Hairimoz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HAIROMOZ (HYRIMOZ)

Composition:

Active substance: adalimumab;

1 pre-filled syringe contains 20 mg of adalimumab in 0.2 ml of solution;

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

Pharmaceutical form. Solution for injection.

Main physico-chemical characteristics: clear or slightly opalescent, colorless or slightly yellowish solution.

Pharmacotherapeutic group.

Immunosuppressants. Tumor necrosis factor-alpha inhibitors. Adalimumab.

ATC code L04A B04.

Pharmacological Properties

Mechanism of Action

Adalimumab specifically binds to tumor necrosis factor (TNF) and neutralizes its biological effects by 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).

Pharmacodynamics

In patients with rheumatoid arthritis (RA), adalimumab rapidly reduced, compared to baseline, levels of acute-phase inflammatory markers (C-reactive protein (CRP), serum cytokines (IL-6), and erythrocyte sedimentation rate (ESR)). A reduction in serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which contribute to tissue remodeling underlying cartilage destruction, was also observed. Treatment with adalimumab typically results in improvement of 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, a significant reduction in TNF-α expression in patients with Crohn’s disease 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 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 single intravenous administration at doses ranging from 0.25 to 10 mg/kg, concentrations were dose-proportional. Following a dose of 0.5 mg/kg (approximately 40 mg), clearance ranged from 11 to 15 mL/hour, 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 RA patients were 31–96% of serum levels.

After subcutaneous administration of adalimumab at 40 mg 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 to subcutaneously administered doses of 20, 40, and 80 mg every 2 weeks or weekly.

After subcutaneous administration of adalimumab at 24 mg/m² (up to 40 mg) every 2 weeks in patients with polyarticular juvenile rheumatoid arthritis (JRA) 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, following adalimumab at 24 mg/m² with methotrexate, mean steady-state concentrations were 6.0 ± 6.1 µg/mL (101% CV) without methotrexate and 7.9 ± 5.6 µg/mL (71.2% CV) with methotrexate.

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 methotrexate and 11.8 ± 4.3 µg/mL with methotrexate.

After subcutaneous administration of adalimumab at 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 concentration was 5 µg/mL during monotherapy with adalimumab 40 mg 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. The mean steady-state concentration from week 12 to week 36 was approximately 8–10 µg/mL during maintenance therapy with 40 mg weekly.

The effect of adalimumab in adolescents with hidradenitis suppurativa was determined using pharmacokinetic modeling and simulation based on pharmacokinetic data from pediatric indications (plaque psoriasis, juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and enthesitis-related arthritis). The recommended dosing regimen for adolescents with hidradenitis suppurativa is 40 mg every 2 weeks. Since the effect of adalimumab may depend on body weight, adolescents with high body weight and inadequate response to treatment may receive the adult recommended 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 concentration was approximately 5.5 µg/mL during induction therapy. After administration of 160 mg at week 0 followed by 80 mg at week 2, serum concentration was approximately 12 µg/mL during induction. The mean steady-state concentration was approximately 7 µg/mL during maintenance therapy with 40 mg 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 weight-based either 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 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 continuing adalimumab treatment over 52 weeks. In patients whose dose was increased from once every two 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 concentration was approximately 12 µg/mL during induction therapy. The mean steady-state concentration 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 weight-based dose of 0.6 mg/kg (maximum 40 mg) every 2 weeks was 5.01 ± 3.28 µg/mL. In patients receiving 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 adult 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 8–10 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 initial adalimumab dosing in children under 6 years of age. In the absence of methotrexate, initial dosing is predicted to result in 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 those receiving 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 (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis), an exposure–response relationship was established between plasma concentration and response as measured by the PedACR 50 criterion. The apparent plasma concentration of adalimumab associated with 50% of maximum probability of PedACR 50 response (EC50) was 3 µg/mL (95% CI: 1–6 µg/mL). An exposure–response relationship between adalimumab concentration and efficacy in children with moderate to severe chronic plaque psoriasis was established for PASI 75 and PGA responses ("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 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) in serum were lower in patients who developed anti-adalimumab antibodies. The use of Hyrimoz has not been studied in patients with hepatic or renal impairment.

Clinical Characteristics

Indications

Rheumatoid Arthritis (RA)

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

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

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

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

Hyrimoz 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 in patients under 2 years of age.

Enthesitis-Related Arthritis

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

Axial Spondyloarthritis

Ankylosing Spondylitis (AS)

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

Axial Spondyloarthritis without Radiographic Confirmation of AS

Hyrimoz is indicated for the treatment of active axial spondyloarthritis with high disease activity without radiographic confirmation of AS, but with evidence of inflammation based on elevated CRP levels and/or MRI (magnetic resonance imaging) findings in adult patients who have not had an adequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) or who have intolerance to these agents.

Psoriatic Arthritis (PsA)

Hyrimoz is indicated for the treatment of active and progressive psoriatic arthritis in adult patients when an inadequate response has been achieved with prior therapy using disease-modifying antirheumatic drugs (DMARDs). Adalimumab has demonstrated slowing of the progression of peripheral joint damage, as assessed radiographically, in patients with symmetric polyarticular disease, and improvement in functional status.

Plaque Psoriasis (PP)

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

Plaque Psoriasis (PP) in Children

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

Hidradenitis Suppurativa (HS)

Hyrimoz is indicated for the treatment of active moderate to severe hidradenitis suppurativa (acne inversa) in adult patients and adolescents aged 12 years and older who have not responded to conventional systemic therapy.

Crohn’s Disease (CD)

Hyrimoz is indicated for the treatment of moderate to severe active Crohn’s disease in adult patients who have not responded to a full course of corticosteroid and/or immunosuppressant therapy, or who have intolerance or medical contraindications to such therapies.

Crohn’s Disease (CD) in Children

Hyrimoz is indicated for the treatment of moderate to severe active Crohn’s disease in children aged 6 years and older who have not responded to conventional therapy, including primary nutritional therapy, corticosteroids and/or immunomodulators, or who have intolerance or medical contraindications to such therapies.

Ulcerative Colitis (UC)

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

Ulcerative Colitis (UC) in Children

Hyrimoz is indicated for the treatment of moderate to severe active ulcerative colitis in children (aged 6 years and older) who have not responded to conventional therapy, including corticosteroids and/or 6-mercaptopurine or azathioprine, or who have intolerance or medical contraindications to such therapies.

Uveitis

Hyrimoz is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients who have not responded to corticosteroid therapy, who require corticosteroid dose reduction, or who have intolerance or medical contraindications to corticosteroid therapy.

Uveitis in Children

Hyrimoz is indicated for the 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 with anakinra is not recommended (see section "Special Warnings and Precautions for Use").
• Concomitant use of Hyrimoz 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, the trade name and batch number of the administered drug should be clearly documented in the patient's medical records.

Infections

Patients treated with TNF blockers are more susceptible to developing severe infections.

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

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

A thorough evaluation and careful monitoring are required for patients who develop a new infection during treatment with Hyrimoz. In case of severe infection or sepsis, treatment should be discontinued and appropriate antimicrobial or antifungal therapy initiated until the infection is controlled. Hyrimoz should be used with particular caution in patients with recurrent infections or underlying conditions that increase susceptibility to infections.

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 treated with adalimumab.

Other severe infections observed in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. There have been reports of hospitalization due to infections (including fatal cases).

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 Hyrimoz therapy, patients should be carefully screened for both active and latent (inactive) tuberculosis. Screening should include a thorough assessment of the patient's history of tuberculosis or 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 (local guidelines may apply). The results of these tests should be documented in the patient's record. Physicians should be aware of the risk of false-negative skin test results, particularly in severely ill or immunocompromised patients.

Hyrimoz 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.

Decisions regarding treatment of patients with suspected latent tuberculosis should be made in consultation with a pulmonologist.

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

Anti-tuberculosis treatment should be considered before initiating Hyrimoz therapy in patients at risk for tuberculosis infection despite a negative latent tuberculosis test, and in patients with a history of latent or active tuberculosis who have not received confirmed appropriate treatment.

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

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

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 and occasionally resulting in death.

In case of fever, malaise, weight loss, increased sweating, cough, dyspnea, and/or lung infiltrates or other signs of serious systemic illness (with or without shock), patients should immediately undergo evaluation for invasive fungal infection and Hyrimoz 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 reactivation

Use of TNF blockers, including adalimumab, has been associated with reactivation of hepatitis B virus in chronic carriers (i.e., those who are surface antigen positive). In some cases, hepatitis B reactivation has been fatal. Prior to initiating Hyrimoz, patients at risk for hepatitis B virus should be tested. If test results are positive, the decision to treat should be made in consultation with a hepatologist.

Hyrimoz should be used cautiously in patients who are hepatitis B virus carriers, and such patients should be closely monitored for signs of hepatitis B 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 reactivation in carriers receiving TNF antagonists. In case of hepatitis B reactivation, Hyrimoz therapy should be discontinued and effective antiviral treatment and appropriate supportive therapy initiated.

Neurological disorders

Rare 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 TNF blockers, including adalimumab. Careful assessment of the benefit-risk ratio of adalimumab use is recommended in patients with demyelinating disorders of the central or peripheral nervous system. Treatment with Hyrimoz should be discontinued if such disorders occur. An association between non-infectious intermediate uveitis and central nervous system demyelinating disorders is known. Neurological evaluation is recommended for patients with non-infectious intermediate uveitis before initiating Hyrimoz therapy and periodically during treatment to monitor for the development of central nervous system demyelinating disorders.

