 weeks
40 kg and above	160 mg at week 0 (administered as four 40 mg injections on the same day or two 40 mg injections per day on two consecutive days) and 80 mg at week 2 (administered as two 40 mg injections on the same day)	80 mg once every two weeks

* Patients who turn 18 years old during treatment with ABRILYDA should continue treatment at the prescribed maintenance dose.

After 8 weeks, the need for continued treatment should be carefully reassessed in patients who have not shown a response to treatment during this period.

Adalimumab is not used for this indication in children under 6 years of age.

Uveitis in children

The recommended dose of ABRILYDA for children with uveitis depends on the patient's body weight (see Table 6). ABRILYDA is administered subcutaneously.

There are no data on the use of adalimumab without concomitant methotrexate therapy in children with uveitis.

Table 6. Dosage of ABRILYDA for children with uveitis

Body weight of the patient	Dose
30 kg and above	40 mg once every two weeks in combination with methotrexate

The initial loading dose of ABILLYDA is 80 mg for patients weighing 30 kg or more; it may be administered one week prior to initiation of maintenance therapy. There are no clinical data on administration of the initial dose of ABILLYDA in children under 6 years of age (see section "Pharmacokinetics").

Adalimumab is not used for this indication in children under 2 years of age.

Long-term therapy should be evaluated annually for benefit-risk ratio (see section "Pharmacodynamics").

Method of administration

ABILLYDA is administered subcutaneously.

Instructions for use

of ABILLYDA (adalimumab) medicinal product

single-dose pre-filled pen, 40 mg, for subcutaneous injection

These instructions explain how to prepare and administer an injection. ABILLYDA for injection is supplied in a single-use pen for one-time use, containing one dose of the medicinal product. Do not attempt to self-administer ABILLYDA unless you have carefully read and understood these instructions for use, or if anything is unclear to you. After appropriate training in the technique of subcutaneous administration, patients or caregivers may administer ABILLYDA at home as directed by a physician or nurse. It is important to speak with your physician or nurse to ensure you understand the dosing instructions for ABILLYDA. To help remember when to administer the next ABILLYDA injection, you may mark your calendar in advance. Contact your physician or nurse if you or your caregiver have any questions about the correct method of administration. After appropriate training, you or your caregiver may administer ABILLYDA injections independently.

1. Required supplies

• For each injection, the following supplies are needed (prepare a clean, flat surface on which to place them):
  • 1 pre-filled pen with ABILLYDA medicinal product (included in the medicinal product package).
  • 1 alcohol swab (included in the medicinal product package).
  • 1 cotton or gauze pad (not included in the medicinal product package).
  • A proper sharps container (not included in the medicinal product package).

Important! If you have any questions about the pre-filled pen or ABILLYDA medicinal product, contact your physician or nurse.

2. Prepare supplies for injection

• Remove the ABILLYDA medicinal product package from the refrigerator.
• Take 1 pre-filled pen and alcohol swab out of the package. Protect the pen from direct sunlight. Return the package with unused pens to the refrigerator.
• Do not use the pen if:
  • the pen or pen packaging has been dropped, even if it appears undamaged;
  • it has been frozen or thawed;
  • it appears damaged;
  • there are signs that the new package has been opened;
  • it has not been stored in the refrigerator for more than 30 days;
  • the expiry date has passed.
• In any of these cases, dispose of the unused pen in the same manner as a used pen. A new pen is required for administration.
• The pen may be used immediately after removal from the refrigerator.
• Administration at room temperature may reduce stinging or discomfort. To achieve this, allow the pen to sit at room temperature, protected from direct sunlight, for 15–30 minutes prior to injection.
• Wash your hands thoroughly with soap and water and dry completely.
• Do not remove the pen cap until you are ready to administer the injection.

cap

window

injection button

expiry date

The appearance of the pen may differ.

Check the medicine

• Look at the medication in the viewing window.
• Gently tilt the pen forward and backward to check the appearance of the liquid.
• Do not shake the pen. Shaking may damage the medication.
• Make sure the liquid in the pen is clear, colorless or slightly pale brown, with no flakes or particles. One or more air bubbles may be visible in the viewing window. This is normal. Do not attempt to remove the air bubbles.

