Hyrimoz 40

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Hyrimoz 40 (Hyrimoz 40)

Composition:

Active substance: adalimumab;

1 pre-filled syringe contains 40 mg of adalimumab in 0.8 ml of solution;

Excipients: adipic acid; citric acid monohydrate; sodium chloride; mannitol (E 421); polysorbate 80; sodium hydroxide (for pH adjustment); hydrochloric acid (for pH adjustment); water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear or slightly opalescent, colorless or slightly yellowish solution.

Pharmacotherapeutic group

Immunosuppressants. Tumor necrosis factor-alpha inhibitors. Adalimumab.

ATC code L04A B04.

Pharmacological Properties

Hyrimoz 40 (adalimumab) is a recombinant human immunoglobulin (IgG1), a monoclonal antibody containing only human peptide sequences. The drug was developed using phage display technology, enabling the production of exclusively human variable regions of heavy and light chains that exhibit specificity for tumor necrosis factor (TNF), along with the human IgG1 heavy chain and kappa-type light chain sequences. Adalimumab binds with high affinity and specificity to soluble TNF-alpha, but not to lymphotoxin (TNF-beta). Adalimumab is produced by recombinant DNA technology using a mammalian cell expression system. It consists of 1300 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab specifically binds to TNF and neutralizes its biological effects by blocking its interaction with p55- and p75-TNF receptors on the cell surface. TNF is a naturally occurring cytokine involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). TNF plays a key role in the development of pathological inflammation and joint tissue destruction characteristic of these diseases. Elevated TNF levels are also found in psoriatic plaques. Treatment with Hyrimoz 40 in patients with plaque psoriasis may reduce epidermal thickening and inflammatory cell infiltration. The relationship between these pharmacodynamic effects and the mechanism(s) by which adalimumab exerts its clinical efficacy is unknown.

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 1–2 × 10⁻¹⁰ M).

Pharmacodynamics

In patients with RA, adalimumab rapidly reduced, compared to baseline, markers of acute-phase inflammation (C-reactive protein [CRP], serum cytokines [IL-6], and erythrocyte sedimentation rate). Reductions in CRP levels were also observed in patients with JRA, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa, along with significant reductions in expression of TNF-alpha and inflammatory markers such as leukocyte antigen (HLA-DR) and myeloperoxidase (MPO) in the colon of patients with Crohn’s disease. Decreases in serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which contribute to tissue remodeling underlying cartilage destruction, were also observed. Patients with RA, PsA, and AS often exhibit mild to moderate anemia and lymphopenia, as well as increased neutrophil and platelet counts. Treatment with adalimumab typically results in improvement in these hematological signs of chronic inflammation.

Pharmacokinetics

Absorption and Distribution

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

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

After subcutaneous administration of 40 mg adalimumab every 2 weeks in RA patients, 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 subcutaneous doses of 20, 40, and 80 mg administered every 2 weeks or weekly.

After subcutaneous administration of adalimumab at 24 mg/m² (up to 40 mg) every 2 weeks in patients aged 4 to 17 years with polyarticular JRA, 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 JRA aged 2–4 years and in children aged ≥4 years with body weight less than 15 kg, after administration of adalimumab at 24 mg/m² with methotrexate, mean steady-state concentrations were 7.9 ± 5.6 µg/mL (101% CV).

After subcutaneous administration of adalimumab at 24 mg/m² (up to 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.

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

After subcutaneous administration of adalimumab at 0.8 mg/kg (up to a maximum of 40 mg) every 2 weeks in children with chronic plaque psoriasis, steady-state concentrations were approximately 7.4 ± 5.8 µg/mL (79% CV).

In patients with hidradenitis suppurativa, after administration of adalimumab at 160 mg at week 0 followed by 80 mg at week 2, serum concentrations were approximately 7–8 µg/mL at weeks 2 and 4. Mean steady-state concentrations from week 12 to week 36 were approximately 8–10 µg/mL with 40 mg adalimumab administered weekly.

The effect of adalimumab in children with hidradenitis was determined using pharmacokinetic modeling and simulation based on pharmacokinetic data from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and enthesitis-related arthritis). The recommended dosing regimen for children with hidradenitis is 40 mg every 2 weeks. Since the effect of adalimumab may depend on patient body weight, children with higher body weight and inadequate response to treatment may be given the recommended adult dose—40 mg once 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. Mean steady-state concentration was approximately 7 µg/mL during maintenance therapy with 40 mg adalimumab every 2 weeks.

In children with moderate to severe Crohn’s disease, initial doses of adalimumab in an open-label study were 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 either weight-based standard dose (40/20 mg every 2 weeks) or low dose (20/10 mg every 2 weeks) for maintenance therapy. Mean steady-state concentrations were 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 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. Mean steady-state concentration was approximately 8 µg/mL during maintenance therapy with 40 mg adalimumab every 2 weeks.

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, mean steady-state concentration was approximately 8–10 µg/mL.

The effect of adalimumab in children with uveitis was determined using pharmacokinetic modeling and simulation based on pharmacokinetic data from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and enthesitis-related arthritis).

There are no clinical data on the effect of the initial adalimumab dose in children under 6 years of age. It is predicted that, in the absence of methotrexate, the initial dose may lead to increased systemic exposure.

Elimination

A population pharmacokinetic analysis of data from over 1300 RA patients revealed a trend toward increased apparent clearance of adalimumab with increasing patient body weight. After adjusting for differences in body weight, patient sex and age were found to have minimal impact on adalimumab clearance. Levels of free adalimumab (not bound to anti-adalimumab antibodies (AAA)) in serum were lower in patients who tested positive for AAA. Hyrimoz 40 has not been studied in patients with hepatic or renal impairment.

Clinical Characteristics

Indications

Rheumatoid Arthritis (RA)

Hyrimoz 40 in combination with methotrexate is indicated for:

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

Hyrimoz 40 may be used as monotherapy in cases of methotrexate intolerance or when continuation of methotrexate therapy is not acceptable.