Allergic reactions

Serious allergic reactions, including anaphylaxis, have been reported after administration of adalimumab during clinical trials. In case of anaphylactic reaction or other serious allergic reaction, Hyrimoz should be discontinued immediately and appropriate therapy initiated.

Immunosuppression

In clinical trials of adalimumab in 64 patients with RA, no cases of delayed-type hypersensitivity suppression, 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 group patients. However, these cases were rare. In post-marketing experience, cases of leukemia associated with TNF antagonist use have been reported. Moreover, patients with long-standing, highly active rheumatoid arthritis have an increased baseline risk of lymphoma and leukemia, complicating risk assessment. Based on available data, the risk of 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 TNF antagonist therapy (age at treatment initiation ≤ 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 malignancy development in children receiving TNF antagonist therapy cannot be excluded (see section "Adverse reactions").

In post-marketing experience, there have been rare reports of hepatosplenic T-cell lymphoma in patients treated with adalimumab. This is a rare type of lymphoma characterized by highly aggressive course and is usually fatal. Some cases of hepatosplenic T-cell lymphoma occurred in young patients who 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. The risk of hepatosplenic T-cell lymphoma in patients receiving Hyrimoz cannot be excluded (see section "Adverse reactions").

No studies have been conducted on the use of adalimumab in patients with a history of malignancy or continuing therapy in patients who develop malignancy. Therefore, this should be taken into account, and decisions regarding adalimumab use in such patients should be made with caution (see section "Adverse reactions").

All patients, especially those with prior intensive immunosuppressive therapy or psoriasis patients previously treated with PUVA (psoralens with UVA), should be screened for non-melanoma skin cancer before and during treatment with Hyrimoz. Melanoma and Merkel cell carcinoma have also been reported in patients receiving TNF antagonist therapy, including adalimumab (see section "Adverse reactions").

In a clinical trial evaluating another TNF antagonist (infliximab) in patients with chronic obstructive pulmonary disease, a higher incidence of new malignancies, mostly in the lungs, head, and neck, was 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 malignancy due to smoking.

Currently, it is unknown whether adalimumab use affects the risk of colorectal dysplasia or cancer. All patients with ulcerative colitis who are at increased risk of colorectal dysplasia or cancer (e.g., those with long-standing ulcerative colitis or primary sclerosing cholangitis) or those with a history of colorectal dysplasia or 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 guidelines.

Hematological disorders

Rare cases of pancytopenia and aplastic anemia have been reported with TNF blockers. With adalimumab use (causal relationship not established), clinically significant cytopenia (thrombocytopenia, leukopenia) has been reported. 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 therapy. Discontinuation of Hyrimoz should be considered in patients with confirmed serious blood disorders.

Vaccination

Similar antibody responses to 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.

For pediatric patients, it is recommended to complete all necessary vaccinations according to the schedule before starting Hyrimoz therapy, if possible.

Vaccination may be performed in patients receiving adalimumab, except for live vaccines. Live vaccines (e.g., BCG vaccine) are not recommended for infants exposed to adalimumab in utero within 5 months after the last maternal adalimumab injection during pregnancy.

Chronic heart failure (CHF)

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

Autoimmune processes

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

Concomitant use with biological DMARDs or other TNF antagonists

Serious infections were 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, 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 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 (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 considered when planning surgery. Patients requiring surgery and receiving Hyrimoz 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 treatment. Available data suggest that adalimumab treatment does not cause or promote stricture formation.

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. 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 contains less than 1 mmol of sodium (23 mg) per 0.2 mL, i.e., practically sodium-free.

Use during pregnancy or breastfeeding

Women of childbearing potential

To prevent pregnancy, women of childbearing potential should use reliable contraception during treatment and for at least five months after the last dose of Hyrimoz.

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 first-trimester exposure) did not show an increased frequency of birth defects 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 frequency 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%), and in the CD group not receiving adalimumab, 3 out of 32 (9.4%) (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 development 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 non-clinical toxicity study in monkeys, no evidence of maternal organ toxicity, embryotoxicity, or teratogenicity was observed. Postnatal toxicity data for adalimumab are lacking.

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

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) are not recommended for infants exposed to adalimumab in utero 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. Considering 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 may be used during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Treatment with Hyrimoz must be prescribed by a physician experienced in the diagnosis and treatment of conditions for which Hyrimoz is indicated. Ophthalmologists are advised to consult with the appropriate specialist before initiating treatment with Hyrimoz. Patients receiving Hyrimoz should be provided with a patient reminder card.

Hyrimoz may be self-administered only if the patient or the parents of a child being treated with adalimumab have received appropriate training from a physician on the injection technique, and the physician has confirmed that self-injection is appropriate. Additionally, information on self-injection contained in this instruction should be carefully reviewed. During treatment with Hyrimoz, concomitant therapies (e.g., corticosteroids and/or immunomodulating agents) should be re-evaluated.

Rheumatoid Arthritis

The recommended dose for adult patients is 40 mg administered subcutaneously every two weeks. Treatment with Hyrimoz should be continued in combination with methotrexate. Concomitant therapy with glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, and analgesics may also be continued. For use of other disease-modifying antirheumatic drugs (DMARDs), see section "Special Instructions".

For 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 usually achieved within 12 weeks of treatment. The need for continuing therapy should be reassessed in patients who do not show a response to treatment within this period.

If necessary, therapy may be interrupted (e.g., prior to surgery or in case of severe infection). Data indicate that upon resuming treatment after 70 days or more, the clinical response and safety profile 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 every two weeks.

Clinical response is usually achieved within 12 weeks of treatment. The need for continuing therapy should be reassessed in patients who do not show a response to treatment within this period.

Plaque Psoriasis

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

The need for continuing therapy should be carefully reassessed after 16 weeks in patients who have not responded to treatment within this period.

For patients who do not achieve an adequate response to Hyrimoz at a dose of 40 mg every two weeks after 16 weeks of therapy, increasing the dose to 40 mg once weekly or 80 mg every two weeks may be effective. The benefit-risk ratio of continuing therapy at a dose of 40 mg weekly or 80 mg every two weeks should be carefully reassessed 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 (HS)

The recommended dosing regimen for adult patients with hidradenitis suppurativa is an initial dose of 160 mg at week 0 (day 1); this dose may be administered as four injections on the same day or as two injections per day on two consecutive days. This is followed by 80 mg at week 2 (day 15), administered as two injections on the same 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 if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

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

If therapy is interrupted, adalimumab may be resumed at a dose of 40 mg once weekly or 80 mg every two weeks (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 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, an initial dose of 160 mg at week 0 (day 1) may be used; this dose may be administered as four injections on the same day or as two 40 mg injections on two consecutive days, followed by 80 mg subcutaneously at week 2 (day 15). It should be noted that in this case, the risk of adverse reactions increases.

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

In case of diminished clinical response, some patients may require increased dosing frequency to 40 mg subcutaneously once weekly or 80 mg every two weeks.

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 continuing therapy should be carefully reassessed in patients who do not show a clinical response within this period.

Ulcerative Colitis

The recommended initial dose for induction of remission in adult patients with moderate to severe active ulcerative colitis is 160 mg at week 0 (day 1); this dose may be administered as four injections on the same day or as 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 every two weeks.

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

In case of diminished clinical response, some patients may require increased dosing frequency to 40 mg once weekly or 80 mg every two weeks.

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

Uveitis

The recommended initial dose of Hyrimoz 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 every two weeks.

Limited data are available on the use of adalimumab alone as initial therapy. Treatment with Hyrimoz may be initiated in combination with corticosteroids and/or other non-biologic immunomodulating agents. Two weeks after starting combination therapy, gradual transition to monotherapy with Hyrimoz may be considered based on clinical experience.

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

Special Patient Populations

Elderly Patients

Dose adjustment is not required.

Patients with Hepatic and/or Renal Impairment

Adalimumab has not been studied in these patients; therefore, dosage recommendations are not available.

Children

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

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

Table 1. Dosing of Hyrimoz for Patients with Polyarticular JIA

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

Body weight	Dosage
10 kg to 30 kg	20 mg once every 2 weeks
30 kg and above	40 mg once every 2 weeks

Clinical response, according to existing 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 is not recommended for use in children under 2 years of age for this indication.

Enthesitis-related arthritis

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

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

Body weight	Dosage
15 kg to 30 kg	20 mg once every 2 weeks
30 kg and above	40 mg once every 2 weeks

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

Psoriasis in children

The recommended dose of Hyrimoz for patients aged 4 to 17 years with psoriasis depends on body weight (Table 3). Hyrimoz is administered subcutaneously.

Table 3. Dosing of Hyrimoz in children with psoriasis

Body weight	Dose
15 kg to 30 kg	Initial dose is 20 mg at week 0, then 20 mg once every 2 weeks starting at week 1
30 kg and above	Initial dose is 40 mg at week 0, then 40 mg once every 2 weeks starting at week 1

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 is indicated, the treatment regimen described above should be followed.

The safety of adalimumab use in children with plaque psoriasis has been studied for up to 13 months on average.

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 aged 12 years and older with hidradenitis suppurativa. The dosing of adalimumab in 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 once every 2 weeks starting at week 1, administered subcutaneously.

For patients with an inadequate response to adalimumab 40 mg once every 2 weeks, increasing the frequency of the 40 mg dose to once weekly may be considered. Concomitant use of antibiotics may be continued during treatment with Hyrimoz, 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, resumption of Hyrimoz may be considered, if necessary.

During long-term therapy, the benefit-risk ratio should be periodically evaluated (see data in adults in section “Pharmacodynamics”).

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

Crohn’s disease in children

The recommended dose of Hyrimoz for patients aged 6 to 17 years with Crohn’s disease depends on body weight (Table 4).