If you have any questions about the medication, consult your doctor or nurse.

Select and prepare the injection site

Abdomen:

Thighs: anterior upper part of the thigh

area at least 5 cm away from the navel

• Always choose a different site for injection each time.
• Do not inject the medicine near bones or areas of skin with bruises, redness, pain (tenderness), or lumps. Avoid areas with scars or stretch marks.
  • If you have psoriasis, do not inject the medicine directly into any raised, thickened, red, or scaly areas of skin or skin lesions.
• Do not inject the medicine through clothing.
• Wipe the injection site with an alcohol swab.
• Allow it to dry.

Remove the cap

• Turn and remove the cap.
• Dispose of the cap in a sharps container; do not reuse it.
• You may see a few drops of liquid at the needle tip after removing the cap, which is normal.

Caution! Handle the pen carefully to avoid accidental needle injury.

Note. After removing the cap, the needle shield remains inside the cap.

Insert the needle

Press

Firmly press the pen against the skin at a 90-degree angle (see step 6).

Note. When pressing the pen, the needle enters the skin. Pressing firmly on the pen unlocks the injection button.

• Keep holding the pen pressed against the skin until step 8 (step 8 "Remove the pen").

Note. Do not reinsert the needle into the skin if you decide to change the injection site. Use a备用 pen if the needle has already been inserted into the skin.

clicking

Enter the drug

Click

Continue to hold

Wait

second click

Hold for another 5 seconds

• Press the injection button fully until it clicks. You may remove your finger from the button once the injection has started.
• Hold the pen firmly against the skin while the orange stripe moves across the viewing window. Delivery of the dose usually takes from 3 to 10 seconds.
• Wait at least 5 seconds after the second click to ensure the medication is fully absorbed.
• Note. If you cannot press the injection button, this means you are not pressing the pen firmly enough against the skin. Remove your finger from the injection button, press the pen more firmly against the skin, and then try pressing the button again. If this does not work, stretch or pinch the skin to make the injection site more stable, which will make it easier to press the injection button.

Remove the pen

• Do not remove the pen until at least 5 seconds have passed after the second click.

• Remove the pen from the injection site.

Note. After removing the pen from the injection site, the needle automatically retracts.

• If more than one small drop of medication remains on the skin after injection, wait a little longer next time before removing the pen.

Check the compartment

• The orange stripe should be visible in the window.
• If the orange stripe is not visible or the window appears as if the medication is still being administered, this means you have not delivered the full dose. Contact your doctor or nurse immediately.

• Do not administer the next dose.

Dispose of the used pen

• Immediately dispose of the pen according to your doctor's or nurse's instructions and in accordance with local sanitary regulations.

After injection

• Carefully examine the injection site. If blood appears, cover the injection site with a clean cotton or gauze pad for several seconds.
• Do not rub the injection site.

Note. Store unused pens in the refrigerator in their original packaging.

Children

See "Vaccination" above.

Abrylada at a dose of 40 mg is not suitable for delivering doses less than 40 mg.

Overdose

During clinical studies, no cases of dose-limiting toxicity were observed. The highest dose administered was 10 mg/kg given repeatedly by intravenous infusion, which is approximately 15 times the recommended dose.

Adverse Reactions

General Information on Safety Profile

Adalimumab has been studied in controlled clinical trials and open-label studies lasting up to 60 months involving 9,506 patients with early and long-standing rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile arthritis and enthesitis-related arthritis), axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), psoriatic arthritis, Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, and uveitis. The data below are derived from the main controlled trials in which 6,089 patients received adalimumab and 3,801 patients received placebo or a comparator during the controlled period.

During the double-blind controlled phase of the main clinical trials, 5.9% of patients receiving adalimumab and 5.4% of patients in the control group discontinued treatment due to adverse reactions.