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

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

Hyrimoz 40 in combination with methotrexate is indicated for treatment of active polyarticular juvenile idiopathic arthritis in children aged 2 years and older who have not had an adequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

Hyrimoz 40 may be used as monotherapy in cases of methotrexate intolerance or when continuation of methotrexate therapy is not acceptable. No studies have been conducted on the use of Hyrimoz 40 in patients under 2 years of age.

Enthesitis-Related Arthritis

Hyrimoz 40 is indicated for treatment of active enthesitis-related arthritis in children aged 6 years and older who have not responded to conventional therapy or in whom there is intolerance or medical contraindications to such therapies.

Axial Spondyloarthritis

Ankylosing Spondylitis (AS)

Hyrimoz 40 is indicated for treatment of adult patients with high disease activity ankylosing spondylitis who have not responded to conventional therapy.

Axial Spondyloarthritis without Radiographic Confirmation of AS

Hyrimoz 40 is indicated for treatment of adult patients with high disease activity axial spondyloarthritis without radiographic confirmation of AS, but with evidence of inflammation based on elevated CRP levels and/or MRI (magnetic resonance imaging) findings.

Psoriatic Arthritis (PsA)

Hyrimoz 40 is indicated for treatment of active and progressive psoriatic arthritis in adult patients who have not achieved an adequate response to prior therapy with disease-modifying antirheumatic drugs (DMARDs). Adalimumab has demonstrated slowing of progression of peripheral joint damage as assessed by radiography in patients with symmetric polyarticular disease and improvement in functional status.

Plaque Psoriasis (PP)

Hyrimoz 40 is indicated for treatment of adult patients with moderate to severe chronic plaque psoriasis who require systemic therapy.

Plaque Psoriasis (PP) in Children

Hyrimoz 40 is indicated for treatment of chronic plaque psoriasis with severe disease in children aged 4 years and older who have not achieved clinical response or have contraindications/intolerance to topical therapy or phototherapy.

Pyoderma Gangrenosum (PG)

Hyrimoz 40 is indicated for treatment of active moderate to severe pyoderma gangrenosum (acne inversa) in adult patients and in children aged 12 years and older who have not responded to conventional systemic therapy.

Crohn’s Disease (CD)

Hyrimoz 40 is indicated for treatment of moderate to high disease activity Crohn’s disease in adult patients who have not responded to a full course of corticosteroid and/or immunosuppressant therapy or in whom there is intolerance or medical contraindications to such therapies.

Crohn’s Disease (CD) in Children

Hyrimoz 40 is indicated for treatment of moderate to high disease activity Crohn’s disease in children aged 6 years and older who have not responded to conventional therapy, including primary nutritional therapy, corticosteroid therapy and/or immunomodulators, or in whom there is intolerance or medical contraindications to such therapies.

Ulcerative Colitis (UC)

Hyrimoz 40 is indicated for treatment of moderate to severe active ulcerative colitis in adults who have not responded to conventional therapy, including corticosteroids and/or 6-mercaptopurine or azathioprine, or in whom there is intolerance or medical contraindications to such therapies.

Ulcerative Colitis (UC) in Children

Hyrimoz 40 is indicated for treatment of moderate to high disease activity ulcerative colitis in children aged 6 years and older who have not responded to conventional therapy, including corticosteroid therapy and/or 6-mercaptopurine or azathioprine, or in whom there is intolerance or medical contraindications to such therapies.

Uveitis

Hyrimoz 40 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 there is intolerance or medical contraindications to corticosteroid therapy.

Uveitis in Children

Hyrimoz 40 is indicated for treatment of chronic non-infectious anterior uveitis in children aged 2 years and older who have not responded to conventional therapy, have intolerance to conventional therapy, or for whom conventional therapy is contraindicated.

Contraindications

• Hypersensitivity to adalimumab or to any other component of the medicinal product.
• Active tuberculosis or other serious infections such as sepsis and opportunistic infections (see section "Special Warnings and Precautions for Use").
• Moderate to severe heart failure (NYHA class III/IV) (see section "Special Warnings and Precautions for Use").

Interaction with Other Medicinal Products and Other Forms of Interaction

Adalimumab has been studied in patients with RA, JIA, and PsA 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. Administration of adalimumab without methotrexate resulted in increased antibody formation, increased clearance, and reduced efficacy of adalimumab.

• Concomitant use of Hyrimoz 40 with anakinra is not recommended (see section "Special Warnings and Precautions for Use").
• Concomitant use of Hyrimoz 40 with abatacept is not recommended (see section "Special Warnings and Precautions for Use").

Special precautions for use

In order to improve control over the use of biological agents, it is essential to clearly record the trade name and batch number of the administered product in the patient's medical documentation to ensure traceability.

Infections

Patients receiving TNF antagonists are more susceptible to developing serious infections.

Impaired lung function may increase the risk of infections. Therefore, patients should be closely monitored for the development of infections, including tuberculosis, before, during, and after treatment with Hyrimoz 40. Since elimination of adalimumab may last up to four months, monitoring should continue throughout this period.

Hyrimoz 40 should not be administered to patients with active infections, including chronic or localized infections, until the infection is controlled. Patients who have been in close contact with individuals with tuberculosis or who have returned from countries with high tuberculosis prevalence or from regions endemic for fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis) should have their benefit-risk ratio evaluated prior to initiating Hyrimoz 40 therapy (see below "Other opportunistic infections").

A complete evaluation is required and careful monitoring of patients who develop a new infection during treatment with Hyrimoz 40 is necessary. Treatment should be discontinued if a serious infection or sepsis develops, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled.

Hyrimoz 40 should be used with particular caution in patients with recurrent infections or underlying conditions that increase susceptibility to infections.

Serious infections
Cases of sepsis, and rarely tuberculosis, candidiasis, listeriosis, legionellosis, and Pneumocystis infection have been reported with the use of TNF antagonists, including adalimumab. Other serious infections observed in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Hospitalizations due to infections, including fatal outcomes, have been reported.

Most serious infections occurred in the context of concomitant immunosuppressive therapy and underlying disease.

