Hyrmoz

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Hyrimoz (Hyrimoz)

Composition:

Active substance: adalimumab;

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

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

Pharmaceutical form. Solution for injection.

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

Pharmacotherapeutic group

Immunosuppressants. Tumor necrosis factor-alpha inhibitors. Adalimumab.

ATC code L04AB04.

Pharmacological Properties

Mechanism of Action

Adalimumab specifically binds to tumor necrosis factor (TNF) and neutralizes the biological effects of TNF 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 acute-phase inflammatory markers (C-reactive protein [CRP], serum cytokines [IL-6], and erythrocyte sedimentation rate [ESR]) compared to baseline. 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 generally improved hematological signs of chronic inflammation.

Following 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). Along with significant reduction in TNF-α expression in patients with Crohn’s disease, a decrease in the number of cells expressing inflammatory markers in the colon was observed. 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 a 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 11–15 mL/hour, volume of distribution (Vss) was 5–6 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 40 mg adalimumab every 2 weeks in RA patients, steady-state concentrations ranged from 5 µg/mL (without concomitant methotrexate) to 8–9 µg/mL (with methotrexate). Serum adalimumab concentrations at steady state increased almost 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, after administration of 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 concomitant methotrexate and 11.8 ± 4.3 µg/mL with methotrexate.

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

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

The effect of adalimumab in adolescents with hidradenitis suppurativa was determined using pharmacokinetic modeling and simulation based on pharmacokinetic data from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and enthesitis-related arthritis). The recommended dosing regimen for 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 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 160 mg at week 0 followed by 80 mg at week 2, serum concentrations were approximately 12 µg/mL during induction therapy. Mean steady-state concentration was approximately 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 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 concentration was approximately 15.7 ± 6.6 µg/mL at week 4 in patients with body weight ≥40 kg (160/80 mg) and 10.6 ± 6.1 µg/mL in patients with body weight <40 kg (80/40 mg).

In patients who continued treatment in their assigned group, mean (± standard deviation) adalimumab concentrations at week 52 were 9.5 ± 5.6 µg/mL in the standard-dose group and 3.5 ± 2.2 µg/mL in the low-dose group. Mean concentrations were maintained in patients continuing adalimumab therapy 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. Mean steady-state concentration was approximately 8 µg/mL during maintenance therapy with 40 mg every 2 weeks.

In children with ulcerative colitis, mean steady-state serum concentration of adalimumab at week 52 after subcutaneous administration of weight-based dose 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, 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, mean steady-state concentration was approximately 8–10 µg/mL.

The effect of adalimumab in children with uveitis was determined using pharmacokinetic modeling and simulation based on pharmacokinetic data from other pediatric indications (plaque psoriasis, juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and enthesitis-related arthritis). There are no clinical data on the effect of the initial dose of adalimumab in children under 6 years of age. In the absence of methotrexate, the initial dose 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 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-maximal 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 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 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 high disease activity rheumatoid arthritis in adult patients who have not achieved an adequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• the 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 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 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.

Non-radiographic Axial Spondyloarthritis (without radiographic confirmation of AS)

Hyrimoz is indicated for the treatment of active non-radiographic 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 NSAID intolerance.

Psoriatic Arthritis (PsA)

Hyrimoz is indicated for the treatment of active and progressive psoriatic arthritis in adult patients who have not achieved an adequate response to prior therapy with disease-modifying antirheumatic drugs (DMARDs). Adalimumab has demonstrated slowing of radiographically determined progression of peripheral joint damage 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 chronic plaque psoriasis with severe disease course 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 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 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 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 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, who require corticosteroid dose reduction, or who have corticosteroid intolerance or 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

In order to improve monitoring of biological medicinal products, the trade name and batch number of the administered medicinal product should be clearly recorded in the patient's medical documentation.

Infections

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

Impaired lung function may increase the risk of 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 from 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").

