Hadlima

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HADLIMA (HADLIMA)

Composition:

Active substance: adalimumab;

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

1 pre-filled single-use pen contains 40 mg of adalimumab in 0.8 mL of solution;

Excipients: sodium citrate; citric acid, monohydrate; L-histidine; L-histidine hydrochloride monohydrate; sorbitol (E 420); polysorbate 20; water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: from clear to opalescent, from colorless to pale brown solution.

Pharmacotherapeutic group. Immunosuppressants. Tumor necrosis factor-alpha (TNF-alpha) inhibitors. Adalimumab.

ATC code L04AB04.

Pharmacological Properties

Adalimumab is a recombinant human immunoglobulin (IgG1), a monoclonal antibody composed entirely of human peptide sequences. Adalimumab was developed using phage display technology, which enabled the selection of fully human variable regions of heavy and light chains specific for tumor necrosis factor (TNF), combined with the human IgG1 heavy chain and kappa-type light chain sequences. Adalimumab binds with high affinity and specificity to soluble TNF-alpha, but not to lymphotoxin (TNF-beta). Adalimumab is produced by recombinant DNA technology using a mammalian cell expression system. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab specifically binds to TNF and neutralizes its biological effects by inhibiting its interaction with p55 and p75 TNF receptors on the cell surface. TNF is a natural cytokine involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis, including juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis. TNF plays a key role in the development of pathological inflammation and joint tissue destruction, which are characteristic features of these diseases. Elevated TNF levels are also observed in psoriatic plaques, contributing to the inflammatory response, keratinocyte proliferation and impaired maturation, and associated vascular damage typical of this condition. The relationship between these pharmacodynamic effects and the mechanism(s) by which adalimumab exerts its clinical efficacy is unknown.

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

Pharmacodynamics

In patients with rheumatoid arthritis, treatment with adalimumab resulted in a rapid reduction, compared to baseline, in acute-phase inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum cytokines (IL-6)]. Following adalimumab administration, serum levels of matrix metalloproteinases (MMP-1 and MMP-3), which mediate tissue remodeling underlying cartilage destruction, decreased. Treatment with adalimumab typically led to improvement in hematological signs of chronic inflammation.

Rapid reduction in CRP levels was also observed in patients with polyarticular juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis, and hidradenitis suppurativa following adalimumab treatment. In patients with Crohn’s disease, a reduction in the number of cells expressing inflammatory markers in the colon was observed, including a significant decrease in TNF-alpha expression. Endoscopic evaluations of intestinal mucosa showed mucosal healing in patients receiving adalimumab.

Immunogenicity
During adalimumab therapy, antibodies to adalimumab may develop. The formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of adalimumab. No clear correlation has been observed between the presence of antibodies and the occurrence of adverse reactions.

Pharmacokinetics

Absorption and Distribution
After a single subcutaneous dose of 40 mg adalimumab, absorption and distribution were slow, with peak serum concentrations reached approximately 5 days after administration. The mean absolute bioavailability of adalimumab, calculated across three studies after a single 40 mg subcutaneous dose, was 64%. Following single intravenous doses ranging from 0.25 to 10 mg/kg, concentrations were dose-proportional. After doses of 0.5 mg/kg (approximately 40 mg), clearance ranged from 11 to 15 mL/h, volume of distribution (Vss) ranged from 5 to 6 liters, and the mean terminal half-life was approximately two weeks. Adalimumab concentrations in synovial fluid in some patients with rheumatoid arthritis ranged from 31% to 96% of serum concentrations.

After subcutaneous administration of 40 mg adalimumab every 2 weeks to adult patients with rheumatoid arthritis, mean steady-state trough concentrations were approximately 5 µg/mL without concomitant methotrexate and 8–9 µg/mL with concomitant methotrexate. Steady-state trough concentrations of adalimumab in serum increased nearly proportionally with subcutaneous doses of 20, 40, and 80 mg administered every 2 weeks and every week.

After subcutaneous administration of 24 mg/m² (up to 40 mg) every 2 weeks to children aged 4 to 17 years with polyarticular juvenile idiopathic arthritis, mean steady-state trough concentrations of adalimumab in serum (values obtained between weeks 20 and 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 concomitant methotrexate.

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

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

After subcutaneous administration of 40 mg adalimumab every 2 weeks to adult patients with axial spondyloarthritis without radiographic evidence of ankylosing spondylitis, the mean (± SD [standard deviation]) steady-state trough concentration at week 68 was 8.0 ± 4.6 µg/mL.

After subcutaneous administration of 40 mg adalimumab every 2 weeks to adult patients with psoriatic arthritis, the mean steady-state trough concentration was 5 µg/mL.

After subcutaneous administration of 0.8 mg/kg (up to 40 mg) every 2 weeks to children with chronic plaque psoriasis, the mean (± SD) steady-state trough concentration of adalimumab in serum was approximately 7.4 ± 5.8 µg/mL (79% CV).

In adult patients with hidradenitis suppurativa, after an initial dose of adalimumab 160 mg at week 0 followed by 80 mg at week 2, mean trough concentrations of adalimumab in serum were approximately 7 to 8 µg/mL at weeks 2 and 4. After subcutaneous administration of 40 mg adalimumab once weekly, mean steady-state trough concentrations (values obtained from weeks 12 to 36) were 8–10 µg/mL.