Hyrimoz is administered subcutaneously.

Table 4. Dosing of Hyrimoz in children with Crohn’s disease

Body weight	Induction dose	Maintenance therapy starting from week 4
< 40 kg	40 mg at week 0 and 20 mg at week 2 If a more rapid response to therapy is required, the following regimen may be used: 80 mg at week 0 and 40 mg at week 2. However, it should be noted that the risk of adverse reactions increases with the use of a higher induction dose.	20 mg once every 2 weeks
≥ 40 kg	80 mg at week 0 and 40 mg at week 2 If a more rapid response to therapy is required, the following regimen may be used: 160 mg at week 0 and 80 mg at week 2. However, it should be noted that the risk of adverse reactions increases with the use of a higher induction dose.	40 mg once every 2 weeks

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

• for patients with body weight < 40 kg: 20 mg once weekly;
• for patients with body weight ≥ 40 kg: 40 mg once weekly or 80 mg once every 2 weeks.

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

Hyrimoz is not recommended for use in children under 6 years of age for this indication.

Ulcerative colitis (UC) in pediatric patients

The recommended dose of Hyrimoz for pediatric patients aged 6 to 17 years with ulcerative colitis is based on body weight (Table 5). Hyrimoz is administered by subcutaneous injection.

Table 5. Dosage of Hyrimoz in pediatric patients with ulcerative colitis (UC)

Body weight	Dose	Maintenance therapy, starting from week 4*
< 40 kg	80 mg at week 0 (as two injections of 40 mg on the same day) 40 mg at week 2 (administered as one 40 mg injection)	40 mg weekly
≥ 40 kg	160 mg at week 0 (as four 40 mg injections on the same day or two 40 mg injections per day on two consecutive days) 80 mg at week 2 (as two 40 mg injections on the same day)	80 mg every two weeks (as two 40 mg injections on the same day)

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

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

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

Hyrimoz is available in other dosage strengths depending on individual treatment needs.

Uveitis in children

The recommended dose of Hyrimoz for children aged 2 years and older with chronic non-infectious uveitis depends on body weight (Table 6). Hyrimoz is administered subcutaneously.

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

Table 6. Dosing of Hyrimoz in children with uveitis

Body weight	Dose
up to 30 kg	20 mg once every 2 weeks in combination with methotrexate
30 kg and above	40 mg once every 2 weeks in combination with methotrexate

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 may 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 (see section "Pharmacokinetics").

The use of Hyrimoz in children under 2 years of age for this indication is not justified. It is recommended to annually evaluate the benefit and risk of long-term treatment (see section "Pharmacodynamics").

Psoriatic arthritis and axial spondyloarthritis, including ankylosing spondylitis

The use of adalimumab in children for the indications ankylosing spondylitis and psoriatic arthritis is not relevant.

Method of administration

Hyrimoz is administered by subcutaneous injection.

Administration

To avoid possible infection and ensure correct use of the medicinal product, strictly follow these instructions.

Before administering Hyrimoz, carefully read these instructions for use of the medicinal product, ensure that everything is clear to you, and follow them. Before you start using Hyrimoz, your doctor will show you how to prepare and administer the injection using a single-dose pre-filled syringe. For any questions, consult your doctor.

Single-dose pre-filled syringe of Hyrimoz

Fig. A. Pre-filled syringe with Hyrimoz

Always follow these instructions:

• Do not use the prefilled syringe if the blister pack seal is broken, as this may be hazardous.
• Do not open the outer packaging until you are ready to use the prefilled syringe containing the medicine Hyrimoz.
• Never leave the prefilled syringe unattended where others may have access to it.
• If you drop the syringe, do not use it if the needle cap is damaged or detached.
• Do not remove the needle cap until you are ready to administer the injection.
• Administer Hyrimoz 15–30 minutes after removing it from the refrigerator for more comfortable administration.
• Immediately dispose of the syringe after use. Do not reuse the syringe. See section 4. "Disposal of used syringes".
• Ask your doctor or nurse which injection site and method to use if you have low body weight or if administering the injection to a child.
• Store the prefilled syringe containing Hyrimoz in its original packaging to protect it from light.
• Store the outer packaging containing the prefilled syringes in the refrigerator at 2–8 °C.
• If necessary (e.g., during travel), the prefilled syringe may be stored at room temperature (up to 25 °C) for no longer than 42 days.
• Discard the prefilled syringe if it has been stored at room temperature for longer than 42 days.
• Record the date when the syringe was first removed from the refrigerator and the date after which it must be discarded.
• Do not store the prefilled syringe at extremely high or extremely low temperatures.
• Do not freeze the prefilled syringe.
• Do not use the prefilled sy游戏副本 if it has passed the expiry date stated on the outer packaging or syringe label. If the expiry date has passed, return the entire package to the pharmacist.

Keep Hyrimoz and all medicines out of the reach of children.

What do you need for the injection?

Lay out the items listed below on a clean, flat surface.

Contents of the prefilled syringe packaging:

• Prefilled syringe containing Hyrimoz (see Fig. A). Each prefilled syringe contains 20 mg / 0.2 mL of adalimumab.

Not included in the prefilled syringe packaging for Hyrimoz (see Fig. B):

• Alcohol swab
• Cotton ball or gauze pad
• Sharps container; see section 4 "Disposal of used syringes"
• Adhesive bandage

Fig. B. Items not included in the packaging

Preparing the prefilled syringe

• For a more comfortable injection, remove the prefilled syringe packaging 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 box and inspect it. The solution should be colorless or slightly yellowish, and clear or slightly opalescent. Do not use the medicine if visible particles are present or if there is a change in color. If you are concerned about the appearance of the solution, consult your pharmacist.
• Do not use the prefilled syringe if it is damaged. Return the syringe with its packaging to the pharmacy.
• Check the expiry date (Exp.) on the prefilled syringe. Do not use the prefilled syringe if it has passed the expiry date.

Selection of the injection site

The injection site is the area of the body where you will administer Hyrimoz using the prefilled syringe. The recommended injection site is the front of the thighs. The medicine may also be administered in the lower part of the abdomen, but at least 5 cm away from the navel (see Fig. C). Always select a different injection site each time. Do not inject the medicine into areas where the skin is tender, bruised, red, scaly, or hardened. Avoid areas with scars or stretch marks. If you have psoriasis, do not inject the medicine directly into plaques.

Fig. C. Selection of the injection site

Cleaning the injection site
Wash your hands thoroughly with soap and water when you are ready to use the prefilled syringe. Wipe the injection site with an alcohol swab using circular motions. Allow it to dry (see Fig. D). Do not touch the cleaned area before injection. Wait until the skin is completely dry. Do not dry the cleaned area with a hair dryer or by blowing on it.	Fig. D. Cleaning the injection site
Injection procedure
Carefully remove the cap from the syringe without tilting it in any direction (see Fig. E). Discard the cap. You may see a drop of liquid at the tip of the needle. This is normal.	Fig. E. Removing the cap
Gently pinch the skin at the injection site (see Fig. F). Insert the needle into the skin at a 45-degree angle, as shown in the image (see Fig. F).	Fig. F. Needle insertion
Hold the prefilled syringe as shown in the image (see Fig. G). Slowly depress the plunger fully. Keep holding the plunger depressed while keeping the syringe in place for 5 seconds. Gently withdraw the needle from the skin, holding the syringe vertically. A drop of blood may appear at the injection site. Press a cotton ball or gauze pad against the injection site and hold for 10 minutes. Do not rub the injection site. A plaster may be applied if needed.	Fig. G. Holding the plunger
Disposal of used syringes
Dispose of the used syringe in a sharps container (a puncture-resistant container with a lid). For your own safety and the protection of others, never reuse syringes or needles. Never dispose of medicines down the drain or with household waste. Ask your doctor or pharmacist how to properly dispose of medicines you no longer need. These measures will help protect the environment. All unused medicines or waste should be disposed of in accordance with local regulations.	Fig. H. Disposal of used prefilled syringe

If you have any questions, consult your doctor, pharmacist, or nurse who is familiar with the use of the medicinal product Hyrimoz.

The prefilled syringe can be stored at a temperature not exceeding 25 °C for a period up to 42 days. The prefilled syringe should be kept protected from light and disposed of if not used within the 42-day period.

Children

Indicated for use in children as described in the section "Indications".

Overdose

During clinical studies of adalimumab, no dose-limiting toxicity has been observed. Multiple doses up to 10 mg/kg, approximately 15 times the recommended dose, have been administered to patients. Such administration was not associated with signs of toxicity related to overdose.

Adverse Reactions

General information on safety profile

Adalimumab has been studied in controlled clinical trials and open-label extension studies lasting up to 60 months or longer, involving 9506 patients. These studies included patients with early and long-standing rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile idiopathic 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 presented below are from the main controlled trials, in which 6089 patients received adalimumab and 3801 patients received placebo or a comparator drug 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.

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.

Serious adverse reactions have been reported with adalimumab use. TNF antagonists, such as Hyrimoz, affect the immune system, and their use may lead to decreased resistance to infections and malignancies.

Infections that may be life-threatening and result in death (including sepsis, opportunistic infections, and tuberculosis), reactivation of hepatitis B, and various malignancies (including leukemia, lymphoma, and hepatosplenic T-cell lymphoma) have been reported during treatment with adalimumab.

Serious hematologic, neurologic, and autoimmune reactions have also been reported. These included 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.