Complete evaluation and close monitoring are required for patients who develop a new infection during treatment with Hyrimoz. In the event of 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 treated with adalimumab.

Other serious infections observed in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Hospitalizations due to infections, including fatal cases, have been reported.

Tuberculosis

Cases of reactivation and new onset of tuberculosis, including pulmonary and extrapulmonary forms (i.e., disseminated tuberculosis), have been reported in patients receiving adalimumab therapy. Prior to initiating treatment with Hyrimoz, patients should be carefully evaluated for active and inactive (latent) tuberculosis. The evaluation should include a thorough assessment of the patient's history of tuberculosis or exposure to individuals with active tuberculosis, as well as prior and/or concomitant immunosuppressive therapy. All patients should undergo a tuberculin skin test (Mantoux test) and chest X-ray before starting therapy (local recommendations may apply). Testing procedures and results should be documented in the patient's medical record. Physicians should be aware of the risk of false-negative tuberculin skin test results, particularly in critically ill or immunocompromised patients.

Treatment with Hyrimoz should not be initiated if active tuberculosis is diagnosed (see section "Contraindications").

The benefit/risk ratio of therapy should be carefully considered in all situations described below.

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

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

Anti-tuberculosis treatment should be considered before initiating therapy with Hyrimoz in patients with risk factors for tuberculosis infection who test negative for latent tuberculosis, as well as 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. Recurrent tuberculosis has been observed in some patients who previously completed successful treatment for active tuberculosis while receiving adalimumab.

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, lethargy) occur during or after treatment with Hyrimoz.

Other opportunistic infections

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

In patients presenting with fever, malaise, weight loss, increased sweating, cough, dyspnea, and/or lung infiltrates or other signs of serious systemic illness (with or without shock), immediate evaluation for invasive fungal infection is required, and administration of 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

The 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). Cases of hepatitis B virus reactivation have sometimes been fatal. Prior to initiating treatment with Hyrimoz, patients at risk should be screened for hepatitis B virus. If screening results are positive, the decision to treat should be made after consultation with a hepatologist.

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

Neurological disorders

Rare cases of new onset or exacerbation of clinical and/or radiographic signs of demyelinating disorders of the central nervous system, including multiple sclerosis, optic neuritis, and demyelinating disorders of the peripheral nervous system, including Guillain-Barré syndrome, have been reported with the use of TNF blockers, including adalimumab. Careful assessment of the benefit/risk ratio of adalimumab use is recommended for 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 required for patients with non-infectious intermediate uveitis before initiating treatment with Hyrimoz and regularly during therapy to monitor for the development of demyelinating disorders of the central nervous system.

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. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Hyrimoz should be immediately discontinued and appropriate therapy initiated.

Immunosuppression

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

Malignancies

In controlled clinical trials of TNF blockers, malignancies have been 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 the use of TNF antagonists have been reported. Moreover, patients with long-standing, highly active rheumatoid arthritis have an increased baseline risk of lymphoma and leukemia, which complicates risk assessment. Based on available data, the risk of developing lymphoma, leukemia, or other malignancies in patients treated with TNF antagonists cannot be excluded.

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

In post-marketing experience, rare cases of hepatosplenic T-cell lymphoma have been reported in patients treated with adalimumab. This is a rare type of lymphoma characterized by a highly aggressive course and is usually fatal. Some cases of hepatosplenic T-cell lymphoma during adalimumab treatment were observed in young individuals 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 treatment with 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 regarding 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 patients with psoriasis 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 treatment with TNF antagonists, including adalimumab (see section "Adverse reactions").

In a clinical trial evaluating the use of another TNF antagonist (infliximab) in patients with chronic obstructive pulmonary disease, more frequent cases of malignancies, mostly in the lungs, head, and neck region, 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 the use of 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 screening for dysplasia before starting therapy and throughout the course of the disease. Screening should include colonoscopy and biopsy according to local recommendations.

