Humira

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HUMIRA® (Humira®)

Composition:

Active substance: adalimumab;

One pre-filled single-dose syringe contains 20 mg of adalimumab in 0.2 mL of solution;

Excipients: mannitol (E 421), polysorbate 80, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless aqueous solution ranging from clear to opalescent, practically free from foreign particles.

Pharmacotherapeutic group.

Immunosuppressants. Tumor necrosis factor-alpha inhibitors. Adalimumab.

ATC code L04AB04.

Pharmacological Properties

HUMIRA® (adalimumab) is a recombinant human immunoglobulin (IgG1), a monoclonal antibody composed exclusively of human peptide sequences. HUMIRA® was developed using phage display technology, which enabled the production 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. HUMIRA® binds with high affinity and specificity to soluble TNF-alpha, but not to lymphotoxin (TNF-beta). HUMIRA® is produced by recombinant DNA technology using a mammalian cell expression system. It consists of 1300 amino acids and has a molecular weight of approximately 148 kilodaltons.

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

Adalimumab also modulates biological responses induced or regulated by TNF, including changes in levels of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 at IC50 1–2 × 10⁻¹⁰ M).

Pharmacodynamics

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

Pharmacokinetics

Absorption and Distribution

After a single subcutaneous dose of 40 mg of HUMIRA®, absorption and distribution of adalimumab were slow, with median peak serum concentration 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%.

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

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

After subcutaneous administration of HUMIRA® at 24 mg/m² (maximum 40 mg) every 2 weeks in patients with polyarticular JIA aged 4 to 17 years, steady-state concentrations (measured between weeks 20 and 48) were 5.6 ± 5.6 µg/mL (102% CV) without concomitant methotrexate and 10.9 ± 5.2 µg/mL (47.7% CV) with methotrexate.

In children with polyarticular JIA aged 2–4 years and in children aged ≥4 years with body weight <15 kg, following administration of HUMIRA® at 24 mg/m² with methotrexate, mean steady-state concentrations were 7.9 ± 5.6 µg/mL (101% CV).

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

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 HUMIRA® at 0.8 mg/kg (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 HUMIRA® at 160 mg at week 0 followed by 80 mg at week 2, serum concentrations were approximately 7–8 µg/mL at weeks 2 and 4. Mean steady-state concentrations from week 12 to week 36 were approximately 8–10 µg/mL during weekly administration of HUMIRA® at 40 mg.

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. Because the effect of adalimumab may depend on body weight, adolescents with high body weight and inadequate response to treatment may be given the recommended adult dose of 40 mg once weekly.

In patients with Crohn’s disease, after administration of HUMIRA® at 80 mg at week 0 followed by 40 mg at week 2, serum concentration was approximately 5.5 µg/mL during induction therapy. After administration of HUMIRA® at 160 mg at week 0 followed by 80 mg at week 2, serum concentration was approximately 12 µg/mL during induction therapy. Mean steady-state concentration was approximately 7 µg/mL during maintenance therapy with HUMIRA® at 40 mg every 2 weeks.

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

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

In patients with uveitis, after administration of HUMIRA® 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 adalimumab initial dosing in children under 6 years of age. It is predicted that in the absence of methotrexate, the initial dose may increase systemic exposure to adalimumab.

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. Serum levels of free adalimumab (not bound to anti-adalimumab antibodies (AAA)) were lower in patients who developed AAA. The use of HUMIRA® has not been studied in patients with hepatic or renal impairment.

Pediatric Use

The safety and efficacy of HUMIRA® in children for indications other than those specified in the "Indications" section have not been established.

Clinical characteristics.

Indications.

Juvenile rheumatoid (idiopathic) arthritis (JIA)

Polyarticular juvenile idiopathic arthritis

HUMIRA® 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 disease-modifying antirheumatic drugs (DMARDs).

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

Enthesitis-related arthritis

HUMIRA® 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 in whom there is intolerance to or medical contraindications for such therapies.