The effect of adalimumab in adolescents with hidradenitis suppurativa was determined using population pharmacokinetic modeling and cross-indication pharmacokinetic modeling based on pediatric data from other indications (plaque psoriasis, juvenile idiopathic arthritis, Crohn’s disease, and enthesitis-related arthritis). The recommended dosing regimen for adolescents with hidradenitis suppurativa is 40 mg every 2 weeks. Because the effect of adalimumab may depend on body weight, for adolescents with high body weight and inadequate response to treatment, administration of the recommended adult dose—40 mg once weekly—may be appropriate.

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

In children with moderate to severe Crohn’s disease, the initial dose of adalimumab was 160/80 mg or 80/40 mg at weeks 0 and 2, depending on a body weight threshold of 40 kg. At week 4, children were randomized in a 1:1 ratio to receive either weight-based standard dose (40/20 mg every 2 weeks) or low dose (20/10 mg every 2 weeks). Mean (± SD) trough concentrations of adalimumab at week 4 were approximately 15.7 ± 6.6 µg/mL in children with body weight ≥40 kg (160/80 mg) and 10.6 ± 6.1 µg/mL in children with body weight <40 kg (80/40 mg).

In children continuing randomized therapy, mean (± SD) trough concentrations of adalimumab 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 trough concentrations were maintained in children continuing adalimumab treatment every 2 weeks for 52 weeks. In children whose dosing frequency was increased from every 2 weeks to weekly, mean (± SD) serum concentrations of adalimumab 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 adult patients with ulcerative colitis, after an initial dose of adalimumab 160 mg at week 0 followed by 80 mg at week 2, the mean trough concentration of adalimumab in serum was approximately 12 µg/mL during induction therapy. The mean steady-state trough concentration was approximately 8 µg/mL in patients with ulcerative colitis receiving a maintenance dose of 40 mg every 2 weeks.

After subcutaneous administration of 0.6 mg/kg (up to 40 mg) every 2 weeks to children with ulcerative colitis, mean (± SD) steady-state trough concentrations of adalimumab in serum at week 52 were approximately 5.01 ± 3.28 µg/mL. After administration of 0.6 mg/kg (up to 40 mg) weekly, mean (± SD) steady-state trough concentrations at week 52 were approximately 15.7 ± 5.60 µg/mL.

In adult patients with uveitis, after an initial dose of adalimumab 80 mg at week 0 followed by 40 mg every 2 weeks starting at week 1, mean steady-state trough concentrations ranged from 8 to 10 µg/mL.

The effect of adalimumab in children with uveitis was determined using population pharmacokinetic modeling and cross-indication pharmacokinetic modeling based on pediatric data from other indications (plaque psoriasis, juvenile idiopathic arthritis, Crohn’s disease, and enthesitis-related arthritis). There are no clinical data on the effect of the initial dose in children under 6 years of age. Predicted exposures suggest that, in the absence of methotrexate, the initial dose may lead to increased systemic exposure.

Population pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and simulations predicted comparable exposure and efficacy of adalimumab in patients receiving 80 mg every 2 weeks and those receiving 40 mg weekly (including adult patients with rheumatoid arthritis, hidradenitis suppurativa, ulcerative colitis, Crohn’s disease, or plaque psoriasis, adolescents with hidradenitis suppurativa, and children with Crohn’s disease or ulcerative colitis with body weight >40 kg).

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

Renal or Hepatic Impairment
There are no pharmacokinetic data available for patients with hepatic or renal impairment.

Clinical characteristics.

Indications.

Rheumatoid arthritis (RA).

HADLIMA, in combination with methotrexate, is indicated for:

• treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• treatment of severe active and progressive rheumatoid arthritis in adult patients who have not previously received methotrexate.

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

Adalimumab, when used concomitantly with methotrexate, has been shown to slow the progression of structural joint damage as demonstrated radiographically and to improve functional status.

Axial spondyloarthritis.

Ankylosing spondylitis (AS).

HADLIMA is indicated for the treatment of severe active ankylosing spondylitis in adult patients who have had an inadequate response to conventional therapy.

Axial spondyloarthritis without radiographic confirmation of AS.

HADLIMA is indicated for the treatment of active non-radiographic axial spondyloarthritis with evidence of inflammation, based on elevated C-reactive protein (CRP) levels and/or magnetic resonance imaging (MRI) findings, in adult patients who have had an inadequate response to conventional therapy or who have nonsteroidal anti-inflammatory drug (NSAID) intolerance.

Psoriatic arthritis (PsA).

HADLIMA is indicated for the treatment of active and progressive psoriatic arthritis in adult patients who have had an inadequate response to prior DMARD therapy.

Adalimumab has been shown to slow the progression of radiographic damage in peripheral joints in patients with symmetric polyarticular disease and to improve functional status.

Plaque psoriasis (PP).

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

Hidradenitis suppurativa (HS).

HADLIMA is indicated for the treatment of moderate to severe hidradenitis suppurativa (acne inversa) in adult patients who have had an inadequate response to conventional systemic therapy for HS (see section "Pharmacological properties. Pharmacodynamics").

Crohn’s disease (CD).

HADLIMA is indicated for the treatment of moderate to severe active Crohn’s disease in adult patients who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants, or in whom such therapies are contraindicated or not tolerated.

Ulcerative colitis (UC).

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

Uveitis.