Hematological disorders

Rare cases of pancytopenia and aplastic anemia have been reported with the use of TNF blockers. Cases of clinically significant cytopenia (thrombocytopenia, leukopenia) have been reported with adalimumab (causal relationship not established). All patients should be informed of the need to consult a physician immediately if symptoms suggestive of blood disorders (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 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 treated with 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 treatment with Hyrimoz, if possible.

Vaccination may be performed in patients during adalimumab treatment, except for live vaccines. The use of live vaccines (e.g., BCG vaccine) in infants exposed to adalimumab in utero is not recommended 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 treated with 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 occur or if congestive heart failure worsens.

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 were observed during clinical trials of concomitant use of anakinra and etanercept, with no therapeutic advantage compared to etanercept monotherapy. Given the nature of adverse events observed during combination therapy with etanercept and anakinra, similar toxicity may develop with the combination of anakinra and another TNF 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 taken into account 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 joint replacement surgery 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 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

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

Use during pregnancy or breastfeeding

Women of childbearing potential

Women of childbearing potential should use reliable contraception methods during treatment and for at least five months after the last dose of 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 use in the first trimester) did not reveal 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 the birth of at least one live infant with a major congenital malformation was 6 out of 69 (8.7%) in the group of women with RA who received adalimumab and 5 out of 74 (6.8%) in the group of women with RA who did not receive the drug (uncorrected 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%) (uncorrected 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 there were no cases of stillbirth or development of malignancies. Interpretation of the data may have been influenced by methodological limitations of the study, including small sample size and non-randomized study design.

In experimental toxicity studies in monkeys, no evidence of toxic effects on the maternal organism, embryotoxicity, or teratogenicity was observed. Preclinical data on postnatal toxicity of adalimumab are lacking.

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

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

Breastfeeding

Limited published data indicate that adalimumab is excreted in breast milk at very low concentrations—ranging from 0.1% to 1% of the level in maternal serum. Given that immunoglobulin G proteins are subject to 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

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

Ability to influence the speed of reactions when driving vehicles or operating machinery

Hyrimoz may have a minor influence on the ability to drive vehicles 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, patients should review the information on self-injection provided in this instruction. 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. Therapy with glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), 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.

Clinical response 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.

If necessary, therapy may be interrupted (e.g., prior to surgery or in case of severe infection). Data indicate that after resuming therapy following an interruption 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.

Clinical response 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.

Plaque Psoriasis

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

The need for continuing therapy should be carefully re-evaluated after 16 weeks in patients who do not show a response to treatment 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 ratio of continuing therapy at 40 mg weekly or 80 mg every 2 weeks should be carefully re-evaluated in patients who do not achieve an adequate response after dose escalation (see section "Pharmacodynamics"). If an adequate response is achieved after switching to 40 mg weekly or 80 mg every 2 weeks, the dose may then 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); this dose may be administered as 4 injections in one day or as 2 injections per day on 2 consecutive days. This is 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. During treatment with Hyrimoz, antibiotics may be continued if necessary. Daily topical antiseptic cleansing of affected areas is also recommended.

The need for continuing therapy beyond 12 weeks should be carefully re-evaluated in patients who do not achieve 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 40 mg at week 2 (day 15), administered subcutaneously. If a more rapid clinical response is required, 160 mg may be administered at week 0 (day 1), which can be given as 4 injections in one day or as two 40 mg injections on each of 2 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 is increased.

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 disease 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 administered. 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 re-evaluated 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 2 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.

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 the use of adalimumab alone as initial therapy. Treatment with Hyrimoz may be initiated in combination with corticosteroids and/or other non-biological immunomodulatory agents. Two weeks after starting combination therapy, a 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, 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 depends on body weight (Table 1). Hyrimoz is administered subcutaneously once every 2 weeks.

Table 1. Dosing of Hyrimoz in Patients with Polyarticular JIA

Clinical response, according to available data, is typically 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 in patients with enthesitis-related arthritis

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

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

If retreatment with Hyrimoz is indicated, the dosing regimen described above should be followed.