Tuberculosis

Cases of reactivation and new-onset tuberculosis, including pulmonary and extrapulmonary forms (e.g., disseminated tuberculosis), have been reported in patients receiving adalimumab therapy. Prior to initiating treatment with Hyrimoz 40, patients should be carefully evaluated for both active and latent (inactive) tuberculosis. This evaluation should include a thorough assessment of the patient’s history of tuberculosis or possible exposure to individuals with active tuberculosis, as well as prior and/or concomitant immunosuppressive therapy. All patients should undergo a tuberculin skin test (Mantoux test) and chest X-ray before starting therapy. A positive tuberculin skin test result is defined as an induration (papule) of 5 mm or greater in diameter (regardless of prior BCG vaccination). Latent tuberculosis may remain undiagnosed in patients returning from countries with high tuberculosis prevalence or those with close contact with individuals with active tuberculosis. Hyrimoz 40 therapy should not be initiated if active tuberculosis is diagnosed.

For patients with latent tuberculosis, specific prophylactic treatment should be administered prior to starting Hyrimoz 40 therapy. The need for anti-tuberculosis treatment should be considered in patients with risk factors for tuberculosis infection but negative latent tuberculosis test results, as well as in patients with a history of latent or active tuberculosis who have not received adequate treatment. The decision to initiate anti-tuberculosis therapy in such patients should be made in consultation with a pulmonologist, after evaluating the risk of latent tuberculosis reactivation and the safety of anti-tuberculosis treatment.

Specific treatment for latent tuberculosis reduces the risk of reactivation in patients receiving Hyrimoz 40. Despite prophylactic anti-tuberculosis therapy, cases of tuberculosis reactivation have occurred in patients receiving Hyrimoz 40. Active tuberculosis has also developed during Hyrimoz 40 treatment in some patients with initially negative screening for latent tuberculosis infection. In addition, some patients previously treated successfully for active tuberculosis have experienced recurrent tuberculosis while receiving TNF blockers. Patients should be monitored during Hyrimoz 40 therapy for symptoms suggestive of active tuberculosis, particularly considering the possibility of false-negative latent tuberculosis tests (especially in severely ill or immunocompromised patients).

All patients should be informed of the need to consult a physician if symptoms suggestive of tuberculosis (e.g., persistent cough, weight loss, low-grade fever, fatigue) develop during or after treatment with Hyrimoz 40.

Other opportunistic infections

Opportunistic infections, including invasive fungal infections, have been reported during adalimumab therapy. Such infections have sometimes not been diagnosed promptly, leading to delayed treatment and occasionally resulting in death. Patients receiving TNF blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, etc. All patients who develop fever, malaise, weight loss, increased sweating, cough, dyspnea, pulmonary infiltrates, or other signs of a serious systemic illness (with or without shock) should be promptly evaluated for opportunistic infections.

In patients living in or traveling to regions endemic for fungal infections, invasive fungal infections should be suspected if symptoms of systemic fungal infection occur. Due to the increased risk of histoplasmosis or other invasive fungal infections, empirical antifungal therapy should be considered before pathogen identification. In some patients, tests for histoplasma antigen or antibodies may yield negative results despite active infection. The decision to initiate empirical antifungal therapy in such patients should be made in consultation with an expert in the diagnosis and treatment of invasive fungal infections, taking into account the risk of fungal infection and the risks associated with antifungal therapy. Discontinuation of TNF blocker therapy is recommended in the event of a serious fungal infection until the infection is controlled.

Hepatitis B reactivation

TNF blockers have been associated with reactivation of hepatitis B virus (HBV) in chronic carriers. In some cases, HBV reactivation during TNF blocker therapy has been fatal. In most cases, patients were also receiving other immunosuppressive medications, which may have contributed to HBV reactivation. Patients at risk for HBV should be screened prior to initiating TNF blocker therapy. TNF blockers should be used with caution in HBV carriers, and such patients should be closely monitored for signs of HBV reactivation during and for several months after discontinuation of therapy. There are no data on the efficacy and safety of antiviral agents for preventing HBV reactivation in carriers receiving TNF blockers. In the event of HBV reactivation, treatment with Hyrimoz 40 should be discontinued and effective antiviral therapy and appropriate supportive treatment initiated.

Neurological disorders

Isolated cases of new onset or exacerbation of clinical and/or radiographic signs of demyelinating diseases of the central nervous system, including multiple sclerosis, optic neuritis, and peripheral nervous system demyelinating disorders, including Guillain-Barré syndrome, have been reported with the use of TNF blockers, including adalimumab. A careful benefit-risk assessment is recommended before using adalimumab in patients with demyelinating disorders of the central or peripheral nervous system. Treatment with Hyrimoz 40 should be discontinued if such disorders occur. A known association exists between non-infectious intermediate uveitis and demyelinating disorders of the central nervous system. Neurological evaluation is recommended for patients with non-infectious intermediate uveitis before initiating Hyrimoz 40 therapy and periodically during treatment to monitor for the development of central nervous system demyelinating disorders.

Allergic reactions

Serious allergic reactions associated with adalimumab were rare in clinical trials. Serious allergic reactions, including anaphylaxis, have been reported following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, Hyrimoz 40 should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

In clinical trials of adalimumab involving 64 patients with RA, no cases of suppressed delayed-type hypersensitivity, decreased immunoglobulin levels, or quantitative changes in effector T- and B-cells, NK cells, monocytes/macrophages, or neutrophils were observed.

Malignancies

In controlled clinical trials of TNF blockers, malignancies were reported more frequently in patients receiving TNF blockers than in control groups. However, the small size of control groups and limited duration of trials preclude definitive conclusions. Furthermore, patients with long-standing, highly active RA have an elevated baseline risk of lymphoma, complicating risk assessment. During long-term open-label clinical trials of adalimumab, the overall incidence of malignancies was similar to that expected in the general population matched for age, sex, and race. Nevertheless, a potential risk of lymphoma or other malignancies in patients treated with TNF antagonists cannot be excluded.