Table 7 lists adverse reactions with a possible causal relationship observed during clinical trials and in the post-marketing period. Adverse reactions are categorized by system organ class and frequency of occurrence (≥1/10 – very common; ≥1/100 to <1/10 – common; ≥1/1000 to <1/100 – uncommon; ≥1/10,000 to <1/1000 – rare; frequency not known (cannot be estimated from available data)). Within each frequency category, reactions are listed in descending order of severity.

The highest frequency observed across different indications is included in the table below. An asterisk (*) in the "System Organ Class" column indicates that additional information is provided in the sections "Contraindications", "Special Warnings and Precautions for Use", and "Adverse Reactions".

Table 7

Organ systems	Frequency	Adverse reactions
Infections and infestations*	very common	respiratory tract infections (including lower and upper respiratory tract infections, pneumonia, sinusitis, pharyngitis, rhinopharyngitis, 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 and tuberculosis (including coccidioidomycosis, histoplasmosis, and infections by the mycobacterium avium complex), bacterial infections, eye infections, diverticulitis1
Benign, malignant and unspecified neoplasms (including cysts and polyps)*	common	skin cancer, excluding melanoma (including basal cell carcinoma and squamous cell carcinoma); benign neoplasms;
	uncommon	lymphoma**, neoplasms of parenchymal organs (including breast cancer, lung tumor, and thyroid tumor), melanoma**;
	occasional	leukemia1;
	frequency unknown	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), anemia;
	common	leukocytosis, thrombocytopenia;
	uncommon	idiopathic thrombocytopenic purpura;
	occasional	pancytopenia
Immune system disorders*	common	hypersensitivity, allergy (including seasonal allergy);
	uncommon	sarcoidosis1, vasculitis;
	occasional	anaphylaxis1
Metabolism and nutrition disorders	very common	elevated blood lipid levels;
	common	hypokalemia, hyperuricemia, plasma sodium concentration abnormalities, hypocalcemia, hyperglycemia, hypophosphatemia, 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	stroke1, tremor, neuropathy;
	occasional	multiple sclerosis, demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome)1
Eye disorders	common	visual acuity disturbances, conjunctivitis, blepharitis, eye swelling;
	uncommon	diplopia
Ear and labyrinth disorders	common uncommon	vertigo; deafness, tinnitus
Cardiac disorders*	common	tachycardia;
	uncommon	myocardial infarction1, arrhythmia, chronic heart failure;
	occasional	cardiac arrest
Vascular disorders	common	arterial hypertension, hot flushes, hematoma;
	uncommon	aortic aneurysm, arterial occlusion, thrombophlebitis
Respiratory, thoracic and mediastinal disorders*	common	asthma, dyspnea, cough;
	uncommon	pulmonary embolism1, chronic obstructive pulmonary disease, interstitial lung disease, pneumonitis, pleural effusion1;
	occasional	pulmonary fibrosis1
Gastrointestinal disorders	very common	abdominal pain, nausea and vomiting;
	common	gastrointestinal hemorrhage, dyspepsia, gastroesophageal reflux, dry syndrome (Sjögren's syndrome);
	uncommon	pancreatitis, dysphagia, facial swelling;
	occasional	intestinal perforation1
Hepatobiliary disorders*	very common	elevated liver enzyme levels;
	uncommon	cholecystitis and cholelithiasis, elevated bilirubin levels, hepatic steatosis;
	occasional	hepatitis, reactivation of hepatitis B1, autoimmune hepatitis1;
	frequency unknown	liver failure1
Skin and subcutaneous tissue disorders	very common	rash (including exfoliative rash);
	common	new onset or worsening of psoriasis (including palmoplantar pustular psoriasis)1, pruritus, urticaria, ecchymoses (including purpura), dermatitis (including eczema), onycholysis, increased sweating, alopecia1;
	uncommon	night sweats, scars;
	occasional	multiform erythema1, Stevens-Johnson syndrome1, angioneurotic edema1, cutaneous vasculitis1, lichenoid skin reaction1;
	frequency unknown	worsening of dermatomyositis symptoms1
Musculoskeletal and connective tissue disorders	very common	musculoskeletal pain;
	common	muscle cramps (including elevated plasma creatine phosphokinase levels);
	uncommon	rhabdomyolysis, systemic lupus erythematosus;
	occasional	lupus-like syndrome1
Renal and urinary disorders	common	hematuria, renal failure;
	uncommon	nocturia
Reproductive system and breast disorders	uncommon	erectile dysfunction
General disorders and administration site conditions*	very common	administration site reactions (including redness at injection site);
	common	chest pain, swelling, pyrexia1;
	uncommon	inflammation
Investigations*	common frequency unknown	coagulation and blood clotting system disorders (including prolonged activated partial thromboplastin time (APTT)), positive autoantibody tests (including antibodies to double-stranded DNA), elevated plasma lactate dehydrogenase levels; weight gain2
Injury, poisoning and procedural complications*	common	delayed healing

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

** Including open-label study periods.

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 use in adult indications compared to (minus) -0.4 kg to 0.4 kg with placebo during a treatment period of 4–6 months. Weight gain of 5–6 kg was also observed in long-term extension studies with a mean exposure 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 not fully understood 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 in adults and children receiving adalimumab, injection site reactions (erythema and/or pruritus, bruising, pain, or swelling) occurred in 12.9% of cases 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 group receiving adalimumab and 1.46/patient-year in the control group. The rate of serious infections was 0.04/patient-year in the adalimumab group and 0.03/patient-year in the control group. These were predominantly nasopharyngitis, upper respiratory tract infections, and sinusitis. Most patients continued adalimumab treatment after recovery.

In controlled and open-label studies in adults and children, severe infections (with fatal outcomes in isolated cases) were reported, including tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (such as disseminated histoplasmosis, Pneumocystis pneumonia, aspergillosis, and 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 pivotal studies of adalimumab use in adults for at least 12 weeks in patients with moderate to high disease activity with 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 neoplasms (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 skin cancer, specifically 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 neoplasms (excluding lymphoma and non-melanoma skin cancer) were approximately 8.5/1000 patient-years in controlled trials and ongoing and completed open-label studies. The rate of non-melanoma skin cancer was approximately 9.6/1000 patient-years, and the rate of lymphomas was 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 neoplasms occurred within 1 year of starting 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 treated with adalimumab, the rate of malignancies was approximately 2.7 per 1000 patient-years. Rates of non-melanoma skin cancer and lymphoma were approximately 0.2 and 0.3 per 1000 patient-years, respectively (see section "Special precautions").

In post-marketing experience, in isolated cases, hepatosplenic T-cell lymphoma has been reported in patients treated with adalimumab (see section "Special precautions").

Autoantibodies

During phases 1–5 clinical trials in rheumatoid arthritis, patients were tested multiple times for autoantibodies. In these controlled trials, positive titers were reported in 11.9% of patients receiving adalimumab and in 8.1% of placebo group patients, with negative antinuclear antibody titers observed at 24 weeks under active monitoring. In two patients (out of 3441 patients with RA, PsA, and AS receiving adalimumab in clinical trials), signs of newly diagnosed lupus-like syndrome developed, which resolved after discontinuation of treatment. No patient developed lupus nephritis or central nervous system involvement.

Hepatic enzyme activity

In phase 3 controlled clinical trials involving patients with rheumatoid arthritis and psoriatic arthritis, during the controlled period lasting 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.

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, during the controlled period lasting 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 concomitantly with immunosuppressants.

In phase 3 controlled clinical trials involving patients with plaque psoriasis, during the controlled period lasting 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 at week 4) involving patients with hidradenitis suppurativa, during the controlled period lasting 12 to 16 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 0.3% of patients receiving adalimumab and in 0.6% of control group patients.

In controlled clinical trials (initial dose 80 mg [week 0], then 40 mg every 2 weeks starting at week 1) involving patients with uveitis, during the controlled period lasting 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 in 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 2 weeks (N = 31) and a maintenance dose of 0.6 mg/kg (maximum 40 mg) administered weekly (N = 32) after induction doses 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 after 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 ≥3 times the upper limit of normal were observed in 1.1% (1/93) of patients.

Across all indications in clinical trials, patients experienced asymptomatic ALT elevations, which were mostly transient during prolonged treatment. However, there have been 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, 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, increased frequencies of neoplasms and serious infections were observed compared to patients receiving adalimumab monotherapy.

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

Shelf life. 2 years.

Do not use the drug 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.

The pre-filled syringe may be stored at temperatures not exceeding 25 °C for up to 42 days. The pre-filled syringe should be stored in a place protected from light and disposed of if not used within 42 days.

Incompatibilities

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

Packaging

20 mg / 0.2 mL solution in a pre-filled syringe; 2 pre-filled syringes in blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Novartis Pharmaceuticals Manufacturing GmbH

or

Sandoz GmbH – Aseptic Medicinal Products Division Schaftlach (Aseptic MP Schaftlach)

Manufacturer's location and address of place of business

Biochemiestrasse 10, Unterlangkampfen, Langkampfen, 6336, Austria

or

Biochemiestrasse 10, 6336 Langkampfen, Austria

INSTRUCTIONS

for medical use of the medicinal product

Hyrimoz

(Hyrimoz)

Composition:

Active substance: adalimumab;

One pre-filled syringe contains 40 mg of adalimumab in 0.4 ml of solution;

Excipients: adipic acid; 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, colourless or slightly yellow solution.

Pharmacotherapeutic group

Immunosuppressants. Tumor necrosis factor-alpha inhibitors. Adalimumab.

ATC code: L04AB04.

Pharmacological Properties

Mechanism of Action

Adalimumab specifically binds to tumor necrosis factor (TNF) and neutralizes its biological effects by blocking its interaction with 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).