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

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

Hidradenitis suppurativa in children aged 12 years and older with body weight of at least 30 kg
There are no clinical studies on the use of adalimumab in children 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 do not show a clinical response within this period.

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

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

Adalimumab is not recommended 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

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

• patients with body weight < 40 kg: 20 mg once weekly;
• 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 children

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

Table 5. Dosing of Hyrimoz in children with ulcerative colitis (UC)

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

The necessity of continuing therapy should be carefully reviewed for 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

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; this dose 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 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 spondylitis, including ankylosing spondylitis

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

Method of administration

Hyrimoz is administered subcutaneously.

Administration

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

Figure A shows a prefilled syringe containing one dose of Hyrimoz medicinal product with a needle safety guard and an additional finger grip.

Always follow these instructions:

• Do not open the outer packaging until you are ready to use the syringe.
• Do not use the syringe if the blister seal is damaged, as this may be unsafe.
• Never leave the syringe unattended where others could access it.
• Do not shake the syringe.
• If you drop the syringe, do not use it if it is damaged or if the cap becomes detached.
• Do not remove the cap until you are ready for injection.
• Do not touch the safety guard wings before use. Doing so may cause premature activation of the safety guard. Do not remove the finger grip before injection.
• Administer Hyrimoz 15–30 minutes after removing it from the refrigerator for more comfortable administration.

Dispose of the syringe immediately after use. Do not reuse the syringe.

Syringe preparation

• For more comfortable injection, take the pre-filled syringe out of the refrigerator and leave it unopened on a flat surface for approximately 15–30 minutes to reach room temperature.
• Remove the pre-filled syringe from the blister.
• Look through the viewing window. The solution should be colourless or slightly yellowish, and clear or slightly opalescent. Do not use the medicinal product if particles are visible and/or if there is a change in colour. If you are concerned about the appearance of the solution, contact your pharmacist for assistance.
• Do not use the pre-filled 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 pre-filled syringe. Do not use the pre-filled syringe if the expiry date has passed.

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

As with any other parenteral medicinal products, the solution should be inspected visually for the presence of foreign particles, discoloration, or loss of clarity prior to administration.

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

Unused solution and syringe must be disposed of after use according to current recommendations.

Children

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

Overdose

During clinical trials of adalimumab, no cases of dose-limiting toxicity have been observed. Multiple doses up to 10 mg/kg, approximately 15 times higher than 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 up to 60 months or longer, involving 9506 patients. These studies included patients with early and longstanding rheumatoid arthritis, JIA (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 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. TNF antagonists, such as Hyrimoz, affect the immune system, and their use may lead to decreased resistance to infections and malignancies.

During adalimumab treatment, infections that may be life-threatening and potentially fatal (including sepsis, opportunistic infections, and tuberculosis) have been reported, as well as reactivation of hepatitis B and the development of various malignancies (including leukemia, lymphoma, and hepatosplenic T-cell lymphoma).

Serious hematological, neurological, and autoimmune reactions have also been reported. These included isolated 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 organ systems 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 group, adverse reactions are listed in order of decreasing severity.

The highest frequency of adverse reactions observed across different indications is included in the table below. An asterisk (*) in the "Organ systems" column indicates that additional information is provided in the sections "Contraindications," "Special precautions for use," and "Adverse reactions."

Table 7

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

** Including the open-label period of studies.

1 Including data from spontaneous reports.

2 The mean change in body weight from baseline ranged from 0.3 kg to 1.0 kg with adalimumab treatment in adult indications compared to (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 unclear but may be related to the anti-inflammatory action of adalimumab.

Hidradenitis suppurativa

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

Uveitis

The safety profile for patients with uveitis receiving adalimumab every 2 weeks is consistent with the known safety profile of adalimumab.