Isolated cases of fatal malignancies have been reported in children receiving TNF blockers. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. Other cases involved various types of malignancies, including rare malignancies typically associated with immunosuppression. Malignancies developed on average after 30 months of therapy. Most patients were also receiving immunosuppressants. These reports were obtained from post-marketing surveillance and various sources, including registries and post-marketing reports.

In post-marketing experience, very rare cases of hepatosplenic T-cell lymphoma (a rare, highly aggressive, and usually fatal type of lymphoma) have been reported in patients treated with adalimumab. Most of these patients had previously received infliximab in combination with azathioprine or 6-mercaptopurine for inflammatory bowel disease. The potential risk of concomitant use of azathioprine or 6-mercaptopurine with adalimumab should be carefully evaluated. A causal relationship between hepatosplenic T-cell lymphoma and adalimumab use has not been established.

No studies have been conducted on the use of adalimumab in patients with a history of malignancy or continuation of therapy in patients who develop malignancy. This should be taken into account when making decisions about using Hyrimoz 40 in such patients.

All patients, especially those with a history of intensive immunosuppressive therapy or psoriasis patients previously treated with PUVA therapy, should be evaluated for non-melanoma skin cancer before and during treatment with Hyrimoz 40.

In post-marketing experience, cases of acute and chronic leukemia associated with TNF blocker use have been reported in rheumatoid arthritis and other indications. Patients with rheumatoid arthritis may have an increased risk of leukemia (approximately two-fold) compared to the general population, even in the absence of TNF blocker therapy.

In a clinical trial evaluating another TNF blocker (infliximab) in patients with chronic obstructive pulmonary disease, a higher incidence of malignancies, mostly in the lungs, head, and neck region, was reported compared to the control group. All patients were long-term smokers. Therefore, TNF blockers should be used with caution in patients with chronic obstructive pulmonary disease and in patients at increased risk of malignancy due to smoking.

Currently, it is unknown whether adalimumab use affects the risk of intestinal dysplasia or colorectal cancer. All patients with ulcerative colitis who are at increased risk of dysplasia or colorectal cancer (e.g., those with long-standing ulcerative colitis or primary sclerosing cholangitis), or those with a history of dysplasia or colorectal cancer, should undergo regular surveillance for dysplasia before starting therapy and throughout the course of the disease. Surveillance should include colonoscopy and biopsy.

Hematological disorders

Rarely, pancytopenia and aplastic anemia have been reported with TNF blocker use. Cases of clinically significant cytopenia (thrombocytopenia, leukopenia) have been reported with adalimumab (causal relationship not established). All patients should be informed of the need to consult a physician immediately if symptoms suggestive of blood disorders (e.g., persistent fever, bruising, bleeding, pallor of skin and mucous membranes) occur during adalimumab use. Discontinuation of Hyrimoz 40 should be considered if serious hematological abnormalities are confirmed.

Vaccination

Patients receiving Hyrimoz 40 may be vaccinated, except with live vaccines. There are no data on secondary transmission of infection from live vaccines in patients receiving adalimumab.

Children should receive all age-appropriate vaccinations according to the immunization schedule before starting Hyrimoz 40 therapy, if possible.

Administration of live vaccines to infants exposed to adalimumab in utero is not recommended within 5 months after the last maternal adalimumab injection during pregnancy.

Chronic heart failure (CHF)

The use of adalimumab in patients with chronic heart failure has not been studied. However, clinical trials with another TNF blocker reported a higher incidence of adverse events related to CHF, including worsening of CHF and newly diagnosed CHF. Cases of CHF progression have also been reported in patients receiving adalimumab therapy. Hyrimoz 40 should be used with caution in patients with heart failure and under close monitoring of their clinical status (see section "Adverse reactions").

Autoimmune processes

Adalimumab treatment may lead to the development of autoantibodies. The impact of long-term Hyrimoz 40 use on the development of autoimmune diseases is unknown. If symptoms suggestive of lupus-like syndrome develop, treatment with Hyrimoz 40 should be discontinued.

Concomitant use with biological DMARDs or other TNF antagonists

Serious infections have been observed in clinical trials of concomitant use of anakinra and etanercept, without therapeutic benefit compared to etanercept monotherapy. Given the nature of adverse events observed with combination therapy of etanercept and anakinra, similar toxicity may occur with anakinra in combination with another TNF blocker. Therefore, the combination of adalimumab and anakinra is not recommended.

Concomitant use of adalimumab with other biological DMARDs (e.g., anakinra, abatacept) or with other TNF antagonists is not recommended due to the potential increased risk of infections and other potential pharmacological interactions.

Surgical procedures

Limited data are available on the safety of surgical procedures in patients receiving adalimumab. The long half-life of adalimumab should be considered when planning surgery. Patients requiring surgery while on Hyrimoz 40 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 undergoing 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 intervention. Available data suggest that adalimumab treatment does not cause the development or progression of strictures.

Elderly patients

The incidence of serious infections in patients aged 65 years and older receiving adalimumab (3.7%) is higher than in younger patients (1.5%). Some cases were fatal. Overall, in clinical trials, patients aged 65 years and older accounted for 9.5%, of whom approximately 2.0% were aged 75 years and older. Due to the higher incidence of infections in elderly patients, adalimumab should be used with caution in this age group.

Children

See the section "Vaccination" above.

Excipients with known effects

Hyrimoz 40 contains less than 1 mmol of sodium (23 mg) per 0.8 mL, i.e., practically sodium-free.

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should use reliable contraception during treatment and for at least five months after the last dose of Hyrimoz 40.

Pregnancy

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

A prospective cohort registry included 257 women with RA or 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 incidence of major congenital malformations in newborns. The frequency of pregnancies resulting in at least one live-born infant with a major congenital malformation was 6 out of 69 (8.7%) in the RA group receiving adalimumab and 5 out of 74 (6.8%) in the RA group not receiving adalimumab (unadjusted odds ratio [OR] 1.31, 95% confidence interval [CI] 0.38–4.52). In the CD group receiving adalimumab, the frequency was 16 out of 152 (10.5%), compared to 3 out of 32 (9.4%) in the CD group not receiving adalimumab (unadjusted OR 1.14, 95% CI 0.31–4.16). In the combined RA and CD group, the adjusted OR (adjusted for baseline differences) was 1.10 (95% CI 0.45–2.73). No clear differences were observed between women who did and did not receive adalimumab regarding secondary endpoints such as spontaneous abortions, minor congenital malformations, preterm births, birth weight and length, or serious or opportunistic infections. No cases of stillbirth or malignancy were reported. Interpretation of these data may be limited by methodological constraints, including small sample size and non-randomized study design.