HADLIMA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients who have had an inadequate response to corticosteroid therapy, when corticosteroid dose reduction is required, or in whom corticosteroid therapy is contraindicated or not tolerated.

In paediatrics

The use of HADLIMA in pre-filled single-use syringes and pre-filled single-use pens is not feasible for children requiring a dose less than 40 mg.

Juvenile idiopathic arthritis (JIA).

Polyarticular juvenile idiopathic arthritis (pJIA).

Adalimumab, in combination with methotrexate, is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in children aged 2 years and older who have had an inadequate response to one or more DMARDs. Adalimumab may be used as monotherapy in cases of methotrexate intolerance or when continued methotrexate therapy is not acceptable. Studies on the use of adalimumab in children under 2 years of age have not been conducted.

Enthesitis-related arthritis.

Adalimumab is indicated for the treatment of active enthesitis-related arthritis in children aged 6 years and older who have had an inadequate response to or intolerance of conventional therapy.

Plaque psoriasis (PP) in children.

Adalimumab is indicated for the treatment of severe chronic plaque psoriasis in children aged 4 years and older who have had an inadequate response to or contraindications to topical therapy and phototherapy.

Hidradenitis suppurativa (HS) in adolescents.

Adalimumab is indicated for the treatment of moderate to severe hidradenitis suppurativa (acne inversa) in adolescents aged 12 years and older who have had an inadequate response to conventional systemic therapy for HS (see section "Pharmacological properties. Pharmacodynamics").

Crohn’s disease (CD) in children.

Adalimumab is indicated for the treatment of moderate to severe active Crohn’s disease in children aged 6 years and older who have had an inadequate response to conventional therapy, including dietary management, corticosteroids and/or immunomodulators, or in whom such therapies are contraindicated or not tolerated.

Ulcerative colitis (UC) in children.

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

Uveitis in children.

Adalimumab is indicated for the treatment of chronic non-infectious anterior uveitis in children aged 2 years and older who have had an inadequate response to or intolerance of conventional therapy, or for whom conventional therapy is not acceptable.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

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

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

Interaction with other medicinal products and other forms of interaction.

The effect of adalimumab has been studied in patients with rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriatic arthritis receiving the drug as monotherapy or concomitantly with methotrexate. In 21 patients with rheumatoid arthritis receiving adalimumab and methotrexate concomitantly, no statistically significant changes in serum methotrexate concentration profiles were observed. In comparison, single and multiple doses of methotrexate reduced adalimumab clearance by 29% and 44%, respectively. However, no dose adjustment of adalimumab or methotrexate is required. 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.

Interactions between adalimumab and other drugs (other than methotrexate) have not been studied in pharmacokinetic trials. No interactions were observed in clinical studies when adalimumab was used concomitantly with disease-modifying antirheumatic drugs (DMARDs) (sulfasalazine, hydroxychloroquine, leflunomide, and gold compounds), glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics.

Concomitant use of HADLIMA and anakinra is not recommended (see section "Special precautions").

Concomitant use of HADLIMA and abatacept is not recommended (see section "Special precautions").

Special precautions for use.

Traceability.

In order to improve the traceability of biological medicinal products, the brand name and batch number of the administered product should be clearly recorded.

Infections.

Patients receiving TNF inhibitors are more susceptible to developing serious infections. Impaired lung function increases the risk of infections. Therefore, patients should be closely monitored for infections, including tuberculosis, before, during, and after treatment with the medicinal product HADLIMA. Since elimination of adalimumab may continue for up to four months, monitoring should be maintained throughout this period.

Therapy with HADLIMA should not be initiated in patients with active infection, including chronic or localized infections, until the infection is controlled. In patients who have had tuberculosis or have returned from countries with a high incidence of tuberculosis or endemic mycoses such as histoplasmosis, coccidioidomycosis, or blastomycosis, the benefit-risk ratio should be carefully evaluated before initiating HADLIMA (see below "Other opportunistic infections").

A complete diagnostic evaluation should be performed and patients should be closely monitored if a new infection develops during treatment with HADLIMA. Treatment with HADLIMA should be discontinued in the event of a serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering the use of HADLIMA in patients with a history of recurrent infections or underlying conditions that may predispose to infections, including concomitant use of immunosuppressants.

Serious infections.

Serious infections, including sepsis, caused by bacterial, mycobacterial, invasive fungal, parasitic, viral, and other opportunistic infections such as listeriosis, legionellosis, and Pneumocystis pneumonia, have been reported in patients treated with HADLIMA. Other serious infections identified in clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Hospitalizations and fatal outcomes associated with infections have been reported.

Tuberculosis.

Cases of tuberculosis, including reactivation and new-onset tuberculosis, have been reported in patients receiving adalimumab. Reports include cases of pulmonary and extrapulmonary (disseminated) tuberculosis.

Before initiating therapy with HADLIMA, patients should be evaluated for both active and latent (inactive) tuberculosis. The evaluation should include a detailed medical history of tuberculosis or possible prior exposure to individuals with active tuberculosis, as well as prior and/or concomitant immunosuppressive therapy. Appropriate screening tests (e.g., tuberculin skin test [Mantoux test] and chest X-ray) should be performed in all patients according to current regulatory requirements. It is recommended that these test results be documented in the patient's reminder card. The risk of false-negative tuberculin skin test results should be considered, particularly in critically ill patients or immunocompromised individuals.

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

The benefit-risk ratio should be carefully assessed before initiating therapy in all the situations described below.