Pediatric Crohn’s disease (CD)

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

Pediatric plaque psoriasis (PP)

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

Pediatric uveitis

HUMIRA® is indicated for the treatment of chronic non-infectious anterior uveitis in children aged 2 years and older who have not responded to or are intolerant of conventional therapy, or for whom conventional therapy is contraindicated.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

• HUMIRA® has been studied in patients with RA, JIA, and PsA receiving the drug as monotherapy or concomitantly with methotrexate. The rate of antibody formation was lower when HUMIRA® was used concomitantly with methotrexate compared to monotherapy. Administration of HUMIRA® without methotrexate resulted in increased antibody formation, increased clearance, and reduced efficacy of adalimumab (see section "Pharmacodynamics").
• Concomitant use of HUMIRA® with anakinra is not recommended (see section "Special precautions. Concomitant use with biologic DMARDs or TNF antagonists").
• Concomitant use of HUMIRA® with abatacept is not recommended (see section "Special precautions. Concomitant use with biologic DMARDs or TNF antagonists").

Special precautions for use.

Traceability

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

Infections

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

Humira® must 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 have returned from countries with a high incidence of tuberculosis or from endemic areas for fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis, the benefit-risk ratio should be carefully evaluated before initiating Humira® therapy (see below "Other opportunistic infections").

A thorough evaluation and close monitoring are required in patients who develop a new infection during Humira® therapy. Treatment should be discontinued in case of severe infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled. Physicians should exercise caution when considering Humira® therapy in patients with a history of recurrent infections or underlying conditions (including concomitant use of immunosuppressive agents) that may predispose to infections.

Serious infections

Serious infections, including sepsis caused by bacterial, mycobacterial, invasive fungal, parasitic, viral, or other opportunistic infections such as listeriosis, legionellosis, and pneumocystosis, have been reported in patients receiving Humira®.

Other serious infections observed during clinical trials include pneumonia, pyelonephritis, septic arthritis, and septicemia. Hospitalizations and fatal outcomes associated with infections have been reported.

Tuberculosis

Cases of tuberculosis reactivation and new-onset tuberculosis, including pulmonary and extrapulmonary forms (e.g., disseminated tuberculosis), have been reported in patients receiving Humira® therapy.

Before initiating Humira® therapy, patients should be thoroughly evaluated for active and inactive (latent) tuberculosis. The evaluation should include a comprehensive assessment of the patient’s history of tuberculosis or exposure to individuals with active tuberculosis, as well as prior and/or concomitant immunosuppressive therapy. All patients should undergo a tuberculin skin test (Mantoux test) and chest X-ray before starting therapy (local guidelines may apply). It is recommended that the results of these tests be recorded in the patient’s medical record. Prescribing physicians should be aware of the risk of false-negative tuberculin skin test results, particularly in severely ill or immunocompromised patients.

Humira® therapy must not be initiated if active tuberculosis is diagnosed (see section "Contraindications").

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

If latent tuberculosis is suspected, consultation with a physician experienced in tuberculosis management is recommended.

If latent tuberculosis is diagnosed before starting Humira® therapy, specific anti-tuberculosis prophylactic treatment should be initiated according to local guidelines.

Anti-tuberculosis prophylaxis should be considered before initiating Humira® therapy in patients at risk of tuberculosis infection but with negative latent tuberculosis test results, and in patients with a history of latent or active tuberculosis who have not received adequate treatment.

Despite prophylactic anti-tuberculosis therapy, cases of tuberculosis reactivation have occurred in patients receiving Humira®. Recurrent tuberculosis has also been observed in some patients who previously completed successful treatment for active tuberculosis while receiving Humira®.

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

Other opportunistic infections

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

Patients receiving TNF blockers are more prone to develop serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, etc. Humira® therapy should be discontinued immediately if a patient develops fever, malaise, weight loss, increased sweating, cough, dyspnea, pulmonary infiltrates, or other signs of a serious systemic illness (with or without shock), and invasive fungal infection should be suspected. The decision to initiate empirical antifungal therapy in such patients should be made in consultation with a specialist in the diagnosis and treatment of invasive fungal infections.