Pharmacodynamics

In patients with rheumatoid arthritis (RA), adalimumab rapidly reduced, compared to baseline, markers of acute-phase inflammation (C-reactive protein (CRP), serum cytokines (IL-6), and erythrocyte sedimentation rate (ESR)). A reduction in serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which mediate tissue remodeling underlying cartilage destruction, was also observed. Treatment with adalimumab typically results in improvement of hematological signs of chronic inflammation.

After adalimumab treatment, rapid reductions in CRP levels were also observed in patients with polyarticular juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), ulcerative colitis (UC), and hidradenitis suppurativa (HS). Concurrently, a significant reduction in TNF-α expression in patients with Crohn’s disease 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 adalimumab, absorption and distribution were slow, with mean peak serum concentration 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 single intravenous administration at doses ranging from 0.25 to 10 mg/kg, concentrations were dose-proportional. Following a dose of 0.5 mg/kg (approximately 40 mg), clearance ranged from 11 to 15 mL/h, 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 RA patients were 31–96% of serum levels.

After subcutaneous administration of adalimumab at 40 mg 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 subcutaneously administered doses of 20, 40, and 80 mg every 2 weeks or weekly.

After subcutaneous administration of adalimumab at 24 mg/m² (up to 40 mg) every 2 weeks in patients with polyarticular juvenile rheumatoid arthritis (JRA) 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 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 6.0 ± 6.1 µg/mL (101% CV) without concomitant methotrexate and 7.9 ± 5.6 µg/mL (71.2% CV) with methotrexate.

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.

After subcutaneous administration of adalimumab at 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 concentration was 5 µg/mL during monotherapy with adalimumab at 40 mg 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. The mean steady-state concentration from week 12 to week 36 was approximately 8–10 µg/mL during administration of 40 mg weekly.

The effect of adalimumab in adolescents with hidradenitis suppurativa was determined using pharmacokinetic modeling and simulation based on pharmacokinetics in pediatric indications (plaque psoriasis, juvenile rheumatoid (idiopathic) arthritis (JRA), Crohn’s disease (CD), and enthesitis-related arthritis). The recommended dosing regimen for adolescents with hidradenitis suppurativa is 40 mg every 2 weeks. Since the effect of adalimumab may depend on body weight, adolescents with high 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 adalimumab at 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 was approximately 7 µg/mL during maintenance therapy with 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 in a 1:1 ratio to groups receiving either standard dose (40/20 mg every 2 weeks) or low dose (20/10 mg every 2 weeks) for maintenance therapy based on body weight. 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 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 were maintained in patients who continued adalimumab treatment for 52 weeks. In patients whose dose was increased from once every two 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 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 weight-based dosing of 0.6 mg/kg (maximum 40 mg) every two weeks was 5.01 ± 3.28 µg/mL. In patients receiving 0.6 mg/kg (maximum 40 mg) weekly, the mean (± standard deviation) steady-state serum concentration of adalimumab at week 52 was 15.7 ± 5.60 µg/mL.

In adult 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 8–10 µg/mL.

The effect of adalimumab in children with uveitis was determined using pharmacokinetic modeling and simulation based on pharmacokinetics in other pediatric indications (plaque psoriasis, juvenile rheumatoid (idiopathic) arthritis (JRA), Crohn’s disease (CD), and enthesitis-related arthritis). There are no clinical data on the effect of the initial dose of adalimumab 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.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and simulation predicted comparable exposure and efficacy of adalimumab in patients receiving 80 mg every 2 weeks versus those receiving 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 (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis), an exposure–response relationship was established between plasma concentration and response according to the PedACR 50 criterion. The apparent plasma concentration of adalimumab providing half of the maximum 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 severe chronic plaque psoriasis was established for PASI 75 and PGA responses ("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 more than 1,300 RA patients revealed a trend toward increased apparent clearance of adalimumab with increasing patient body weight. After adjusting for body weight differences, patient sex and age were found to have minimal impact on adalimumab clearance. Levels of free adalimumab (not bound to anti-adalimumab antibodies) in serum were lower in patients who developed anti-adalimumab antibodies. The use of the medicinal product Hyrimoz has not been studied in patients with hepatic or renal impairment.

Clinical Characteristics

Indications

Rheumatoid Arthritis (RA)

Hyrimoz in combination with methotrexate is indicated for:

• the treatment of moderate to severe active rheumatoid arthritis in adult patients who have not responded adequately to therapy with disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• the treatment of active, progressive, severe rheumatoid arthritis in adult patients who have not previously been treated with methotrexate.

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

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

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

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

Hyrimoz may be used as monotherapy in cases of methotrexate intolerance or when continuation of methotrexate therapy is not acceptable. Studies on the use of Hyrimoz in patients under 2 years of age have not been conducted.

Enthesitis-Related Arthritis

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

Axial Spondyloarthritis

Ankylosing Spondylitis (AS)

Hyrimoz is indicated for the treatment of severe active ankylosing spondylitis in adult patients who have not responded to conventional therapy.

Axial Spondyloarthritis without Radiographic Confirmation of AS

Hyrimoz is indicated for the treatment of active axial spondyloarthritis without radiographic confirmation of AS but with evidence of inflammation based on elevated CRP levels and/or MRI (magnetic resonance imaging) findings in adult patients who have not responded adequately to nonsteroidal anti-inflammatory drugs (NSAIDs) or who are intolerant to these drugs.

Psoriatic Arthritis (PsA)

Hyrimoz is indicated for the treatment of active and progressive psoriatic arthritis in adult patients who have not responded adequately to prior therapy with disease-modifying antirheumatic drugs (DMARDs). Adalimumab has demonstrated slowing of the progression of peripheral joint damage, as assessed radiographically, in patients with symmetric polyarticular disease and improvement in functional status.

Plaque Psoriasis (PP)

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

Plaque Psoriasis (PP) in Children

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

Hidradenitis Suppurativa (HS)

Hyrimoz is indicated for the treatment of moderate to severe active hidradenitis suppurativa (acne inversa) in adult patients and adolescents aged 12 years and older who have not responded to conventional systemic therapy.

Crohn’s Disease (CD)

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

Crohn’s Disease (CD) in Children

Hyrimoz is indicated for the treatment of moderate to severe active 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 who have intolerance or medical contraindications to such therapies.

Ulcerative Colitis (UC)

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

Ulcerative Colitis (UC) in Children

Hyrimoz is indicated for the treatment of moderate to severe active 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 who have intolerance or medical contraindications to such therapies.

Uveitis

Hyrimoz is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients who have not responded to corticosteroid therapy, require corticosteroid dose reduction, or have intolerance or medical contraindications to corticosteroid therapy.

Uveitis in Children

Hyrimoz is indicated for the 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 led to increased antibody formation, increased clearance, and reduced efficacy of adalimumab.

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

Special precautions for use

To improve the control of biological medicinal products, the trade name and batch number of the administered product should be clearly documented in the patient's medical records.

Infections

Patients receiving TNF blockers are more susceptible to serious infections.

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

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

A full evaluation and careful monitoring are required for patients who develop a new infection during treatment with Hyrimoz. In the event of a serious infection or sepsis, treatment should be discontinued and appropriate antimicrobial or antifungal therapy initiated until the infection is controlled. Hyrimoz should be used with particular caution in patients with recurrent infections or underlying conditions that increase susceptibility to infections.

Serious infections

Serious 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 serious infections observed in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Cases of hospitalization due to infections, including fatal outcomes, have been reported.

Tuberculosis

Cases of reactivation and new-onset tuberculosis, including pulmonary and extrapulmonary forms (e.g., disseminated tuberculosis), have been reported in patients receiving adalimumab. Prior to initiating treatment with Hyrimoz, patients should be carefully evaluated for both active and latent (inactive) tuberculosis. The evaluation should include a thorough assessment of the patient's history of tuberculosis or possible 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 guidelines may apply). The results of these tests should be documented in the patient's record. Physicians should be aware of the risk of false-negative tuberculin skin test results, especially in severely ill or immunocompromised patients.

Treatment with Hyrimoz 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 suspected of having latent tuberculosis should be made in consultation with a pulmonologist.

In cases of latent tuberculosis, specific anti-tuberculosis treatment should be initiated before starting therapy with Hyrimoz, according to local guidelines.

Consideration should be given to initiating anti-tuberculosis treatment before starting Hyrimoz in patients with risk factors for tuberculosis infection who have a negative latent tuberculosis test, 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. Some patients who previously completed successful treatment for active tuberculosis have experienced recurrent tuberculosis while receiving adalimumab.

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

Other opportunistic infections

Opportunistic infections, including invasive fungal infections, have been reported during treatment with adalimumab. These 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 lung infiltrates or other signs of serious systemic illness (with or without shock), patients should undergo immediate evaluation for invasive fungal infection and treatment with Hyrimoz should be discontinued immediately. The decision to initiate empirical antifungal therapy should be made after consultation with an expert in the diagnosis and treatment of invasive fungal infections.

Hepatitis B reactivation

The use of TNF blockers, including adalimumab, has been associated with reactivation of hepatitis B virus in chronic carriers (i.e., those who are hepatitis B surface antigen positive). In some cases, hepatitis B reactivation has been fatal. Prior to initiating treatment with Hyrimoz, patients at risk should be screened for hepatitis B virus. If the screening result is positive, the decision to treat should be made in consultation with a hepatologist.