Description of selected adverse reactions

Injection site reactions

In controlled clinical 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. Most reactions were mild and generally did not require discontinuation of the drug.

Infections

In controlled clinical studies in adults and children, the infection rate was 1.51/patient-year in the group of patients receiving adalimumab and 1.46/patient-year in the control group of patients. The rate of serious infections was 0.04/patient-year in the group of patients receiving adalimumab and 0.03/patient-year in the control group. Most commonly reported 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) have been reported: tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (such as disseminated histoplasmosis, Pneumocystis pneumonia, aspergillosis, listeriosis). Most cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect reactivation of latent disease.

Neoplasms and lymphoproliferative disorders

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

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

During the controlled periods of main studies of adalimumab use in adults for at least 12 weeks in 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 incidence 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, 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 neoplasm development (excluding lymphoma and non-melanoma skin cancer) were approximately 8.5/1000 patient-years in controlled studies and in ongoing and completed open-label studies. The rate of non-melanoma skin cancer was approximately 9.6/1000 patient-years, and the rate of lymphoma development 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 from the start of therapy, amounting to more than 26,439 patient-years of therapy.

In the post-marketing period from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis treated with adalimumab, the rate of malignant neoplasms 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, cases of hepatosplenic T-cell lymphoma have been reported in isolated cases in patients treated with adalimumab (see section "Special precautions").

Autoantibodies

During phases 1–5 clinical trials of rheumatoid arthritis, patients underwent multiple blood tests 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 titers of antinuclear antibodies observed at 24 weeks under active treatment monitoring. Two patients (out of 3441 patients with RA, PsA, and AS receiving adalimumab in clinical trials) developed signs of lupus-like syndrome (newly diagnosed), 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 from 4 to 104 weeks, ALT (alanine aminotransferase) elevations ≥3 times the upper limit of normal were observed in 3.7% of patients receiving adalimumab and in 1.6% of control group patients.

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 in 1.3% of control group patients. Most cases of ALT elevation occurred during concomitant methotrexate therapy. No ALT elevations ≥3 times the upper limit of normal were observed in phase 3 clinical trials in patients with polyarticular arthritis aged 2–4 years.

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

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

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

In controlled clinical trials (initial dose 160 mg (week 0) and 80 mg (week 2), then 40 mg once weekly starting from 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 group patients.

In controlled clinical trials (initial dose 80 mg (week 0), then starting from week 1, 40 mg every 2 weeks) involving patients with uveitis, with a controlled period duration up to 80 weeks (mean exposure of 166.5 days and 105 days in the adalimumab treatment group and control group, 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 study of adalimumab use 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 administration of a weight-based induction dose of 2.4 mg/kg (maximum 160 mg) at week 0 and week 1 and a dose of 1.2 mg/kg (maximum 80 mg) at week 2 (N = 63) or after administration of an induction dose of 2.4 mg/kg (maximum 160 mg) at week 0, placebo at week 1, and a dose of 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 elevations in ALT levels, which were mostly transient during long-term treatment. However, very rare post-marketing reports of liver failure and less severe hepatic reactions that may lead to liver failure, such as hepatitis, including autoimmune hepatitis, have been reported in patients receiving adalimumab.

Concomitant therapy with azathioprine/6-mercaptopurine

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

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the drug. 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. 30 months.

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 a temperature not exceeding 25 °C for up to 21 days. The pre-filled syringe should be stored in a light-protected place and disposed of if not used within 21 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 / 0.8 mL solution in a pre-filled syringe; 2 pre-filled syringes in blisters in a cardboard box.

Prescription status. By prescription only.

Manufacturer

Novartis Pharmaceuticals Manufacturing GmbH

or

Sandoz GmbH – Aseptic Medicinal Products Schaftenu (AMP-S)

Manufacturer's address and location of its business operations

Biochemiestrasse 10, Unterlangkampfen, Langkampfen, 6336, Austria

or

Biochemiestrasse 10, 6336 Langkampfen, Austria