In a non-clinical toxicity study in monkeys, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. Postnatal toxicity data for adalimumab are lacking.

Since adalimumab inhibits TNF-α, its use during pregnancy may interfere with normal immune responses in the newborn. Adalimumab should be used during pregnancy only if clearly needed.

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

Breastfeeding

Limited published data indicate that adalimumab is excreted in breast milk at very low concentrations—0.1 to 1% of maternal serum levels. Given that immunoglobulin G proteins undergo proteolytic degradation in the gastrointestinal tract and have low bioavailability, systemic effects of adalimumab on breastfed infants are unlikely. Therefore, Hyrimoz 40 may be used during breastfeeding.

Fertility

No preclinical data are available on the effect of adalimumab on fertility.

Ability to influence the speed of reaction when driving or operating machinery

Hyrimoz 40 may have a minor influence on the ability to drive or operate machinery. Use of Hyrimoz 40 may cause vertigo and visual disturbances (see section "Adverse reactions").

Dosage and Administration

Treatment with Hyrimoz 40 must be initiated by a physician experienced in the diagnosis and management of conditions for which Hyrimoz 40 is indicated. Ophthalmologists are advised to consult with the appropriate specialist before initiating therapy with Hyrimoz 40. Hyrimoz 40 may be self-administered only if the patient or the parents of a child being treated with adalimumab have received proper training from a physician on injection technique, and the physician has confirmed that self-injection is appropriate. Additionally, patients should review the self-injection instructions provided in this leaflet. During treatment with Hyrimoz 40, concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be re-evaluated.

Rheumatoid Arthritis

The recommended dose for adult patients is 40 mg administered subcutaneously once every two weeks. Concomitant methotrexate therapy should be continued during treatment with Hyrimoz 40. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics may also be continued. For use of other disease-modifying antirheumatic drugs (DMARDs), refer to section "Special Warnings and Precautions for Use".

In some RA patients not receiving methotrexate, increasing the frequency of administration to 40 mg subcutaneously once weekly or 80 mg every two weeks may be justified.

Clinical response is typically achieved within 12 weeks of treatment. The need for continued therapy should be reassessed in patients who do not show a response within this timeframe.

If necessary, therapy may be interrupted (e.g., prior to surgery or in the event of a serious infection). Data indicate that clinical response and safety profile upon resuming treatment after 70 days or more are similar to those observed prior to the interruption.

Axial Spondyloarthritis (Ankylosing Spondylitis and Non-Radiographic Axial Spondyloarthritis) and Psoriatic Arthritis

The recommended dose for adult patients is 40 mg administered subcutaneously once every two weeks.

Clinical response is typically achieved within 12 weeks of treatment. The need for continued therapy should be reassessed in patients who do not show a response within this timeframe.

Plaque Psoriasis

The recommended initial dose for adults is 80 mg, followed one week later by 40 mg subcutaneously. Maintenance therapy is 40 mg administered subcutaneously once every two weeks.

For patients who do not achieve a clinical response within 16 weeks of therapy, increasing the frequency of administration to 40 mg once weekly may be effective.

The need for continued treatment with Hyrimoz 40 should be carefully reassessed in patients who do not achieve a clinical response after increasing the dosing frequency.

If a clinical response is achieved after increasing the dosing frequency, the dose may be gradually reduced back to 40 mg once every two weeks.

Hyrimoz 40 is available only in a pre-filled syringe containing 40 mg of adalimumab. Therefore, it is not possible to administer Hyrimoz 40 to patients requiring a dose less than 40 mg.

Hidradenitis Suppurativa (HS)

The recommended dosing regimen for adult patients with hidradenitis suppurativa is an initial dose of 160 mg at week 0 (day 1), which may be administered as four injections in one day or two injections per day on two consecutive days, followed by 80 mg at week 2 (day 15), given as two injections in one day. Starting at week 4 (day 29), the recommended dose is 40 mg once weekly.

Concomitant antibiotic therapy may be continued during treatment with Hyrimoz 40, if clinically indicated.

Daily topical antiseptic cleansing of affected areas is also recommended.

The need for continued therapy beyond 12 weeks should be carefully reassessed in patients who do not achieve a clinical response within this period.

If therapy is interrupted, treatment with adalimumab may be resumed at a dose of 40 mg once weekly.

During long-term therapy, the benefit-risk ratio should be periodically evaluated.

Crohn's Disease

For induction of remission, the recommended initial dose for adult patients is 80 mg at week 0 (day 1), followed by a reduced dose of 40 mg at week 2 (day 15), administered subcutaneously. To achieve a more rapid clinical response, 160 mg may be administered at week 0 (day 1), given as four injections in one day or two injections per day on two consecutive days, followed by 80 mg at week 2 (day 15), administered subcutaneously. It should be noted that in such cases, the risk of adverse reactions may be increased.

After induction therapy, maintenance treatment should be initiated at a dose of 40 mg administered subcutaneously once every two weeks. Alternatively, if a patient has discontinued therapy and disease symptoms reappear, treatment with Hyrimoz 40 may be restarted. Limited data are available on re-initiating Hyrimoz 40 after a treatment interruption of more than 8 weeks from the last administered dose. During maintenance therapy, corticosteroid doses may be tapered according to clinical practice.

If clinical response diminishes, some patients may require an increase in dosing frequency to 40 mg administered subcutaneously once weekly.

Some patients who do not achieve a clinical response by week 4 of treatment should continue maintenance therapy up to week 12. The need for continued therapy should be carefully reassessed in patients who do not achieve a clinical response within this timeframe.