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

Neurological disorders

Rare 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 demyelinating disorders of the peripheral nervous system, including Guillain-Barré syndrome, have been reported with TNF blockers, including adalimumab. Careful assessment of the benefit-risk ratio of adalimumab use is recommended in patients with demyelinating disorders of the central or peripheral nervous system. Treatment with Hyrimoz 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 is recommended for patients with non-infectious intermediate uveitis before initiating treatment with Hyrimoz and periodically during therapy to monitor for the development of central nervous system demyelinating disorders.

Allergic reactions

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

Immunosuppression

During clinical trials of adalimumab in 64 patients with RA, no cases of suppression of delayed-type hypersensitivity, reduction in 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 group patients. However, these cases were rare. In post-marketing experience, cases of leukemia associated with TNF antagonists have been reported. Moreover, patients with longstanding, highly active rheumatoid arthritis have an increased baseline risk of lymphoma and leukemia, complicating risk assessment. Based on available data, a risk of 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 (treatment initiation age ≤ 18 years), including adalimumab. Lymphomas accounted for approximately half of these cases. The remainder included various malignancies, including rare malignancies typically associated with immunosuppression. A risk of malignancy in children receiving TNF antagonists cannot be excluded.

In post-marketing experience, rare cases of hepatosplenic T-cell lymphoma have been reported in patients receiving adalimumab. This is a rare type of lymphoma characterized by a very aggressive course and is usually fatal. Some cases of hepatosplenic T-cell lymphoma during adalimumab treatment occurred in young patients who had previously received therapy with 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. The risk of hepatosplenic T-cell lymphoma in patients receiving Hyrimoz cannot be excluded (see section "Adverse reactions").

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

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

In a controlled clinical trial evaluating another TNF antagonist (infliximab) in patients with chronic obstructive pulmonary disease, more frequent cases of malignancies, mostly in the lungs, head, and neck, 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 malignancy due to smoking.

Currently, it is unknown whether adalimumab 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 (particularly patients 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 according to local guidelines.

Hematological disorders

Rare cases of pancytopenia and aplastic anemia have been reported with TNF blockers. Cytopenia (thrombocytopenia, leukopenia) of clinical significance has been reported with adalimumab (causal relationship not established). All patients should be informed of the need to seek immediate medical consultation if symptoms typical of blood disorders (such as persistent fever, bruising, bleeding, pallor of skin and mucous membranes) occur during adalimumab treatment. Discontinuation of Hyrimoz should be considered in patients with confirmed serious hematological disorders.

Vaccination

Similar antibody responses to 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 transmission of infection from live vaccines in patients receiving adalimumab.

For pediatric patients, it is recommended to complete all necessary vaccinations according to the schedule before starting treatment with Hyrimoz, 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 dose of adalimumab administered to the mother during pregnancy.

Chronic heart failure (CHF)

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

Autoimmune processes

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

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 during combination therapy with etanercept and anakinra, similar toxicity may occur with the combination of anakinra and another TNF blocker. 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 DMARDs (e.g., anakinra and abatacept) or with other TNF antagonists is not recommended due to the potential increased risk of 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 considered when planning surgical procedures. Patients requiring surgery and receiving treatment with Hyrimoz 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 have undergone arthroplasty during adalimumab therapy.

Small bowel obstruction

Lack of response to treatment in Crohn's disease may indicate the presence of a fixed fibrotic stricture requiring surgical treatment. 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. Due to the higher incidence of infections in elderly patients, adalimumab should be used with caution in this age group.

Children

See subsection "Vaccination" above.

Excipients with known effects

Hyrimoz contains less than 1 mmol (23 mg) of sodium per 0.4 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 during treatment and for at least five months after the last dose of Hyrimoz.

Pregnancy

Prospective analysis of data on the use of adalimumab 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 frequency 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 frequency of major congenital malformations in newborns. The frequency of pregnancies resulting in at least one live birth with a major congenital malformation was 6 out of 69 (8.7%) in the group of women with RA who received adalimumab and 5 out of 74 (6.8%) in the group of women with RA who did not receive the drug (unadjusted odds ratio [OR] 1.31, 95% confidence interval [CI] 0.38–4.52). In the group of women with CD who received adalimumab, the frequency was 16 out of 152 (10.5%), and in the group of women with CD who did not receive the drug, it was 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 malignancy 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 non-clinical toxicity study in monkeys, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed. Non-clinical data on postnatal toxicity of 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 in pregnant women only if clearly necessary.

Adalimumab may cross the placenta and be present in the serum of newborns whose mothers received adalimumab during pregnancy. Therefore, these 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 dose of adalimumab administered to the mother 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. Considering that immunoglobulin G proteins undergo proteolysis in the gastrointestinal tract and have low bioavailability, systemic effects of adalimumab on breastfed infants are unlikely. Therefore, Hyrimoz may be used during breastfeeding.

Fertility

Non-clinical data on the effect of adalimumab on fertility are lacking.

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

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

Method of Administration and Dosage

Treatment with Hyrimoz must be prescribed by a physician experienced in the diagnosis and management of diseases for which Hyrimoz is indicated. Ophthalmologists are advised to consult with the appropriate specialist before initiating therapy with Hyrimoz. Patients receiving Hyrimoz should be provided with a patient reminder card.

Hyrimoz may be self-administered only if the patient or the parents of a child prescribed adalimumab therapy have received proper training from a physician on the injection technique, and the physician has confirmed that self-injection is appropriate. Additionally, the information on self-injection provided in this instruction must be reviewed. During treatment with Hyrimoz, concomitant therapies (e.g., corticosteroids and/or immunomodulatory drugs) should be re-evaluated.

Rheumatoid Arthritis

The recommended dose for adult patients is 40 mg administered subcutaneously once every 2 weeks. During therapy with Hyrimoz, methotrexate should be continued. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, and analgesics may also be continued. For use of other disease-modifying antirheumatic drugs (DMARDs), see section "Special Instructions".

For some RA patients not receiving methotrexate, increasing the frequency of administration to 40 mg subcutaneously once weekly or 80 mg every 2 weeks may be justified.

A clinical response is usually achieved within 12 weeks of treatment. The need for continuing therapy should be reassessed in patients who do not show a response within this period.

If necessary, therapy may be interrupted (e.g., prior to surgery or in case of severe infection). Data indicate that after resuming therapy following a break of 70 days or more, the clinical response and safety profile are similar to those observed before 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 2 weeks.

A clinical response is usually achieved within 12 weeks of treatment. The need for continuing therapy should be reassessed in patients who do not show a response within this period.

Plaque Psoriasis

The recommended initial dose for adults is 80 mg, followed by 40 mg subcutaneously one week later. Maintenance therapy is 40 mg administered subcutaneously once every 2 weeks.

The need for continuing therapy beyond 16 weeks should be carefully reassessed in patients who do not show a response within this period.

For patients who do not achieve an adequate response to Hyrimoz at a dose of 40 mg every 2 weeks after 16 weeks of therapy, increasing the dose to 40 mg once weekly or 80 mg every 2 weeks may be effective. The benefit-risk balance of continuing therapy at 40 mg weekly or 80 mg every 2 weeks should be carefully reassessed in patients who do not achieve an adequate response after dose escalation (see section "Pharmacodynamics"). If an adequate response is achieved after dose escalation to 40 mg weekly or 80 mg every 2 weeks, the dose may subsequently be reduced to 40 mg every 2 weeks.

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 4 injections in one day or as 2 injections per day on two consecutive days, followed by 80 mg at week 2 (day 15), administered as 2 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 if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

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

After interruption of therapy, adalimumab may be resumed at a dose of 40 mg once weekly or 80 mg every 2 weeks (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 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. If a more rapid clinical response is needed, an initial dose of 160 mg at week 0 (day 1) may be administered as 4 injections in one day or as two 40 mg injections on each of two consecutive days, followed by 80 mg subcutaneously at week 2 (day 15). It should be noted that in this case, the risk of adverse reactions increases.

After induction therapy, maintenance treatment should be initiated at a dose of 40 mg administered subcutaneously once every 2 weeks. Alternatively, if a patient has discontinued therapy and symptoms reappear, treatment with Hyrimoz may be restarted. Limited data are available on re-initiating Hyrimoz after a treatment interruption of more than 8 weeks from the last dose. During maintenance therapy, corticosteroid doses may be tapered according to clinical practice.

In case of diminished clinical response, some patients may require increased dosing frequency to 40 mg subcutaneously once weekly or 80 mg every 2 weeks.

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 continuing therapy should be carefully reassessed in patients who do not show a clinical response within this period.

Ulcerative Colitis

The recommended initial dose for induction of remission in adult patients with moderate to severe active ulcerative colitis is 160 mg at week 0 (day 1), which may be administered as 4 injections in one day or as 2 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 2 weeks.

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

In case of diminished clinical response, some patients may require increased dosing frequency to 40 mg once weekly or 80 mg every 2 weeks.

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

Uveitis

The recommended initial dose of Hyrimoz 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 2 weeks.

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

An annual assessment of the benefit-risk ratio of long-term therapy is recommended.

Special Patient Populations

Elderly Patients

Dose adjustment is not required.

Patients with Hepatic and/or Renal Impairment

Adalimumab has not been studied in such patients; therefore, no dosage recommendations can be made.

Children

Juvenile Idiopathic Arthritis (JIA)

Polyarticular Juvenile Idiopathic Arthritis

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

Table 1. Dosage of Hyrimoz for patients with polyarticular JIA

Body weight	Dose
10 kg to 30 kg	20 mg once every 2 weeks
30 kg and above	40 mg once every 2 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 is not recommended for use in children under 2 years of age for this indication.

Enthesitis-related arthritis

The recommended dose of Hyrimoz for children aged 6 years and older depends on body weight (Table 2). Hyrimoz should be administered subcutaneously once every 2 weeks.