The most commonly reported adverse reactions were infections (e.g., nasopharyngitis, upper respiratory tract infections, and sinusitis), injection site reactions (redness, itching, haemorrhage, pain or swelling), headache, and musculoskeletal pain. Serious adverse reactions have been reported with adalimumab. TNF antagonists, such as adalimumab, affect the immune system and their use may lead to reduced resistance to infections and malignancies.

During treatment with adalimumab, life-threatening and potentially fatal infections (including sepsis, opportunistic infections, and tuberculosis), reactivation of hepatitis B virus, and various malignancies (including leukemia, lymphoma, and hepatosplenic T-cell lymphoma) have been reported.

Serious hematological, neurological, and autoimmune reactions have also been reported, including rare cases of pancytopenia, aplastic anemia, central and peripheral demyelinating disorders, development of lupus and lupus-like syndromes, and Stevens-Johnson syndrome.

Children

Adverse reactions observed in children were generally similar in frequency and nature to those observed in adult patients.

List of Suspected Adverse Reactions

The list of adverse reactions below is based on clinical trial experience and post-marketing data and is presented by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse effects are listed in order of decreasing severity. The highest frequency observed across different indications is indicated. An asterisk (*) in the "System Organ Class" column indicates that additional information is provided in other sections: "Contraindications", "Special Warnings and Precautions for Use", and "Adverse Reactions".

Infections and infestations*. Very common: respiratory tract infections (including lower and upper respiratory tract infections, pneumonia, sinusitis, pharyngitis, nasopharyngitis, pneumonia caused by herpes virus); common: systemic infections (including sepsis, candidiasis, and influenza), gastrointestinal infections (including viral gastroenteritis), skin and soft tissue infections (paronychia, cellulitis, impetigo, necrotizing fasciitis, herpes zoster), ear infections, oral infections (including herpes simplex virus, oral herpes, and dental infections), genital infections (including fungal vulvovaginitis), urinary tract infections (including pyelonephritis), fungal infections, joint infections; uncommon: neurological infections (including viral meningitis), opportunistic infections (including coccidioidomycosis, histoplasmosis, and Mycobacterium avium complex infections), bacterial infections, eye infections, diverticulitis1.

Benign, malignant and unspecified neoplasms (including cysts and polyps)*. Common: non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma), benign neoplasms; uncommon: lymphoma**, parenchymal organ neoplasms (including breast cancer, lung tumour, and thyroid tumour), melanoma**; rare: leukemia1; frequency not known: hepatosplenic T-cell lymphoma1, Merkel cell carcinoma (neuroendocrine carcinoma of the skin)1, Kaposi’s sarcoma.

Blood and lymphatic system disorders*. Very common: leukopenia (including neutropenia and agranulocytosis), anaemia; common: leukocytosis, thrombocytopenia; uncommon: idiopathic thrombocytopenic purpura; rare: pancytopenia;

Immune system disorders*. Common: hypersensitivity, allergy (including seasonal allergy); uncommon: sarcoidosis1, vasculitis; rare: anaphylaxis1.

Metabolism and nutrition disorders. Very common: increased lipid levels; common: hypokalaemia, increased uric acid concentration, abnormal plasma sodium concentration, hypocalcaemia, hyperglycaemia, hypophosphataemia, dehydration.

Psychiatric disorders. Common: mood changes (including depression), anxiety, insomnia.

Nervous system disorders*. Very common: headache; common: paraesthesia (including hypoesthesia), migraine, nerve root compression; uncommon: cerebrovascular accident1, tremor, neuropathy; rare: multiple sclerosis, demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome)1.

Eye disorders. Common: visual disturbance, conjunctivitis, blepharitis, eye swelling; uncommon: diplopia.

Ear and labyrinth disorders. Common: vertigo; uncommon: deafness, tinnitus. Cardiac disorders*. Common: tachycardia; uncommon: myocardial infarction1, arrhythmia, congestive heart failure; rare: cardiac arrest.

Vascular disorders. Common: hypertension, flushing, haematomas; uncommon: aortic aneurysm, arterial occlusion, thrombophlebitis.