If latent tuberculosis is suspected, consultation with a physician experienced in the treatment of tuberculosis is recommended.

If latent tuberculosis is diagnosed prior to initiating HADLIMA therapy, appropriate anti-tuberculosis prophylactic treatment should be initiated according to current regulatory requirements.

Prophylactic anti-tuberculosis treatment should also be considered before initiating HADLIMA in patients with multiple or significant risk factors for tuberculosis, despite a negative tuberculosis test, as well as in patients with a history of latent or active tuberculosis who have not received appropriate treatment. The decision to initiate anti-tuberculosis treatment in such patients should be made after consultation with a physician experienced in the treatment of tuberculosis and evaluation of the risk of developing latent tuberculosis and the safety of anti-tuberculosis therapy.

Despite prophylactic treatment, cases of tuberculosis reactivation have occurred in patients receiving HADLIMA. Recurrent tuberculosis has been observed in some patients who had previously completed successful treatment for active tuberculosis while receiving HADLIMA.

During treatment with HADLIMA, patients should be monitored for symptoms of active tuberculosis, particularly considering the possibility of false-negative results in latent tuberculosis tests (especially in severely ill and immunocompromised patients).

Patients should seek medical advice if signs/symptoms suggestive of tuberculosis infection (e.g., persistent cough, weight loss, low-grade fever, fatigue) occur during or after HADLIMA therapy.

Other opportunistic infections.

Opportunistic infections, including invasive fungal infections, have been reported in patients receiving adalimumab. In patients receiving TNF inhibitors, such infections have not been promptly diagnosed, leading to delayed initiation of appropriate treatment and sometimes fatal outcomes. Patients receiving TNF inhibitors are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, etc.

All patients who develop fever, malaise, weight loss, increased sweating, cough, dyspnea, and/or lung infiltrates or other symptoms of serious systemic illness, with or without signs of shock, should be immediately evaluated for opportunistic pathogens and HADLIMA should be discontinued. Diagnostic evaluation and initiation of empirical antifungal therapy in these patients should be performed after consultation with a physician experienced in the treatment of invasive fungal infections. Due to the increased risk of histoplasmosis or other invasive fungal infections, empirical antifungal therapy should be initiated before pathogen identification. In some patients, tests for histoplasmosis antigen or antibodies may be negative despite active infection. If necessary, the decision to initiate empirical antifungal therapy in such patients should be made after consultation with a specialist in the diagnosis and treatment of invasive fungal infections, considering the risk of fungal infection and the risks associated with antifungal therapy. Discontinuation of TNF inhibitor therapy is recommended in the event of a serious fungal infection until the infection is controlled.

Hepatitis B reactivation.

The use of TNF inhibitors, including adalimumab, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of the virus (i.e., positive hepatitis B surface antigen test). In some cases, therapy was fatal. Before initiating treatment with HADLIMA, patients should be screened for signs of HBV. Patients with a positive test for hepatitis B infection should consult a physician experienced in the treatment of hepatitis B.

Patients who are HBV carriers and require treatment with HADLIMA should be closely monitored for signs and symptoms of active HBV infection throughout the treatment period and for several months after discontinuation. There are insufficient data on the use of antiviral therapy in combination with TNF inhibitors in HBV carriers for the prevention of HBV reactivation. In patients who develop HBV reactivation, treatment with HADLIMA should be discontinued and effective antiviral therapy with appropriate supportive treatment should be initiated.

Neurological disorders.

Isolated cases of onset or exacerbation of clinical and/or radiographic signs of demyelinating disease of the central nervous system (CNS), including multiple sclerosis and optic neuritis, as well as demyelinating disease of the peripheral nervous system, including Guillain-Barré syndrome, have been reported with the use of TNF inhibitors, including adalimumab. Physicians should exercise caution when considering the use of HADLIMA in patients with existing or recently developed demyelinating disorders of the CNS or peripheral nervous system, and therapy with HADLIMA should be discontinued if such disorders occur. An association between non-infectious intermediate uveitis and demyelinating disorders of the CNS is known. Neurological evaluation should be performed in patients with non-infectious intermediate uveitis before initiating HADLIMA therapy and regularly during therapy to assess for existing signs or development of CNS demyelinating disorders.

Allergic reactions.

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

Immunosuppression.

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

Malignancies and lymphoproliferative disorders.

In controlled clinical trials of TNF inhibitors, malignancies, including lymphoma, were reported more frequently in patients receiving TNF inhibitors, including adalimumab, than in control group patients. However, such events were rare. During post-marketing use of the medicinal product, cases of leukemia have been reported in patients receiving TNF inhibitors. Patients with long-standing, highly active inflammatory rheumatoid arthritis have an increased baseline risk of lymphoma and leukemia, which complicates risk assessment. However, the risk of developing lymphoma, leukemia, or other malignancies in patients receiving TNF inhibitors cannot be excluded.

During post-mark游戏副本

Method of Administration and Dosage

Treatment with the medicinal product HADLIMA must be prescribed by a physician experienced in the diagnosis and management of conditions for which HADLIMA is indicated. Ophthalmologists are advised to consult with the appropriate specialist before prescribing HADLIMA (see section "Special Warnings and Precautions for Use").

Patients receiving HADLIMA should be provided with a patient reminder card. HADLIMA may be self-administered only if the patient or the parents of a child prescribed HADLIMA have been adequately trained by a physician in the injection technique, and the physician has confirmed that self-injection is appropriate.