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

Body weight	Dose
15 kg to 30 kg	20 mg once every 2 weeks
30 kg and above	40 mg once every 2 weeks

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

Plaque psoriasis in children

The recommended dose of Hyrimoz for patients aged 4 to 17 years with plaque psoriasis depends on body weight (Table 3). Hyrimoz is administered subcutaneously.

Table 3. Dosage of Hyrimoz in children with plaque psoriasis

Body weight	Dose
15 kg to 30 kg	Initial dose is 20 mg at week 0, then 20 mg once every 2 weeks starting at week 1
30 kg and above	Initial dose is 40 mg at week 0, then 40 mg once every 2 weeks starting at week 1

Careful reassessment of the need to continue therapy is required for patients who have not shown a clinical response within 16 weeks.

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

The safety of adalimumab use in children with plaque psoriasis has been studied for an average 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 aged 12 years and older with hidradenitis suppurativa. The dosing of adalimumab in 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 patients with an inadequate response to adalimumab 40 mg every 2 weeks, increasing the frequency of 40 mg dosing to once weekly may be considered. Concomitant use of antibiotics during Hyrimoz therapy is allowed if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

Careful reassessment of the need to continue therapy beyond 12 weeks is required for patients who have not shown a clinical response within this period.

If treatment is interrupted, resumption of Hyrimoz therapy may be considered, if necessary.

During long-term therapy, the benefit-risk ratio should be periodically evaluated (see adult data in section “Pharmacodynamics”).

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

Pediatric Crohn’s disease

The recommended dose of Hyrimoz for patients aged 6 to 17 years with Crohn’s disease depends on body weight (Table 4).

Hyrimoz is administered subcutaneously.

Table 4. Dosing of Hyrimoz in pediatric patients with Crohn’s disease

Body weight	Induction dose	Maintenance therapy, starting from week 4
< 40 kg	40 mg at week 0 and 20 mg at week 2 If a more rapid response to therapy is needed, the following regimen may be used: 80 mg at week 0 and 40 mg at week 2. However, it should be noted that the risk of adverse events increases with the use of higher induction doses.	20 mg once every 2 weeks
≥ 40 kg	80 mg at week 0 and 40 mg at week 2 If a more rapid response to therapy is needed, the following regimen may be used: 160 mg at week 0 and 80 mg at week 2. However, it should be noted that the risk of adverse events increases with the use of higher induction doses.	40 mg once every 2 weeks

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

• for patients with body weight < 40 kg: 20 mg once weekly;
• for patients with body weight ≥ 40 kg: 40 mg once weekly or 80 mg once every 2 weeks.

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

Hyrimoz is not recommended for use in children under 6 years of age for this indication.

Ulcerative colitis (UC) in pediatric patients

The recommended dose of Hyrimoz for pediatric patients aged 6 to 17 years with ulcerative colitis is based on body weight (Table 5). Hyrimoz is administered by subcutaneous injection.

Table 5. Dosage of Hyrimoz in pediatric patients with ulcerative colitis (UC)

Body weight	Dose	Maintenance therapy, starting from week 4*
< 40 kg	80 mg at week 0 (as two injections of 40 mg on the same day) 40 mg at week 2 (administered as one injection of 40 mg)	40 mg weekly
≥ 40 kg	160 mg at week 0 (as four injections of 40 mg on the same day or two injections of 40 mg per day on two consecutive days) 80 mg at week 2 (as two injections of 40 mg on the same day)	80 mg every two weeks (as two injections of 40 mg on the same day)

* Patients who turn 18 years old during treatment with Hyrimoz should continue treatment with maintenance therapy.

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

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

Hyrimoz is available in other dosage strengths depending on individual treatment needs.

Uveitis in children

The recommended dose of Hyrimoz for children aged 2 years and older with chronic non-infectious uveitis depends on body weight (Table 6). Hyrimoz is administered subcutaneously.

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

Table 6. Dosage of Hyrimoz in children with uveitis

Body weight	Dosage
up to 30 kg	20 mg once every 2 weeks in combination with methotrexate
30 kg and above	40 mg once every 2 weeks in combination with methotrexate

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 may be administered one week before starting maintenance therapy. There are no clinical data on administration of the initial loading dose of adalimumab in children under 6 years of age (see section “Pharmacokinetics”).

The use of Hyrimoz in children under 2 years of age for this indication is not justified. It is recommended to annually evaluate the benefit and risk of long-term treatment (see section “Pharmacodynamics”).

Psoriatic arthritis and axial spondyloarthritis, including ankylosing spondylitis

The use of adalimumab in children for the indications of ankylosing spondylitis and psoriatic arthritis is not relevant.

Route of administration

Hyrimoz is administered subcutaneously.

Administration

To avoid possible infection and ensure proper use of the medicinal product, strictly follow these instructions.

Before administering Hyrimoz, carefully read these instructions for use of the medicinal product, ensure that you fully understand them, and follow them accordingly. Prior to starting treatment with Hyrimoz, your doctor will demonstrate how to prepare and administer the injection using the single-dose prefilled syringe. For any questions, consult your physician.

Single-dose prefilled syringe of Hyrimoz with needle guard and additional finger grip

Fig. A. Pre-filled syringe with Hyrimoz with needle safety guard and finger grip

Always follow these instructions:

• Do not use the prefilled syringe if the blister seal is broken, as this may be dangerous.
• Do not open the outer packaging until you are ready to use the syringe.
• Never leave the prefilled syringe unattended where others may access it.
• If you drop the syringe, do not use it if it is damaged or 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. Doing so may cause the safety guard to 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.
• Immediately dispose of the syringe after use. Do not reuse the syringe. See section 4. "Disposal of used syringes" at the end of this Instructions for Use.

Storage conditions for the single-dose prefilled syringe containing Hyrimoz

• Store in the refrigerator at 2–8 °C in the original outer packaging.
• If necessary (e.g., during travel), the prefilled syringe may be stored at room temperature (up to 25 °C) for no longer than 42 days, protected from light. Once the syringe has been removed from the refrigerator and warmed to room temperature, it must be used within 42 days or discarded, even if returned to the refrigerator later. Record the date the syringe was first removed from the refrigerator and the date after which it must be discarded.
• Store prefilled syringes in their original packaging to protect from light.
• Do not store prefilled syringes at extremely high or extremely low temperatures.
• Do not freeze prefilled syringes.

Keep Hyrimoz and all medicines out of the reach of children.

What is needed for injection?

Lay out the items listed below on a clean, flat surface.

Contents of the prefilled syringe package:

• Prefilled syringe containing Hyrimoz (see Fig. A). Each prefilled syringe contains 40 mg / 0.4 mL of adalimumab.
• Not included in the prefilled syringe package for Hyrimoz (see Fig. B):
• Alcohol swab
• Cotton ball or gauze pad
• Sharps container; see section 4, "Disposal of used syringes"
• Adhesive bandage

Fig. B. Items not included in the package

Before injection
Fig. C. Safety shield not activated – syringe ready for use In this configuration, the safety shield is NOT ACTIVATED. The syringe is ready for use (see Fig. C).	Fig. D. Safety shield activated – do not use! In this configuration, the safety shield is ACTIVATED. DO NOT USE the syringe (see Fig. D).

Preparing the syringe

• 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 colourless 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 colour. If you are concerned about the appearance of the solution, consult your pharmacist.
• Do not use the prefilled syringe if it is damaged or if the safety shield 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 expired.

Contact your pharmacist if the prefilled syringe does not meet any of these conditions.

Selection of the injection site
The recommended injection site is the front of the thighs. The lower part of the abdomen may also be used, but at least 5 cm away from the navel (see Fig. E). Always choose a different injection site each time. Do not inject into areas where the skin is tender, bruised, red, scaly, or hardened. Avoid areas with scars or stretch marks. If you have psoriasis, DO NOT INJECT the medicine directly into plaques.		Fig. E. Selection of the injection site
Cleaning the injection site
Wash your hands thoroughly with soap and water. Clean the injection site with an alcohol swab using circular motions. Allow it to dry (see Fig. F). Do not touch the cleaned area before injection.		Fig. F. Cleaning the injection site
Injection procedure
Carefully remove the cap from the syringe (see Fig. G). Dispose of the cap. You may see a drop of liquid at the tip of the needle. This is normal.	Fig. G. Removing the cap
Gently pinch the skin at the injection site (see Fig. H). Insert the needle as shown in the image. Insert the needle completely to ensure full delivery of the medicine. Use the syringe within 5 minutes after removing the cap.	Fig. H. Inserting the needle
Hold the syringe as shown in the image (see Fig. I). Gradually push the plunger fully until the plunger head is completely between the wings of the safety guard. Keep pressing the plunger and hold the syringe in place for 5 seconds.	Fig. I. Holding the syringe
Keep the plunger fully depressed while carefully removing the needle from the injection site and releasing the skin (see Fig. J).	Fig. J. Removing the needle
Carefully release the plunger and wait until the safety guard automatically covers the needle (see Fig. K). Bleeding at the injection site may occur. Cover the injection site with a cotton ball or gauze and press for 10 seconds. Do not rub the injection site. If needed, you may cover it with a plaster.	Fig. K. Releasing the plunger
Disposal of used syringes
Dispose of the used syringe in a sharps container (a puncture-resistant container with a lid, see Fig. L). For your own safety and the protection of others, never reuse syringes or needles. Never dispose of medicines via sewage systems or with household waste. Ask your doctor or pharmacist how to properly dispose of medicines you no longer need. These measures help protect the environment. All unused medicines or waste must be disposed of in accordance with local regulations.			Fig. L. Disposal of a used pre-filled syringe

If you have any questions, consult your doctor, pharmacist, or nurse who is familiar with the specific use of the drug Hyrimoz.