Respiratory, thoracic and mediastinal disorders*. Common: asthma, dyspnoea, cough; uncommon: pulmonary embolism1, interstitial lung disease, chronic obstructive pulmonary disease, pneumonitis, pleural effusion1; rare: pulmonary fibrosis1.

Gastrointestinal disorders. Very common: abdominal pain, nausea and vomiting; common: gastrointestinal haemorrhage, dyspepsia, gastroesophageal reflux, dry eye syndrome (Sjögren’s syndrome); uncommon: pancreatitis, dysphagia, facial swelling; rare: intestinal perforation1.

Hepatobiliary disorders*. Very common: increased liver enzymes; uncommon: cholecystitis and gallstones, hepatic steatosis, increased bilirubin levels; rare: hepatitis, reactivation of hepatitis B1, autoimmune hepatitis1; frequency not known: liver failure1.

Skin and subcutaneous tissue disorders. Very common: rash (including exfoliative rash); common: worsening or development of psoriasis (including palmoplantar pustular psoriasis)1, urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia1, pruritus; uncommon: night sweats, scarring; rare: erythema multiforme1, Stevens-Johnson syndrome1, angioneurotic oedema1, cutaneous vasculitis1, lichenoid skin reaction1; frequency not known: exacerbation of dermatomyositis symptoms1.

Musculoskeletal and connective tissue disorders. Very common: musculoskeletal pain; common: muscle spasms (including elevated plasma creatine phosphokinase); uncommon: rhabdomyolysis, systemic lupus erythematosus; rare: lupus-like syndrome1.

Renal and urinary disorders. Common: renal failure, haematuria; uncommon: nocturia.

Reproductive system and breast disorders. Uncommon: erectile dysfunction.

General disorders and administration site conditions*. Very common: injection site reaction (including injection site erythema); common: chest pain, swelling, pyrexia1; uncommon: inflammation.*

Investigations*. Common: coagulation and blood clotting disorders (including prolonged activated partial thromboplastin time), positive autoantibody tests (including anti-double-stranded DNA antibodies), increased plasma lactate dehydrogenase levels; frequency not known: weight gain2.

Injury, poisoning and procedural complications. Common: delayed healing.

* Additional information is provided in the sections "Contraindications", "Special Warnings and Precautions for Use", and "Adverse Reactions".

** Includes data from the open-label period of studies.

1 Includes spontaneous reports from patients.

2 The mean change in body weight from baseline during adalimumab treatment in adult indications ranged from 0.3 kg to 1.0 kg compared to -0.4 kg to 0.4 kg in the placebo group over a 4–6 month treatment period. Weight gain of 5–6 kg was also observed in long-term studies with a mean exposure duration of approximately 1–2 years without a control group, particularly in patients with Crohn’s disease and ulcerative colitis. The mechanism underlying this effect is unknown but is likely related to the anti-inflammatory action of adalimumab.

Hidradenitis Suppurativa

The safety profile for patients with HS receiving weekly adalimumab is consistent with the known safety profile of adalimumab.

Uveitis

The safety profile for patients with uveitis receiving adalimumab every two weeks is consistent with the known safety profile of adalimumab.

Description of Selected Adverse Reactions

Injection Site Reactions

In controlled clinical trials, injection site reactions (erythema and/or itching, haemorrhage, pain or swelling) occurred in 12.9% of adults and children receiving adalimumab compared to 7.2% in the control group. Most injection site reactions did not require discontinuation of the drug.

Infections

In the main controlled clinical trials in adults and children, the infection rate was 1.51/patient-year in the adalimumab group and 1.46/patient-year in the control group. These were predominantly nasopharyngitis, upper respiratory tract infections, and sinusitis. Most patients continued adalimumab treatment after recovery from infection.

The rate of serious infections was 0.04/patient-year in the adalimumab group and 0.03/patient-year in the control group.

In controlled and open-label studies in adults and children receiving adalimumab, severe infections (rarely fatal) have been reported, including tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (such as disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, pneumocystosis, candidiasis, aspergillosis, and listeriosis). Most cases of tuberculosis occurred within the first eight months of therapy and may have represented reactivation of latent disease.