Hepatitis B reactivation

Cases of hepatitis B reactivation have occurred in patients receiving TNF blockers who were chronic carriers of hepatitis B virus (HBV), i.e., those with detectable surface antigen. Some cases were fatal. Before initiating Humira® therapy, patients should be tested for HBV infection. Patients with a positive HBV test are advised to consult a physician experienced in hepatitis B management.

HBV carriers requiring Humira® therapy should be closely monitored for signs and symptoms of active HBV infection during therapy and for several months after discontinuation. There are insufficient data on treating HBV carriers with antiviral agents in combination with TNF antagonists to prevent HBV reactivation. Patients who develop HBV reactivation should discontinue Humira® and initiate effective antiviral therapy with appropriate supportive treatment.

Neurological disorders

During the use of TNF blockers, including Humira®, isolated cases of onset or exacerbation of clinical symptoms 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. Physicians prescribing the medicinal product should carefully consider the potential use of Humira® in patients with prior or recent-onset demyelinating disorders of the central or peripheral nervous system; therapy with Humira® should be discontinued if such disorders occur. Intermediate uveitis is known to be associated with demyelinating disorders of the central nervous system. Neurological evaluation should be performed in patients with non-infectious intermediate uveitis before initiating Humira® therapy and regularly during treatment to monitor for the development of prior or newly occurring demyelinating disorders of the central nervous system.

Allergic reactions

During clinical trials, serious allergic reactions associated with Humira® were rare. Non-serious allergic reactions associated with Humira® were infrequent during clinical trials.

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

Immunosuppression

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

Malignancies and lymphoproliferative disorders

In controlled clinical trials of TNF blockers, malignancies, including lymphoma, were reported more frequently in patients receiving a TNF blocker than in control group patients. However, this phenomenon was rare. During the post-marketing period, cases of leukemia have been reported in patients receiving TNF antagonists. Patients with long-standing, highly active rheumatoid arthritis have an increased background risk of developing lymphoma and leukemia, complicating risk assessment. Available data do not allow exclusion of the risk of lymphoma, leukemia, and other malignancies in patients receiving TNF antagonists.

During the post-marking period, isolated cases of malignancies, sometimes fatal, have been reported in children, adolescents, and young adult patients (up to 22 years of age) who received treatment with TNF blockers (therapy initiation at age ≤ 18 years), including adalimumab. In approximately half of these cases, the malignancies were lymphomas. Other cases included various types of malignancies, including those typically associated with immunosuppression. The risk of malignancy development in children and adolescents receiving TNF antagonists cannot be excluded.

During the post-marketing period, very rare cases of hepatosplenic T-cell lymphoma have been reported in patients receiving adalimumab. This rare type of lymphoma is characterized by a highly aggressive course and is usually fatal. Some of these cases of hepatosplenic T-cell lymphoma associated with Humira® occurred in young adult patients who received concomitant therapy with azathioprine or 6-mercaptopurine for inflammatory bowel disease. The potential risk of concomitant use of azathioprine or 6-mercaptopurine with Humira® should be carefully evaluated. The risk of hepatosplenic T-cell lymphoma in patients taking Humira® cannot be excluded (see section "Adverse reactions").

No studies have been conducted on the use of Humira® in patients with a history of malignancies or on continuing Humira® therapy in patients who develop malignancies. This should be taken into account, and decisions on prescribing Humira® to such patients should be made cautiously (see section "Adverse reactions").

All patients, especially those with a history of intensive immunosuppressive therapy and patients with psoriasis who have undergone PUVA therapy, should be screened for non-melanoma skin cancer before and during Humira® therapy. Cases of 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 blocker (infliximab) in patients with moderate to severe chronic obstructive pulmonary disease (COPD), a higher incidence of malignancies, mostly in the lungs, head, and neck area, was reported compared to the control group. All patients were long-term smokers. Therefore, TNF blockers should be used cautiously in patients with chronic obstructive pulmonary disease and in patients at increased risk of malignancy due to smoking.