Ulcerative Colitis

The recommended initial dose for induction of remission in adult patients with moderately to severely active ulcerative colitis is 160 mg at week 0 (day 1), which may be administered as four injections in one day or two injections per day on two consecutive days, followed by 80 mg at week 2 (day 15). After induction therapy, the recommended dose is 40 mg administered subcutaneously once every two weeks.

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

If clinical response diminishes, some patients may require an increase in dosing frequency to 40 mg once weekly.

Clinical response should be achieved within 2–8 weeks of treatment. Treatment with Hyrimoz 40 should be continued only in patients who achieve a clinical response within the first 8 weeks of therapy.

Uveitis

The recommended initial dose of Hyrimoz 40 for adult patients with uveitis is 80 mg. Starting from the first week after the initial dose, maintenance therapy should be initiated with 40 mg administered subcutaneously once every two weeks.

Limited data are available on adalimumab monotherapy as initial treatment. Therapy with Hyrimoz 40 may be initiated in combination with corticosteroids and/or other non-biologic immunomodulatory agents. Two weeks after starting combination therapy, a gradual transition to monotherapy with Hyrimoz 40 may be considered based on clinical experience.

The benefit-risk ratio of long-term therapy should be evaluated annually.

Pediatrics

Hyrimoz 40 is available only in a pre-filled syringe containing 40 mg of adalimumab. Therefore, it is not possible to administer Hyrimoz 40 to patients requiring a dose less than 40 mg.

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

The recommended dose of Hyrimoz 40 for children aged 2 years and older with polyarticular JIA depends on body weight (Table 1). Hyrimoz 40 is administered subcutaneously once every two weeks.

Table 1. Dosing of Hyrimoz 40 in patients with polyarticular JIA

| Body Weight | Dose | |-------------|------| | < 30 kg | 20 mg every two weeks | | ≥ 30 kg | 40 mg every two weeks |

Clinical response, according to available data, is usually achieved within 12 weeks of treatment. The need for continuing therapy should be re-evaluated in patients who do not show a response to treatment within this period.

Hyrimoz 40 is not recommended for use in children under 2 years of age for this indication.

Enthesitis-related arthritis

The recommended dose of Hyrimoz 40 for children aged 6 years and older depends on the patient's body weight (Table 2). Hyrimoz 40 is administered subcutaneously once every 2 weeks.

Table 2. Dosage of Hyrimoz 40 for patients with enthesitis-related arthritis

The use of Hyrimoz 40 in children under 6 years of age with enthesitis-related arthritis has not been studied.

Psoriatic plaque in children

The recommended dose of Hyrimoz 40 for patients aged 4 to 18 years with plaque psoriasis depends on the patient's body weight (Table 3). Hyrimoz 40 is administered subcutaneously.

Table 3. Dosage of Hyrimoz 40 for children with plaque psoriasis

Careful consideration should be given to the need for continuing therapy in patients who have not shown a clinical response within 16 weeks.

If retreatment with Hyrimoz 40 is prescribed, the dosing regimen specified above should be followed.

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

The use of adalimumab in children under 4 years of age with plaque psoriasis has not been studied.

Hidradenitis suppurativa in children aged 12 years and older with body weight of at least 30 kg

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

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

For children with an inadequate response to adalimumab 40 mg every 2 weeks, increasing the frequency of administration to 40 mg once weekly may be considered. Concomitant use of antibiotics during treatment with Hyrimoz 40 may be continued if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

Careful consideration should be given to the need for continuing therapy beyond 12 weeks in patients who have not shown a clinical response within this period.

If treatment is interrupted, resuming therapy with Hyrimoz 40 may be considered, if necessary.

Crohn’s disease in children

The recommended dose of Hyrimoz 40 for children aged 6 to 18 years with Crohn’s disease depends on the patient's body weight (Table 4).

Hyrimoz 40 is administered subcutaneously.

Table 4. Dosing of Hyrimoz 40* for children with Crohn’s disease

*HYRIMOZ 40 is available only in a pre-filled syringe containing 40 mg of adalimumab. Therefore, HYRIMOZ 40 cannot be prescribed to patients who require a dose lower than 40 mg.

For patients with an inadequate response, increasing the frequency of HYRIMOZ 40 administration may be considered:

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

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

HYRIMOZ 40 is not indicated for use in children under 6 years of age for this indication.

During long-term therapy, the benefit-risk balance should be periodically assessed.

Uveitis in children

The recommended dose of HYRIMOZ 40 for children aged 2 years and older with chronic non-infectious uveitis depends on the patient's body weight (Table 5). HYRIMOZ 40 is administered subcutaneously.

There are no data on the use of HYRIMOZ 40 without concomitant methotrexate therapy in children with uveitis.

Table 5. Dosing of HYRIMOZ 40 in children with uveitis

Hyrimoz 40 may be used in combination with methotrexate or other non-biological immunomodulating agents according to clinical experience.

The initial loading dose of adalimumab is 40 mg for patients with body weight below 30 kg and 80 mg for patients with body weight of 30 kg and above; it can be administered one week prior to initiation of maintenance therapy. There are no clinical data on administration of the initial loading dose of adalimumab to children under 6 years of age.

Use of Hyrimoz 40 in children under 2 years of age for the indication uveitis is not justified. It is recommended to annually evaluate the benefit and risk of long-term treatment.

Ulcerative colitis (UC)

The recommended dose of Hyrimoz 40 for patients aged 6 to 18 years with ulcerative colitis is based on the patient's body weight (Table 6). Hyrimoz 40 is administered by subcutaneous injection.

Table 6. Dosing of Hyrimoz 40 in pediatric patients with ulcerative colitis (UC)

Patients who turn 18 years of age during treatment with Hyrimoz 40 should continue treatment with maintenance therapy.

The need for continuing therapy should be carefully reconsidered in patients who do not show a clinical response within 8 weeks.

The use of Hyrimoz 40 in children under 6 years of age with ulcerative colitis has not been studied.

Geriatric patients

Dose adjustment for this patient group is not required.