Malignancies and Lymphoproliferative Disorders

During studies of adalimumab use in children with juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis), no malignancies were observed (249 children, 655.6 patient-years). Specifically, no malignancies were observed during studies of adalimumab use in children with Crohn’s disease (192 children, 498.1 patient-years). No malignancies were observed during studies of adalimumab use in children with chronic plaque psoriasis (77 children, 80.0 patient-years). No malignancies were observed during studies of adalimumab use in children with ulcerative colitis (93 children, 65.3 patient-years). No malignancies were observed during studies of adalimumab use in children with uveitis (60 children, 58.4 patient-years).

During the controlled periods of the main adalimumab studies in adults lasting at least 12 weeks in patients with moderate to severe rheumatoid arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis, and uveitis, the incidence of malignancies (excluding lymphoma and non-melanoma skin cancer) was (95% confidence interval) 6.8 (4.4; 10.5) per 1,000 patient-years in 5,291 patients receiving adalimumab, compared to 6.3 (3.4; 11.8) per 1,000 patient-years in 3,444 patients in the control group (mean treatment duration was 4.0 months in the adalimumab group and 3.8 months in the control group). The incidence of non-melanoma skin cancer (95% confidence interval) was 8.8 (6.0; 13.0) per 1,000 patient-years in patients receiving adalimumab and 3.2 (1.3; 7.6) per 1,000 patient-years in the control group. Among these cases, the incidence of squamous cell carcinoma (95% confidence interval) was 2.7 (1.4; 5.4) per 1,000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5) per 1,000 patient-years in the control group. The incidence of lymphoma (95% confidence interval) was 0.7 (0.2; 2.7) per 1,000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5) per 1,000 patient-years in the control group. In controlled and open-label studies, ongoing and completed, with a mean duration of approximately 3.3 years and involving 6,427 patients (more than 26,439 patient-years of therapy), the observed rates of malignancy development (excluding lymphoma and non-melanoma skin cancer) were approximately 8.5 per 1,000 patient-years. The rates of non-melanoma skin cancer were approximately 9.6 per 1,000 patient-years, and the rates of lymphoma were approximately 1.3 per 1,000 patient-years.

In post-marketing experience (from January 2003 to December 2010), spontaneous reports of malignancies, primarily in patients with rheumatoid arthritis, were approximately 2.7 per 1,000 patient-years of therapy. Spontaneous reports of non-melanoma skin cancer and lymphoma were approximately 0.2 and 0.3 per 1,000 patient-years of therapy, respectively (see section "Special Warnings and Precautions for Use").

In post-marketing experience, hepatosplenic T-cell lymphoma has been very rarely reported in patients receiving adalimumab (see section "Special Warnings and Precautions for Use").

Autoantibodies

During phases I–V clinical trials of rheumatoid arthritis, patients were tested multiple times for autoantibodies. In these controlled trials, positive titres were reported in 11.9% of patients receiving adalimumab and 8.1% of patients in the placebo group. With active monitoring, negative antinuclear antibody titres were observed at week 24. In two of 3,441 patients receiving adalimumab across all rheumatoid arthritis and psoriatic arthritis studies, signs of a newly diagnosed lupus-like syndrome developed, which resolved after discontinuation of treatment. No patient developed lupus nephritis or central nervous system involvement.

Hepatobiliary Disorders

In phase 3 controlled clinical trials of adalimumab in patients with rheumatoid arthritis and psoriatic arthritis, during the controlled period lasting 4 to 104 weeks, alanine aminotransferase (ALT) levels increased to three or more times the upper limit of normal in 3.7% of patients receiving adalimumab and 1.6% of control group patients.

In phase 3 controlled clinical trials of adalimumab in patients aged 4–17 years with polyarticular arthritis and patients aged 6–17 years with enthesitis-related arthritis, ALT levels increased to three or more times the upper limit of normal in 6.1% of patients receiving adalimumab and 1.3% of control group patients. Most cases of elevated ALT occurred during concomitant methotrexate therapy. No increases in ALT to three or more times the upper limit of normal were observed in phase 3 clinical trials of adalimumab in patients with polyarticular arthritis aged 2–4 years.