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

Hematological disorders

Rarely, the use of TNF blockers has been associated with the development of pancytopenia, including aplastic anemia. Adverse reactions related to the blood system, including clinically significant cytopenias (e.g., thrombocytopenia, leukopenia), have been reported with Humira®. 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 Humira® therapy. Discontinuation of Humira® should be considered if serious hematological abnormalities are confirmed in a patient.

Vaccination

In a study involving 226 adult patients with rheumatoid arthritis receiving adalimumab or placebo, a similar humoral response to the standard 23-valent pneumococcal vaccine and trivalent influenza vaccine was observed. Data on secondary transmission of infection to patients receiving live vaccines and Humira® are lacking.

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

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.

Chronic heart failure (CHF)

In clinical trials with another TNF blocker, worsening of CHF and increased CHF-related mortality were reported. Cases of worsening CHF have also been reported in patients receiving Humira® therapy. Humira® should be used with caution in patients with mild heart failure (NYHA class I/II). Humira® is contraindicated in patients with moderate to severe CHF (see section "Adverse reactions"). Humira® therapy should be discontinued if a patient develops new or worsening symptoms of chronic heart failure.

Autoimmune processes

Treatment with Humira® may lead to the development of autoantibodies. The impact of long-term Humira® use on the development of autoimmune diseases is unknown. If symptoms suggestive of lupus-like syndrome occur after starting Humira® therapy, along with positive anti-double-stranded DNA antibody test results, Humira® therapy should be discontinued.

Concomitant use with biological DMARDs or other TNF antagonists

Serious infections were observed during clinical trials of concomitant use of anakinra and another TNF antagonist, etanercept, which provided no therapeutic advantage compared to etanercept monotherapy. Given the nature of adverse events observed during combination therapy with etanercept and anakinra, similar toxicity may occur with the combination of anakinra and another TNF blocker. Therefore, the combination of adalimumab and anakinra is not recommended.

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 Humira®. The long half-life of adalimumab should be considered when planning surgery. A patient requiring surgery while on Humira® therapy should be thoroughly evaluated for infections and appropriate measures taken. Limited data are available on the safety of use in patients undergoing arthroplasty during Humira® 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 Humira® therapy does not cause the development or progression of strictures.

Elderly patients

The incidence of serious infections in patients aged 65 years and older receiving Humira® (3.7%) is higher than in younger patients (1.5%). Some cases were fatal. Particular attention should be paid to assessing the risk of infection when treating elderly patients.

Children

See subsection “ Vaccination ” above.

Use during pregnancy or breastfeeding.

Women of reproductive age

Women of reproductive age should use reliable contraception methods during treatment and for at least five months after the last dose of Humira®.

Pregnancy

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

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

In experimental toxicity studies in monkeys, no signs of maternal toxicity, embryotoxicity, or teratogenicity were observed. Preclinical data on postnatal toxicity of adalimumab are lacking.

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

Adalimumab can cross the placenta and be detected in the serum of newborns whose mothers received adalimumab during pregnancy. Therefore, these newborns may have an increased risk of infection. 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 maternal serum levels. Since immunoglobulin G proteins undergo proteolytic degradation in the gastrointestinal tract and have low systemic bioavailability, systemic effects of adalimumab on breastfed infants are unlikely. Therefore, Humira® may be used during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

Treatment with the medicinal product HUMIRA® should be prescribed by a physician experienced in the diagnosis and treatment of diseases for which HUMIRA® is indicated. Ophthalmologists are advised to consult with the appropriate specialist before prescribing therapy with the medicinal product HUMIRA®. The medicinal product HUMIRA® may be self-administered only if the patient or the parents of a child prescribed HUMIRA® therapy have received appropriate training from a physician on the injection technique, and the physician has confirmed that self-injection is appropriate. Additionally, the information on self-injection provided in this instruction must be carefully reviewed. The patient or the parents of a child prescribed HUMIRA® therapy should read the informational card. During treatment with HUMIRA®, concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be re-evaluated.