Concomitant therapies (e.g., corticosteroids and/or immunomodulating agents) should be optimized during treatment with HADLIMA.

Dosage

Rheumatoid Arthritis

The recommended dose of HADLIMA for adult patients with rheumatoid arthritis is 40 mg as a single dose administered subcutaneously once every 2 weeks. Methotrexate therapy should be continued during treatment with HADLIMA.

Concomitant therapy with glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), and analgesics may be continued during treatment with HADLIMA. For use of other disease-modifying antirheumatic drugs (DMARDs) besides methotrexate, see section "Special Warnings and Precautions for Use".

For some patients receiving monotherapy, if there is a diminished response to the 40 mg dose of HADLIMA administered once every 2 weeks, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered.

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

Interruption of Therapy

Consideration should be given to interrupting therapy, for example, prior to surgical procedures or in the event of a serious infection.

Available data indicate that clinical response and safety profile after resuming adalimumab therapy following an interruption of 70 days or more are similar to those observed prior to interruption.

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

The recommended dose of HADLIMA for patients with ankylosing spondylitis, non-radiographic axial spondyloarthritis, and psoriatic arthritis is 40 mg of adalimumab as a single subcutaneous dose once every 2 weeks.

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

Plaque Psoriasis

The recommended dose of HADLIMA for adult patients is: initial dose of 80 mg subcutaneously, followed by 40 mg subcutaneously once every 2 weeks starting one week after the initial dose.

The need for continued therapy should be carefully reassessed in patients who do not show a clinical response within 16 weeks of treatment.

For patients who do not achieve an adequate response with 40 mg of HADLIMA administered once every 2 weeks over 16 weeks of therapy, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered. The continued appropriateness of HADLIMA therapy at 40 mg once weekly or 80 mg once every 2 weeks should be carefully reassessed in patients who do not achieve an adequate response. If an adequate response is achieved with 40 mg once weekly or 80 mg once every 2 weeks, the dose may be gradually reduced to 40 mg once every 2 weeks.

Pyoderma Gangrenosum

The recommended dosing regimen of HADLIMA for adult patients with pyoderma gangrenosum is: initial dose of 160 mg (Day 1) administered as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days, followed by 80 mg at Week 2 (Day 15) as two 40 mg injections in one day. At Week 4 (Day 29), continue with 40 mg once weekly or 80 mg once every 2 weeks, administered as two 40 mg injections in one day. Concomitant antibiotic therapy may be continued during treatment with HADLIMA if necessary. Daily topical antiseptic cleansing of affected areas is also recommended during treatment of pyoderma gangrenosum with HADLIMA.

The need for continued therapy beyond 12 weeks should be carefully reassessed in patients who do not show improvement.

If treatment is interrupted, resumption of HADLIMA at 40 mg once weekly or 80 mg once every 2 weeks may be considered.

Periodic evaluation of the benefit-risk ratio is recommended during long-term treatment.

Crohn's Disease

The recommended induction regimen for HADLIMA in adult patients with moderate to severe Crohn's disease is 80 mg at Week 0, followed by 40 mg at Week 2. If a more rapid response is needed, the following regimen may be used: 160 mg at Week 0 (administered as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg at Week 2 (as two 40 mg injections in one day); however, it should be noted that the risk of adverse reactions may be increased during induction dosing.

After induction therapy, the recommended maintenance dose is 40 mg subcutaneously once every 2 weeks. Alternatively, if a patient has discontinued therapy and symptoms reappear, resumption of HADLIMA may be considered. Experience with re-treatment after discontinuation for more than 8 weeks following the last dose is limited.

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

For some patients who exhibit a diminished response to 40 mg of HADLIMA administered once every 2 weeks, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered.

For some patients who do not achieve a clinical response within 4 weeks of treatment, continuation of maintenance therapy up to 12 weeks may be considered. The need for continued therapy should be reassessed in patients who do not show a response within this period.

Ulcerative Colitis

The recommended induction regimen for HADLIMA in adult patients with moderate to severe ulcerative colitis is 160 mg at Week 0 (administered as four 40 mg injections in one day or two 40 mg injections per day for two consecutive days), followed by 80 mg at Week 2 (as two 40 mg injections in one day). After induction therapy, the recommended dose is 40 mg subcutaneously once every 2 weeks.

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

For some patients who exhibit a diminished response to 40 mg of HADLIMA administered once every 2 weeks, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered.

Available data indicate that a clinical response is usually achieved within 2–8 weeks of treatment. Treatment with HADLIMA should not be continued in patients who do not show a clinical response within this timeframe.

Uveitis

The recommended dose of HADLIMA for adult patients with uveitis is: initial dose of 80 mg, followed by 40 mg once every 2 weeks starting one week after the initial dose.

Limited experience exists with initiating treatment with HADLIMA alone. Treatment with HADLIMA may be initiated in combination with corticosteroids and/or other non-biological immunomodulating agents. Concomitant corticosteroid doses may be tapered according to clinical practice, starting 2 weeks after initiation of HADLIMA. Two weeks after starting combination therapy, transition to HADLIMA monotherapy may be considered gradually, based on clinical experience.

Annual assessment of the benefit-risk ratio during long-term therapy is recommended.

Special Patient Populations

Elderly Patients

Dose adjustment is not required for this patient group.