Impaired hepatic and/or renal function

The use of Hyrimoz 40 in such patients has not been studied; therefore, no dosage recommendations can be made.

Administration

Hyrimoz 40 must be administered under the supervision of a physician. Upon physician's recommendation, patients or their parents/caregivers may self-administer the medication after proper training in the technique of subcutaneous injection.

To avoid potential infection and ensure correct use of the medication, strictly follow these instructions.

Before administering Hyrimoz 40, carefully read these instructions for use, ensure that everything is clearly understood, and follow them accordingly. Before you start using Hyrimoz 40, your doctor will demonstrate how to prepare and administer an injection using the single-dose prefilled syringe. For any questions, consult your doctor.

Single-dose prefilled syringe of Hyrimoz 40 with a needle guard and an additional finger support

Always follow these instructions:

• Do not use the prefilled syringe if the blister seal is broken, as it may not be safe to use.
• Do not open the outer packaging until you are ready to use the syringe.
• Never leave the prefilled syringe unattended where others could access it.
• If you drop the syringe, do not use it if it is damaged or if the cap becomes detached.
• Do not remove the cap until you are ready for injection.
• Do not touch the wings of the safety guard before use. Otherwise, the safety guard may activate prematurely.
• Do not remove the finger grip before injection.
• Administer Hyrimoz 15–30 minutes after removing it from the refrigerator for more comfortable administration.
• Dispose of the syringe immediately after use. Do not reuse the syringe.

Syringe Preparation

• For a more comfortable injection, remove the prefilled syringe from the refrigerator and leave it unopened on a flat surface for approximately 15–30 minutes to reach room temperature.
• Remove the prefilled syringe from the blister pack.
• Look through the viewing window. The solution should be colorless or slightly yellowish, and clear or slightly opalescent. Do not use the medicine if particles are visible and/or if there is a change in color. If you are concerned about the appearance of the solution, consult your pharmacist for assistance.
• Do not use the prefilled syringe if it is damaged or if the safety guard has been activated. Return the syringe and outer packaging to the pharmacy.
• Check the expiry date on the prefilled syringe. Do not use the prefilled syringe if it has passed the expiry date.

Recommended sites for self-injection are the thigh and abdomen. Within these recommended areas, the injection site should be rotated regularly. The medication should not be administered into areas with sensitive skin, bruising, redness, or skin hardening.

As with any other parenteral medication, the solution should be visually inspected for the presence of particulate matter, discoloration, or loss of clarity before administration.

Hyrimoz 40 must not be mixed in the same syringe with any other medicinal products.

Unused solution and syringe after administration must be disposed of according to current guidelines.

Children

Indicated for use in children as specified in the "Indications" section. Hyrimoz 40 in a pre-filled single-use syringe is available only in a 40 mg dose. Therefore, administration of Hyrimoz 40 in a pre-filled single-use syringe to children requiring a dose lower than 40 mg is not feasible.

Overdose

During clinical trials of adalimumab, no dose-limiting toxicity was observed. Multiple doses up to 10 mg/kg, approximately 15 times higher than the recommended dose, were administered to patients without causing signs of toxicity related to overdose.

Adverse Reactions

During clinical trials

Adalimumab has been studied in controlled clinical trials and open-label extension studies lasting up to approximately 60 months, involving 9506 patients with early and longstanding rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile arthritis and enthesitis-related arthritis), psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), Crohn’s disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, and uveitis.

The data presented below are from the main controlled trials, in which adalimumab was administered to 6089 patients and placebo or a comparator drug was administered to 3801 patients during the controlled period.

During 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.

General information on safety profile

The most commonly reported adverse reactions were infections (such as nasopharyngitis, upper respiratory tract infections, and sinusitis), injection site reactions (redness, itching, hemorrhage, pain, or swelling), headache, and musculoskeletal pain.

TNF antagonists, such as Hyrimoz 40, affect the immune system and their use may result in decreased resistance to infections and malignancies. During treatment with Hyrimoz 40, serious and potentially life-threatening 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 pancytopenia, aplastic anemia, central and peripheral demyelinating disorders, development of lupus, 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.

Table 7 lists adverse reactions observed during clinical trials and the post-marketing period that may be causally related to the use of the medicinal product. Adverse reactions are listed by system organ class and frequency of occurrence (≥ 1/10 – very common; ≥ 1/100 to < 1/10 – common; ≥ 1/1000 to < 1/100 – uncommon; ≥ 1/10000 to < 1/1000 – rare; unknown (cannot be estimated from available data)).

Table 7

* See also sections "Contraindications", "Special precautions".

** Including the open-label period of studies.

1 Including data from spontaneous reports.

2 The mean change in body weight from baseline ranged from 0.3 kg to 1.0 kg with adalimumab treatment in adult indications compared to from (minus) -0.4 kg to 0.4 kg with placebo during the 4–6 month treatment period. Weight gain of 5–6 kg was also observed in long-term extension 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 of this effect is unclear but may be related to the anti-inflammatory action of adalimumab.

Hidradenitis suppurativa

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

Uveitis

The safety profile for patients with uveitis receiving adalimumab every 2 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 pruritus, bruising, pain, or swelling) occurred in 12.9% of adults and children receiving Hyrimoz 40, compared to 7.2% in the control group. Most reactions were mild and generally did not require discontinuation of the drug.

Infections

In controlled clinical trials in adults and children, the infection rate was 1.51/patient-year in the Hyrimoz 40 treatment group and 1.46/patient-year in the control group. The rate of serious infections was 0.04/patient-year in the Hyrimoz 40 group and 0.03/patient-year in the control group. These were predominantly nasopharyngitis, upper respiratory tract infections, and sinusitis. Most patients continued treatment with Hyrimoz 40 after recovery.

In controlled and open-label studies in adults and children, severe infections (rarely with fatal outcomes) were reported: tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (such as disseminated histoplasmosis, Pneumocystis pneumonia, aspergillosis, listeriosis). Most cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect reactivation of latent disease.