Juvenile Rheumatoid (Idiopathic) Arthritis (JRA)

Polyarticular Juvenile Rheumatoid (Idiopathic) Arthritis

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

Table 1. Dosing of HUMIRA® for patients with polyarticular JRA

| Body weight | Dose | |-------------|------| | < 10 kg | Not recommended | | ≥ 10 kg to < 15 kg | 10 mg every 2 weeks | | ≥ 15 kg to < 30 kg | 20 mg every 2 weeks | | ≥ 30 kg | 40 mg every 2 weeks |

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

The medicinal product HUMIRA® is not recommended for use in children under 2 years of age for this indication.

The medicinal product HUMIRA® is available in other dosage strengths depending on individual treatment needs.

Enthesitis-related arthritis

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

Table 2. Dosing of the medicinal product HUMIRA® for patients with enthesitis-related arthritis

The use of HUMIRA® in children under 6 years of age with enthesitis-related arthritis has not been studied. HUMIRA® is available in other dosage strengths depending on individual treatment needs.

Crohn’s Disease in Children

The recommended dose of HUMIRA® for patients aged 6 to 17 years with Crohn’s disease depends on body weight (Table 3). HUMIRA® is administered subcutaneously.

Table 3. Dosing of HUMIRA® for children with Crohn’s disease

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

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

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

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

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

Plaque psoriasis in children

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

Table 4. Dosing of Humira® in children with plaque psoriasis

Careful consideration should be given to the need for continuing therapy in patients who have not shown a clinical response within 16 weeks. If retreatment with HUMIRA® is indicated, the dosing regimen described above should be followed. The safety of HUMIRA® in children with plaque psoriasis has been studied for a mean duration of 13 months.

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

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

Uveitis in children

The recommended dose of HUMIRA® for children aged 2 years and older with chronic non-infectious uveitis depends on body weight (Table 5). HUMIRA® is administered by subcutaneous injection. There are no data on the use of HUMIRA® without concomitant methotrexate therapy in children with uveitis.

Table 5. Dosing of HUMIRA® in children with uveitis

The medicinal product Humira® can be used in combination with methotrexate or other non-biological immunomodulating agents according to clinical experience. The initial loading dose of Humira® is 40 mg for patients with body weight below 30 kg and 80 mg for patients with body weight of 30 kg or more; this dose may be administered one week prior to starting maintenance therapy. There are no clinical data on administration of the initial loading dose of Humira® to children under 6 years of age. The use of Humira® in children under 2 years of age for this indication is not justified. It is recommended to evaluate the benefit and risk of long-term treatment annually. Humira® is available in other dosage strengths depending on individual treatment needs.

Geriatric patients

Dose adjustment for this patient group is not required.

Hepatic and/or renal impairment

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

Administration

Humira® must be used under the supervision of a physician. With a physician's approval, patients or their parents/caregivers may self-administer the medication after appropriate training in the technique of subcutaneous injection.

Children.

Indicated for use in children according to the section "Indications".

Overdose.

The maximum tolerated dose of the medicinal product Humira® in humans has not been established. In clinical studies of adalimumab, there were no cases of dose-limiting toxicity. Multiple doses of up to 10 mg/kg were administered to patients without associated signs of toxicity related to overdose. In the event of overdose, patients should be monitored for the appearance of any symptoms of adverse reactions, and appropriate symptomatic treatment should be initiated immediately.

Adverse reactions.

General information on safety profile

The medicinal product HUMIRA® was studied in controlled clinical trials and open-label trials lasting approximately 60 months or longer, involving 9506 patients. These studies included patients with early and long-standing 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 were obtained during the main controlled trials, in which 6089 patients received HUMIRA® and 3801 patients received placebo or a comparator drug during the controlled period.