In phase 3 controlled clinical trials of adalimumab in patients with Crohn’s disease and ulcerative colitis, with a controlled period lasting 4 to 52 weeks, ALT levels increased to three or more times the upper limit of normal in 0.9% of patients in both groups.

In a phase 3 clinical trial of adalimumab in children with Crohn’s disease evaluating the efficacy and safety of a weight-based dosing regimen followed by a weight-based maintenance regimen with a treatment duration of up to 52 weeks, ALT levels increased to three or more times the upper limit of normal in 2.6% (5/192) of patients, four of whom were receiving adalimumab with concomitant immunosuppressants.

In phase 3 controlled clinical trials of adalimumab in patients with plaque psoriasis, with a controlled period lasting 12 to 24 weeks, ALT levels increased to three or more times the upper limit of normal in 1.8% of patients in both groups.

No increases in ALT to three or more times the upper limit of normal were observed in a phase 3 trial of adalimumab in children with plaque psoriasis.

In phase 3 controlled clinical trials of adalimumab (initial dose 160 mg at week 0 and 80 mg at week 2, then 40 mg once weekly starting at week 4) in patients with hidradenitis suppurativa, with a controlled period lasting 12 to 16 weeks, ALT levels increased to three or more times the upper limit of normal in 0.3% of patients receiving adalimumab and 0.6% of control group patients.

In phase 3 controlled clinical trials of adalimumab (initial dose 80 mg at week 0, then 40 mg every two weeks starting at week 1) in patients with uveitis, with a controlled period lasting up to 80 weeks (mean exposure of 166.5 days and 105 days in the adalimumab and control groups, respectively), ALT levels increased to three or more times the upper limit of normal in 2.4% of patients receiving adalimumab and 2.4% of control group patients.

In a phase 3 controlled trial of adalimumab in children with ulcerative colitis (N = 93), evaluating the efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum 40 mg) administered every two weeks (N = 31) or weekly (N = 32) following an induction dose based on body weight of 2.4 mg/kg (maximum 160 mg) at week 0 and week 1 and 1.2 mg/kg (maximum 80 mg) at week 2 (N = 63), or following an induction dose of 2.4 mg/kg (maximum 160 mg) at week 0, placebo at week 1, and 1.2 mg/kg (maximum 80 mg) at week 2 (N = 30), cases of ALT elevation to three or more times the upper limit of normal were observed in 1.1% (1/93) of patients.

Across all indications in clinical trials, patients experienced asymptomatic increases in ALT levels, which were mostly transient during long-term treatment. However, very rare post-marketing reports of liver failure and less severe hepatic reactions that may lead to liver failure, such as hepatitis, including autoimmune hepatitis, have been reported in patients receiving adalimumab.

Concomitant Therapy with Azathioprine/6-Mercaptopurine

In studies of adult patients with Crohn’s disease receiving adalimumab in combination with azathioprine/6-mercaptopurine, an increased incidence of malignancies and serious infections was observed compared to patients receiving adalimumab monotherapy.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf Life. 3 years.

Storage Conditions

Keep out of reach and sight of children.

Store in a refrigerator at 2–8°C in the original cardboard packaging to protect from light. Do not freeze.

One pre-filled pen may be stored at a temperature not exceeding 30°C for up to 30 days in a place protected from light.

Dispose of if the medicine has not been used within 30 days.

Incompatibilities

Since compatibility studies of this medicinal product have not been conducted, it must not be mixed with other medicinal products.

Packaging

2 pre-filled single-use pens containing pre-filled syringes, together with 2 alcohol swabs, or 6 pre-filled single-use pens containing pre-filled syringes, together with 6 alcohol swabs, in a cardboard box labelled in Ukrainian and English.

Prescription Category. Prescription only.

Manufacturer

Pfizer Service Company B.V.

Manufacturer’s Location and Address of Business Operations

Goddewaersvelde Way 10, Zaventem, 1930, Belgium