Renal or Hepatic Impairment

The use of adalimumab in these patient groups has not been studied; therefore, no dosage recommendations can be made.

Pediatrics

HADLIMA in the form of a pre-filled single-use syringe and pre-filled single-use pen is available only in a 40 mg dose. Therefore, use of HADLIMA in the form of a pre-filled single-use syringe or pre-filled single-use pen is not feasible for children requiring a dose less than 40 mg. If an alternative dose is required, other available dosage forms should be used.

Juvenile Idiopathic Arthritis

Polyarticular Juvenile Idiopathic Arthritis

The recommended dose of HADLIMA for children with polyarticular juvenile idiopathic arthritis and body weight ≥30 kg is 40 mg subcutaneously once every 2 weeks.

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

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

Enthesitis-Related Arthritis

The recommended dose of HADLIMA for children with enthesitis-related arthritis and body weight ≥30 kg is 40 mg subcutaneously once every 2 weeks.

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

Pediatric Plaque Psoriasis

The recommended dose of HADLIMA for children with plaque psoriasis and body weight ≥30 kg is: initial dose of 40 mg subcutaneously, followed by 40 mg subcutaneously once every 2 weeks starting one week after the initial dose.

The need for continued therapy should be carefully reassessed in children who do not show a response within 16 weeks of treatment.

If retreatment with HADLIMA 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.

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

Pyoderma Gangrenosum in Adolescents (with body weight ≥30 kg)

There are no clinical studies evaluating the use of adalimumab in adolescents with pyoderma gangrenosum. The dosing regimen in these patients was determined by pharmacokinetic modeling and simulation (see section "Pharmacological Properties. Pharmacodynamics").

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

For adolescents who do not achieve an adequate response with 40 mg of HADLIMA administered once every 2 weeks, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered.

Concomitant antibiotic therapy may be continued during treatment with HADLIMA if necessary. Daily topical antiseptic cleansing of affected areas is also recommended during treatment of pyoderma gangrenosum with HADLIMA.

Treatment should be carefully reassessed in patients who do not show improvement after 12 weeks of therapy.

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

Periodic evaluation of the benefit-risk ratio is recommended during long-term treatment.

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

Crohn's Disease in Children

The recommended induction regimen for HADLIMA in children with Crohn's disease and body weight ≥40 kg is 80 mg at Week 0 and 40 mg at Week 2, administered subcutaneously.

If a more rapid response 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 reactions may be increased during induction dosing.

The maintenance dose, starting at Week 4, is 40 mg subcutaneously once every 2 weeks.

For some children with body weight ≥40 kg who do not achieve an adequate response, dose escalation to 40 mg once weekly or 80 mg once every 2 weeks may be considered.

The need for continued therapy should be carefully reassessed in children who do not show a response within 12 weeks of treatment.

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

Ulcerative Colitis in Children

The recommended dose of HADLIMA for children with ulcerative colitis depends on body weight (see Table 1). HADLIMA is administered subcutaneously.

Table 1

Dosage of HADLIMA for Children with Ulcerative Colitis

* Children who turn 18 years old during treatment with the medicinal product HADLIMA should continue receiving the prescribed maintenance dose.

The necessity of continuing therapy should be carefully reviewed in children who show no response to treatment within 8 weeks.

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

Psoriatic arthritis, axial spondylitis, including ankylosing spondylitis.

Adalimumab is not used for this indication in children.

Pediatric uveitis.

The recommended dose of the medicinal product HADLIMA for children with uveitis and body weight of 30 kg or more is 40 mg administered subcutaneously once every 2 weeks in combination with methotrexate.

There is limited experience with adalimumab use without concomitant methotrexate therapy in children.

The initial loading dose of the medicinal product HADLIMA is 40 mg for children with body weight below 30 kg or 80 mg for children with body weight of 30 kg or more; it may be administered one week prior to initiation of maintenance therapy. There are no clinical data on administration of an initial loading dose of adalimumab to children under 6 years of age (see section "Pharmacological properties. Pharmacodynamics").

The use of adalimumab in children under 2 years of age for uveitis is not justified.

It is recommended to annually evaluate the benefit-risk ratio during long-term treatment.

Administration method

HADLIMA is intended for use under the supervision of a physician.

Patients may self-inject the medicinal product HADLIMA if their physician determines it is appropriate, and provided medical supervision or, if necessary, proper training in subcutaneous injection technique has been received.

HADLIMA is supplied as a single-use pre-filled syringe and a single-use pre-filled pen, each containing a 40 mg dose.

Instructions for self-administration of the medicinal product HADLIMA

Children.

HADLIMA in the form of a prefilled single-use syringe and prefilled single-use pen is available only in a 40 mg dose. Therefore, the use of HADLIMA in the form of a prefilled single-use syringe and prefilled single-use pen is not feasible for children who require a dose lower than 40 mg. If an alternative dose is required, other available dosage forms should be used.

The safety and efficacy of HADLIMA in pediatric patients for indications other than those listed in the section “Indications” have not been established.

The medicinal product should be administered to children according to the recommendations provided in the section “Dosage and administration”.

Overdose.

During clinical studies of adalimumab, no cases of dose-limiting toxicity were observed. The highest doses studied were multiple intravenous doses of 10 mg/kg, approximately 15 times higher than the recommended dose.