During the main clinical trials, 5.9% of patients receiving HUMIRA® 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 the use of HUMIRA®. TNF antagonists, such as HUMIRA®, affect the immune system; their use may lead to decreased resistance to infections and malignancies.

During the use of HUMIRA®, infections that may be life-threatening and may lead to death (including sepsis, opportunistic infections, and tuberculosis), reactivation of hepatitis B, 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. These reactions included individual cases of pancytopenia, aplastic anemia, cases of central and peripheral demyelinating disorders, development of lupus, lupus-like syndromes, and Stevens-Johnson syndrome.

Children

Overall, adverse reactions in children were similar in frequency and type to those observed in adult patients.

Tabulated list of adverse reactions

Table 6 presents a list of adverse reactions observed during clinical trials and post-marketing surveillance, categorized by system organ class and frequency of occurrence: ≥ 1/10 – very common; ≥ 1/100 to < 1/10 – common; ≥ 1/1000 to < 1/100 – uncommon; ≥ 1/10000 to < 1/1000 – rare.

Table 6. Adverse reactions

* See sections "Contraindications", "Special precautions", "Side effects".

** Including open-label periods of studies.

1. Including data from spontaneous reports.

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

Uveitis

The safety profile for patients with uveitis receiving Humira® every two weeks was consistent with the known safety profile of Humira®.

Description of selected adverse reactions

Injection site reactions

In controlled clinical trials in adults and children receiving Humira®, injection site reactions (erythema and/or pruritus, bruising, pain or swelling) occurred in 12.9% of cases, compared to 7.2% in placebo or active control groups. Injection site reactions generally did not require discontinuation of the drug.

Infections

In controlled clinical trials in adults and children, the rate of infections was 1.51/patient-year in the group receiving Humira® and 1.46/patient-year in placebo or active control groups. These were mostly nasopharyngitis, upper respiratory tract infections, and sinusitis. Most patients continued treatment with Humira® after recovery.

The rate of serious infections was 0.04/patient-year in the group receiving Humira® and 0.03/patient-year in placebo or active control groups. In controlled and open-label trials in adults and children, severe infections (rarely with fatal outcome) were reported, including tuberculosis (including miliary and extrapulmonary forms) and invasive opportunistic infections (e.g., disseminated or extrapulmonary histoplasmosis, blastomycosis, coccidioidomycosis, Pneumocystis pneumonia, candidiasis, aspergillosis, listeriosis). Most cases of tuberculosis occurred within the first eight months after initiation of therapy and may represent reactivation of latent disease.

Neoplasms and lymphoproliferative disorders

During clinical trials of adalimumab in children with JIA (juvenile idiopathic 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), or uveitis (n = 60; 58.4 patient-years).

During controlled periods of pivotal trials of Humira® in adults for at least 12 weeks in patients with moderate to high disease activity rheumatoid arthritis, axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis), psoriatic arthritis, psoriasis, hidradenitis suppurativa, Crohn’s disease, ulcerative colitis, and uveitis, the rate of neoplasms (excluding lymphoma and non-melanoma skin cancer) was (95% confidence interval) 6.8 (4.4; 10.5) per 1000 patient-years in 5291 patients receiving Humira®, compared to 6.3 (3.4; 11.8) per 1000 patient-years in 3444 control group patients (mean duration of treatment was 4.0 months in the Humira® 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 Humira® and 3.2 (1.3; 7.6) per 1000 patient-years in control group patients. Among reported cases, the incidence of squamous cell carcinoma of the skin (95% confidence interval) was 2.7 (1.4; 5.4) per 1000 patient-years in patients receiving Humira® 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 Humira® and 0.6 (0.1; 4.5) per 1000 patient-years in control group patients.