Neoplasms and lymphoproliferative disorders

During clinical trials of adalimumab in children with JIA (polyarticular juvenile arthritis and enthesitis-related arthritis), no malignancies were observed (n = 249, 655.6 patient-years).

Additionally, no malignancies were observed in clinical trials in children with Crohn’s disease (n = 192; 498.1 patient-years), plaque psoriasis (n = 77; 80.0 patient-years), uveitis (n = 60; 58.4 patient-years).

During the controlled periods of main studies with adalimumab treatment for at least 12 weeks in adult patients with moderate to high disease activity rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), Crohn’s disease, ulcerative colitis, hidradenitis suppurativa, uveitis, and psoriasis, the rate of malignancies (excluding lymphoma and non-melanoma skin cancer) was (95% confidence interval) 6.8 (4.4; 10.5) per 1000 patient-years in 5291 patients receiving adalimumab, compared to 6.3 (3.4; 11.8) per 1000 patient-years in 3444 control group patients (mean treatment duration was 4.0 months in the adalimumab group and 3.8 months in the control group).

The rate of non-melanoma skin cancer (95% confidence interval) was 8.8 (6.0; 13.0) per 1000 patient-years in patients receiving adalimumab and 3.2 (1.3; 7.6) per 1000 patient-years in control group patients. Among reported cases, the incidence of squamous cell carcinoma (95% confidence interval) was 2.7 (1.4; 5.4) per 1000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5) per 1000 patient-years in control group patients.

The rate of lymphomas (95% confidence interval) was 0.7 (0.2; 2.7) per 1000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5) per 1000 patient-years in control group patients.

The observed rates of malignancy development (excluding lymphoma and non-melanoma skin cancer) were approximately 8.5/1000 patient-years in controlled trials and ongoing or completed open-label studies. The rates of non-melanoma skin cancer were approximately 9.6/1000 patient-years, and lymphoma rates were approximately 1.3/1000 patient-years. These studies lasted approximately 3.3 years and included 6427 patients who received adalimumab for at least 1 year or in whom malignancies occurred within 1 year from the start of therapy, amounting to more than 26,439 patient-years of therapy.

In the post-marketing period from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the rate of malignancies was approximately 2.7 per 1000 patient-years in patients treated with adalimumab. The reported rates of non-melanoma skin cancer and lymphoma were approximately 0.2 and 0.3 per 1000 patient-years, respectively.

Autoantibodies

During phases 1–5 clinical trials of rheumatoid arthritis, patients were tested several times for autoantibodies. In these controlled studies, positive titers were reported in 11.9% of patients receiving adalimumab and in 8.1% of placebo group patients; negative antinuclear antibody titers were observed at week 24 under active treatment monitoring.

Two patients (out of 3441 patients with RA, PsA, and AS receiving adalimumab in clinical trials) developed signs of newly diagnosed lupus-like syndrome, which resolved after discontinuation of treatment. No patient developed lupus nephritis or central nervous system involvement.

Liver enzyme activity

In phase 3 controlled clinical trials involving patients with rheumatoid arthritis and psoriatic arthritis, during the controlled period lasting from 4 to 104 weeks, ALT (alanine aminotransferase) elevations ≥3 times the upper limit of normal were observed in 3.7% of patients receiving adalimumab and in 1.6% of control group patients. Since many patients in these trials were taking medications known to cause elevated liver enzymes (e.g., NSAIDs, methotrexate), the relationship between adalimumab use and elevated liver enzymes has not been established.

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

In phase 3 controlled clinical trials involving patients with Crohn’s disease and ulcerative colitis, with a controlled period duration of 4 to 52 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 0.9% of patients in both groups.

In a phase 3 clinical trial involving children with Crohn’s disease, evaluating the efficacy and safety of a weight-based dosing regimen followed by a weight-based maintenance regimen with treatment duration up to 52 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 2.6% (5/192) of patients, 4 of whom received adalimumab while concurrently receiving immunosuppressants.

In phase 3 controlled clinical trials involving patients with plaque psoriasis, with a controlled period duration of 12 to 24 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 1.8% of patients in both groups.

In controlled clinical trials (initial dose 160 mg (week 0) and 80 mg (week 2), then 40 mg once weekly starting week 4) involving patients with hidradenitis suppurativa, with a controlled period duration of 12 to 16 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 0.3% of patients receiving adalimumab and 0.6% of control group patients.

In controlled clinical trials (initial dose 80 mg (week 0), then 40 mg every 2 weeks starting week 1) involving patients with uveitis and with a controlled period duration of up to 80 weeks (mean exposure of 166.5 days and 105 days in the adalimumab and control groups, respectively), ALT elevations ≥3 times the upper limit of normal were observed in 2.4% of patients receiving adalimumab and 2.4% of control group patients.

Across all indications in clinical trials, patients had asymptomatic ALT elevations, and in most cases, elevations were transient during continued treatment. However, very rare post-marketing reports of liver failure and less severe hepatic reactions potentially leading to liver failure, such as hepatitis, including autoimmune hepatitis, have been reported in patients receiving adalimumab. A causal relationship with adalimumab remains unconfirmed.

Concomitant therapy with azathioprine/6-mercaptopurine

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

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals, pharmacists, patients, and 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.

Incompatibility

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Shelf life. 30 months.

Do not use the medicinal product after the expiry date.

Storage conditions

Store at 2–8 °C in the original packaging to protect from light. Do not freeze. Keep out of reach of children.

Pre-filled syringes may be stored at room temperature (not above 25 °C) for up to 21 days in a place protected from light. Do not use more than 21 days after removal from the refrigerator (even if the product was returned to the refrigerator).

Packaging

0.8 mL of solution in a pre-filled syringe; 1 or 2 pre-filled syringes in blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Novartis Pharmaceuticals Manufacturing GmbH

or

Sandoz GmbH – Aseptic Pharmaceuticals Schaftenu (APS)

Manufacturer’s address and location of its business activities

Biochemiestrasse 10, Unterlangkampfen, Langkampfen, 6336, Austria

or

Biochemiestrasse 10, 6336 Langkampfen, Austria