Adverse Reactions

Adalimumab has been studied in pivotal controlled and open-label trials involving 9,506 patients for 60 months or longer. The studies included patients with early and longstanding rheumatoid arthritis, juvenile idiopathic arthritis (polyarticular juvenile idiopathic arthritis and enthesitis-related arthritis), axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis), psoriatic arthritis, Crohn’s disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. In the pivotal controlled trials, 6,089 patients received adalimumab and 3,801 patients received placebo or active comparator during the controlled period.

During the double-blind controlled period of the pivotal studies across all indications, 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 associated with adalimumab have been reported. Tumor necrosis factor (TNF) inhibitors, such as adalimumab, affect the immune system, and their use may lead to decreased resistance to infections and cancer.

During treatment with adalimumab, infections that may be life-threatening or result in fatal outcomes (including sepsis, opportunistic infections, and tuberculosis), reactivation of hepatitis B virus, and development of various malignancies (including leukemia, lymphoma, and hepatosplenic T-cell lymphoma) have been reported.

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

Adverse reactions observed during clinical trials and post-marketing use of adalimumab are listed by system organ class and frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); frequency not known (cannot be estimated from available data) (see Table 2). Within each category, adverse reactions are listed in order of decreasing severity. The highest frequency across different indications is included.

Table 2

* See details in sections «Contraindications», «Special precautions» and «Adverse reactions».

** Including the open-label period of extended studies.

1. Including data from spontaneous reporting.
2. Change in mean body weight from baseline in the adalimumab treatment group ranged from 0.3 kg to 1.0 kg across all indications in adult patients and from –0.4 kg to 0.4 kg in the placebo group during the 4–6 month treatment period. Weight gain of 5–6 kg was also observed in long-term extension studies with a mean exposure duration of approximately 1–2 years in the adalimumab treatment group (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.

Children.

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

Hidradenitis suppurativa.

The safety profile for patients with hidradenitis suppurativa receiving adalimumab once weekly was consistent with the established safety profile of adalimumab.

Uveitis.

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

Specific adverse reactions

Injection site reactions.

In the main controlled clinical studies in adults and children, injection site reactions (erythema and/or pruritus, haemorrhage, pain or swelling) occurred in 12.9% of patients receiving adalimumab compared with 7.2% of patients receiving placebo or active control. Most injection site reactions did not require discontinuation of the medicinal product.

Infections.

In the main controlled studies in adults and children, the incidence rate of infections was 1.51/patient-year in patients receiving adalimumab and 1.46/patient-year in patients receiving placebo or active control. The most common infections were nasopharyngitis, upper respiratory tract infections and sinusitis. Most patients continued adalimumab treatment after resolution of the infection.

The incidence rate of serious infections was 0.04/patient-year in patients receiving adalimumab and 0.03/patient-year in patients receiving placebo or active control.

In controlled and open-label studies in adults and children, serious infections (rarely with fatal outcome) have been reported during adalimumab treatment, including tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (e.g. disseminated histoplasmosis, blastomycosis, coccidioidomycosis, Pneumocystis jirovecii pneumonia, candidiasis, aspergillosis and listeriosis). Most cases of tuberculosis occurred within the first eight months after initiation of therapy and may represent reactivation of latent disease.

Malignant neoplasms and lymphoproliferative disorders.

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

During the controlled period of the main studies of adalimumab in adults for at least 12 weeks in patients with moderate to high disease activity rheumatoid arthritis, ankylosing spondylitis, non-radiographically confirmed axial spondyloarthritis, psoriatic arthritis, plaque psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis and uveitis, the incidence rate of malignancies, excluding lymphoma and non-melanoma skin cancer, was (95% confidence interval) 6.8 (4.4; 10.5)/1000 patient-years in 5291 patients receiving adalimumab compared with 6.3 (3.4; 11.8)/1000 patient-years in 3444 patients in the control group (mean duration of treatment was 4.0 months in the adalimumab group and 3.8 months in the control group). The incidence rate of non-melanoma skin cancer (95% confidence interval) was 8.8 (6.0; 13.0)/1000 patient-years in patients receiving adalimumab and 3.2 (1.3; 7.6)/1000 patient-years in control group patients. The incidence rate of squamous cell carcinoma (95% confidence interval) was 2.7 (1.4; 5.4)/1000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5)/1000 patient-years in control group patients. The incidence rate of lymphoma (95% confidence interval) was 0.7 (0.2; 2.7)/1000 patient-years in patients receiving adalimumab and 0.6 (0.1; 4.5)/1000 patient-years in control group patients.

In controlled and open-label extension studies with a duration of approximately 3.3 years, including 6427 patients and more than 26439 patient-years of therapy, the incidence rate of malignancies, excluding lymphoma and non-melanoma skin cancer, was approximately 8.5/1000 patient-years. The incidence rate of non-melanoma skin cancer was approximately 9.6/1000 patient-years, and the incidence rate of lymphoma was approximately 1.3/1000 patient-years.

During post-marketing use from January 2003 to December 2010, predominantly in patients with rheumatoid arthritis, the incidence rate of malignancies was approximately 2.7/1000 patient-years. The incidence rates of non-melanoma skin cancer and lymphoma were approximately 0.2 and 0.3/1000 patient-years, respectively (see section «Special precautions»).

During post-marketing use of the medicinal product, isolated cases of hepatosplenic T-cell lymphoma have been reported in patients receiving adalimumab (see section «Special precautions»).