The incidence of neoplasms (excluding lymphoma and non-melanoma skin cancer) was approximately 8.5/1000 patient-years when combining data from controlled and ongoing or completed open-label trials. In this pooled analysis, the median observation period was approximately 3.3 years, including 6427 patients and more than 26,439 patient-years of therapy. The incidence of non-melanoma skin cancer was approximately 9.6/1000 patient-years, and the incidence of lymphomas was approximately 1.3/1000 patient-years.

During post-marketing surveillance from January 2003 to December 2010, primarily in patients with rheumatoid arthritis, the rate of spontaneously reported malignancies was approximately 2.7 per 1000 patient-years of treatment. The reported incidence of non-melanoma skin cancer and lymphomas was approximately 0.2 and 0.3 per 1000 patient-years of treatment, respectively (see section "Special precautions").

Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients receiving adalimumab (see section "Special precautions").

Autoantibodies

During phases 1–5 clinical trials in rheumatoid arthritis, patients were tested multiple times for autoantibodies. In these trials, among patients who initially had negative antinuclear antibody titers, positive titers were reported at week 24 in 11.9% of patients receiving Humira® and 8.1% of patients in placebo or active control groups.

In two of 3441 patients receiving Humira® across all RA and PsA clinical trials, signs of newly developed lupus-like syndrome emerged. Their condition improved after discontinuation of therapy. None of the patients developed lupus nephritis or central nervous system involvement.

Liver enzyme activity

In phase 3 controlled clinical trials in patients with rheumatoid arthritis and psoriatic arthritis, during controlled periods lasting 4 to 104 weeks, ALT (alanine aminotransferase) elevations ≥3 times the upper limit of normal were observed in 3.7% of patients receiving Humira® and 1.6% of control group patients.

In phase 3 controlled clinical trials in patients aged 4–17 years with polyarticular juvenile idiopathic 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 Humira® and 1.3% of control group patients. Most cases of ALT elevation occurred during concomitant methotrexate therapy. No ALT elevations ≥3 times the upper limit of normal were observed in phase 3 clinical trials in patients with polyarticular juvenile idiopathic arthritis aged 2 to 4 years.

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

In a phase 3 clinical trial in children with Crohn’s disease evaluating the efficacy and safety of a weight-based dosing regimen followed by a weight-based maintenance regimen with 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 were receiving Humira® concomitantly with immunosuppressants.

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

In phase 3 clinical trials in children with plaque psoriasis, no ALT elevations ≥3 times the upper limit of normal were observed.

In controlled clinical trials of Humira® in adult patients with uveitis lasting up to 80 weeks (initial dose 80 mg at week 0 and 40 mg once every 2 weeks starting at week 1), with a median treatment duration of 166.5 days in the Humira® group and 105.0 days in the control group, ALT elevations ≥3 times the upper limit of normal were observed in 2.4% of patients in both the Humira® and control groups.

Across clinical trials for all indications, patients experienced asymptomatic ALT elevations, which were mostly transient and resolved while continuing treatment. However, post-marketing reports of cases 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 trials in adult patients with Crohn’s disease receiving Humira® in combination with azathioprine/6-mercaptopurine, increased frequencies of neoplasms and serious infections were observed compared to patients receiving Humira® monotherapy.

Reporting suspected adverse reactions

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

Shelf life: 2 years.

Do not use the medicinal product after the expiry date.

Storage conditions.

Store out of reach and sight of children at 2 to 8 °C (in a refrigerator), in the original carton. Do not freeze.

Storage at room temperature (not above 25 °C) for up to 14 days in a place protected from light is permitted. Do not use the product more than 14 days after removal from the refrigerator (even if the product was returned to the refrigerator).

Packaging.

0.2 mL of solution in a pre-filled single-dose syringe.

One syringe together with one wipe impregnated with 70% isopropyl alcohol is placed in a blister pack. Two syringes (each in a blister pack with one wipe) are placed in a cardboard box.

Prescription status: Prescription only.

Manufacturer.

Batch release.

AbbVie Biotechnology GmbH, Germany.

Manufacturer's address.

Knollstrasse, 67061 Ludwigshafen, Germany.