The prefilled syringe can be stored at a temperature not exceeding 25 °C for a period of up to 42 days. The prefilled syringe should be kept protected from light and must be discarded if not used within the 42-day period.

Children

Indicated for use in children as specified in the section "Indications".

Overdose

During clinical studies of adalimumab, no cases of dose-limiting toxicity were observed. Multiple doses of up to 10 mg/kg, approximately 15 times the recommended dose, were administered to patients. Such administration was not associated with signs of toxicity related to overdose.

Adverse Reactions

General information on safety profile

Adalimumab has been studied in controlled clinical trials and open-label extension studies lasting approximately 60 months or longer, involving 9,506 patients. These studies included patients with early and long-standing rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile idiopathic 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 presented below are 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 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 (such as nasopharyngitis, upper respiratory tract infections, and sinusitis), injection site reactions (redness, itching, hemorrhage, pain, or swelling), headache, and musculoskeletal pain.

Serious adverse reactions have been reported with adalimumab use. TNF antagonists, such as Hyrimoz, affect the immune system, and their use may lead to decreased resistance to infections and malignancies.

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

Serious hematological, neurological, and autoimmune reactions have also been reported. These included individual 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.

Table 7 presents adverse reactions with a possible causal relationship observed during clinical trials and in the post-marketing period. Adverse reactions are listed by system organ class and frequency of occurrence (≥ 1/10 – very common; ≥ 1/100 to < 1/10 – common; ≥ 1/1,000 to < 1/100 – uncommon; ≥ 1/10,000 to < 1/1,000 – rare; frequency not known (cannot be estimated from available data)). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

The highest frequency observed across different indications is included in the table below. An asterisk (*) in the "System Organ Class" column indicates that additional information is provided in the sections "Contraindications", "Special Warnings and Precautions for Use", and "Adverse Reactions".

Table 7

Organ systems	Frequency	Adverse reactions
Infections and infestations*	very common	respiratory tract infections (including lower and upper respiratory tract infections, pneumonia, sinusitis, pharyngitis, rhinopharyngitis, 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 and tuberculosis (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**, neoplasms of parenchymal organs (including breast cancer, lung tumor, and thyroid tumor), melanoma**;
	occasional	leukemia1;
	frequency unknown	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), anemia;
	common	leukocytosis, thrombocytopenia;
	uncommon	idiopathic thrombocytopenic purpura;
	occasional	pancytopenia
Immune system disorders*	common	hypersensitivity, allergy (including seasonal allergy);
	uncommon	sarcoidosis1, vasculitis;
	occasional	anaphylaxis1
Metabolism and nutrition disorders	very common	increased blood lipid levels;
	common	hypokalemia, hyperuricemia, plasma sodium concentration abnormality, hypocalcemia, hyperglycemia, hypophosphatemia, 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	stroke1, tremor, neuropathy;
	occasional	multiple sclerosis, demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome)1
Eye disorders	common	visual acuity disturbances, conjunctivitis, blepharitis, eye swelling;
	uncommon	diplopia
Ear and labyrinth disorders	common uncommon	vertigo; deafness, tinnitus
Cardiac disorders*	common	tachycardia;
	uncommon	myocardial infarction1, arrhythmia, chronic heart failure;
	occasional	cardiac arrest
Vascular disorders	common	arterial hypertension, flushing, hematoma;
	uncommon	aortic aneurysm, arterial occlusion, thrombophlebitis
Respiratory, thoracic and mediastinal disorders*	common	asthma, dyspnea, cough;
	uncommon	pulmonary embolism1, chronic obstructive pulmonary disease, interstitial lung disease, pneumonitis, pleural effusion1;
	occasional	pulmonary fibrosis1
Gastrointestinal disorders	very common	abdominal pain, nausea and vomiting;
	common	gastrointestinal hemorrhage, dyspepsia, gastroesophageal reflux, dry syndrome (Sjögren's syndrome);
	uncommon	pancreatitis, dysphagia, facial swelling;
	occasional	intestinal perforation1
Hepatobiliary disorders*	very common	elevated liver enzymes;
	uncommon	cholecystitis and cholelithiasis, elevated bilirubin levels, hepatic steatosis;
	occasional	hepatitis, reactivation of hepatitis B1, autoimmune hepatitis1;
	frequency unknown	liver failure1
Skin and subcutaneous tissue disorders	very common	rash (including exfoliative rash);
	common	new onset or worsening of psoriasis (including palmoplantar pustulosis)1, pruritus, urticaria, ecchymoses (including purpura), dermatitis (including eczema), onycholysis, increased sweating, alopecia1;
	uncommon	night sweats, scarring;
	occasional	erythema multiforme1, Stevens-Johnson syndrome1, angioedema1, cutaneous vasculitis1, lichenoid skin reaction1;
	frequency unknown	worsening of dermatomyositis symptoms1
Musculoskeletal and connective tissue disorders	very common	musculoskeletal pain;
	common	muscle spasms (including elevated plasma creatine phosphokinase levels);
	uncommon	rhabdomyolysis, systemic lupus erythematosus;
	occasional	lupus-like syndrome1
Renal and urinary system disorders	common	hematuria, renal failure;
	uncommon	nocturia
Reproductive system and breast disorders	uncommon	erectile dysfunction
General disorders and administration site conditions*	very common	injection site reactions (including injection site erythema);
	common	chest pain, swelling, pyrexia1;
	uncommon	inflammation
Investigations*	common frequency unknown	coagulation and blood clotting system disorders (including prolonged activated partial thromboplastin time (aPTT)), positive autoantibody tests (including anti-double-stranded DNA antibodies), elevated plasma lactate dehydrogenase levels; weight gain2
Injury, poisoning and procedural complications*	common	slow healing

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

** Including open-label study periods.

1 Including data from spontaneous reports.

2 Mean change in body weight from baseline ranged from 0.3 kg to 1.0 kg with adalimumab use in adult indications compared to (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 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 not well understood 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 studies in adults and children receiving adalimumab, injection site reactions (erythema and/or pruritus, bruising, pain, or swelling) occurred in 12.9% of cases, compared to 7.2% in the control group. The majority of reactions were mild and generally did not require discontinuation of the drug.

Infections

In controlled clinical studies in adults and children, the rate of infections was 1.51/patient-year in the group receiving adalimumab and 1.46/patient-year in the control group. The rate of serious infections was 0.04/patient-year in the adalimumab group and 0.03/patient-year in the control group. Most commonly reported infections were nasopharyngitis, upper respiratory tract infections, and sinusitis. Most patients continued adalimumab treatment after recovery.

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

Malignancies and lymphoproliferative disorders

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

No malignancies were additionally observed in clinical studies 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 pivotal studies involving at least 12 weeks of adalimumab use 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 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 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 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 patients.

The observed rates of malignancies (excluding lymphoma and non-melanoma skin cancer) were approximately 8.5 per 1000 patient-years in controlled studies and in ongoing and completed open-label studies. The rate of non-melanoma skin cancer was approximately 9.6 per 1000 patient-years, and the rate of lymphomas was approximately 1.3 per 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 treatment initiation, 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 treated with adalimumab, the rate of malignancies was approximately 2.7 per 1000 patient-years. Rates of non-melanoma skin cancer and lymphoma were approximately 0.2 and 0.3 per 1000 patient-years, respectively (see section "Special precautions").

In post-marketing practice, hepatosplenic T-cell lymphoma has been reported rarely in patients treated with adalimumab (see section "Special precautions").

Autoantibodies

During phases 1–5 clinical studies in rheumatoid arthritis, patients were tested multiple 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, with negative antinuclear antibody titers observed under active treatment monitoring at week 24. 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.

Hepatic enzyme activity

In phase 3 controlled clinical studies involving patients with rheumatoid arthritis and psoriatic arthritis, during the controlled period of 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 patients.

In phase 3 controlled clinical studies 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 in 1.3% of control 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 studies in patients with polyarticular arthritis aged 2–4 years.

In phase 3 controlled clinical studies 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 study 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 therapy duration up to 52 weeks, ALT elevations ≥3 times the upper limit of normal were observed in 2.6% (5/192) of patients, four of whom received adalimumab concomitantly with immunosuppressants.

In phase 3 controlled clinical studies 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 studies (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 in 0.6% of control patients.

In controlled clinical studies (initial dose 80 mg [week 0], then 40 mg every 2 weeks starting week 1) involving patients with uveitis, 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 in 2.4% of control patients.

In a phase 3 controlled study 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 2 weeks (N = 31) and weekly (N = 32) after induction doses 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 after induction doses 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 ≥3 times the upper limit of normal were observed in 1.1% (1/93) of patients.

Across all indications in clinical trials, patients experienced asymptomatic ALT elevations, which were mostly 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.

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 enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, 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. 2 years.

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.

The pre-filled syringe may be stored at temperatures not exceeding 25 °C for up to 42 days. The pre-filled syringe should be kept in a place protected from light and must be discarded if not used within 42 days.

Incompatibilities

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

Packaging

40 mg / 0.4 mL solution in a pre-filled syringe; 2 pre-filled syringes in blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

Novartis Pharma Manufacturing GmbH

or

Sandoz GmbH – Aseptic Pharmaceutical Division Schaftlach (Aseptic PD Schaftlach)

Manufacturer’s address and location of operations

Biochemiestrasse 10, Unterlangkampfen, Langkampfen, 6336, Austria

or

Biochemiestrasse 10, 6336 Langkampfen, Austria