Autoantibodies.

During phases I–V rheumatoid arthritis studies, serum samples were analysed for autoantibodies at various time points. In these studies, a positive titre was detected at week 24 in 11.9% of patients receiving adalimumab and in 8.1% of patients receiving placebo or active control who had a negative baseline titre of antinuclear antibodies. In 2 out of 3441 patients with rheumatoid arthritis and psoriatic arthritis receiving adalimumab in clinical studies, signs of newly diagnosed lupus-like syndrome developed, which resolved after discontinuation of treatment. No patient developed lupus nephritis or symptoms of central nervous system involvement.

Hepatobiliary disorders.

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

In phase III controlled clinical studies of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 4 to 17 years and children with enthesitis-related arthritis aged 6 to 17 years, elevation of ALT levels to 3 or more times ULN was observed in 6.1% of children receiving adalimumab and in 1.3% of children in the control group. Most cases of ALT elevation occurred with concomitant methotrexate use. In the phase III clinical study of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years, elevation of ALT levels to 3 or more times ULN was not observed.

In phase III controlled clinical studies of adalimumab in patients with Crohn’s disease and ulcerative colitis during the controlled period of 4 to 52 weeks, elevation of ALT levels to 3 or more times ULN was observed in 0.9% of patients in both groups.

In the phase III clinical study of adalimumab in children with Crohn’s disease, evaluating the efficacy and safety of two weight-based maintenance dosing regimens followed by a weight-based induction dosing regimen up to 52 weeks of therapy, elevation of ALT levels to 3 or more times ULN was observed in 2.6% (5/192) of children, of whom 4 were concomitantly receiving immunosuppressants at baseline.

In phase III controlled clinical studies of adalimumab in patients with plaque psoriasis during the controlled period of 12 to 24 weeks, elevation of ALT levels to 3 or more times ULN was observed in 1.8% of patients in both groups.

In the phase III clinical study in children with plaque psoriasis, elevation of ALT levels to 3 or more times ULN was not observed.

In controlled clinical studies of adalimumab (initial dose 160 mg at week 0 and 80 mg at week 2, then 40 mg once weekly starting at week 4) in patients with hidradenitis suppurativa during the controlled period of 12 to 16 weeks, elevation of ALT levels to 3 or more times ULN was observed in 0.3% of patients receiving adalimumab and in 0.6% of patients in the control group.

In controlled clinical studies of adalimumab (initial dose 80 mg at week 0, then 40 mg every two weeks starting at week 1) in adult patients with uveitis over 80 weeks with mean exposure durations of 166.5 days and 105 days in the adalimumab treatment group and control group, respectively, elevation of ALT levels to 3 or more times ULN was observed in 2.4% of patients in both groups.

In the phase III controlled clinical study of adalimumab in children with ulcerative colitis (n = 93), evaluating the efficacy and safety of maintenance therapy dosing of 0.6 mg/kg (up to 40 mg) every two weeks (n = 31) and 0.6 mg/kg (up to 40 mg) once weekly (n = 32), followed by a weight-based induction dosing regimen of 2.4 mg/kg (up to 160 mg) at week 0 and week 1 and 1.2 mg/kg (up to 80 mg) at week 2 (n = 63) or followed by a weight-based induction dosing regimen of 2.4 mg/kg (up to 160 mg) at week 0, placebo at week 1 and 1.2 mg/kg (up to 80 mg) at week 2 (n = 30), elevation of ALT levels to 3 or more times ULN was observed in 1.1% (1/93) of children.

Across all indications in clinical studies, patients had asymptomatic elevations in ALT levels, and in most cases, these elevations were transient and resolved during long-term treatment. However, there have been rare post-marketing reports of liver failure and less severe hepatic disorders that may lead to liver failure, such as hepatitis, including autoimmune hepatitis, in patients receiving adalimumab.

Concomitant therapy with azathioprine/6-mercaptopurine.

In studies in adult patients with Crohn’s disease who received adalimumab concomitantly with azathioprine/6-mercaptopurine, an increased frequency of adverse reactions related to malignancies and serious infections was observed compared to patients receiving adalimumab alone.

Reporting of suspected adverse reactions.

Reporting of adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

42 months.

Storage conditions.

Store in a refrigerator (at 2 to 8 ºC) in the original packaging to protect from light. Do not freeze.

Storage at temperatures not exceeding 25 °C for up to 28 days in a light-protected place is permitted. Do not use after 28 days from removal from the refrigerator (even if the medicinal product was returned to the refrigerator).

Keep out of reach of children.

Incompatibilities.

Due to the lack of compatibility studies, HADLIMA should not be mixed with other medicinal products.

Packaging.

0.8 ml in a pre-filled single-use syringe made of Type I glass with a stainless steel needle, needle cap with rigid sheath and rubber stopper; 2 pre-filled single-use syringes with protective housings, finger rests and piston rods in a standard export pack in a cardboard box, or 2 pre-filled single-use pens containing pre-filled single-use syringes in a standard export pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Samsung Bioepis NL B.V.

Manufacturer’s address and place of business.

Olof Palmestraat 10, Delft, 2616 LR, Netherlands.

Marketing authorization holder.

SAMSUNG BIOEPIS CO., LTD.

Address of the marketing authorization holder.

76, Sondogjuk-ro, Yeonsu-gu, Incheon, Republic of Korea.