Modern approaches to the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic immune-mediated systemic inflammatory disease of connective tissue. It occurs in approximately 1% of the total population. The disease develops at any age, but most often between 45–60 years. Women develop rheumatoid arthritis approximately 3 times more often than men. In Russia, approximately 300,000 people suffer from it. The Yusupov Hospital has all the conditions for the treatment of patients suffering from rheumatoid arthritis:

• Cozy rooms with a European level of comfort;
• Timely diagnosis of the disease;
• Use of the latest drugs and non-drug therapies.

The development and progression of the pathological process in the joints occurs during the first years of the disease. The modern strategy for the treatment of rheumatoid arthritis involves the earliest possible administration of basic anti-inflammatory drugs in the most effective and tolerable doses. Despite the unconditional effectiveness of such therapy, the number and severity of side effects sometimes exceed the severity of the therapeutic effect. Even timely administration of basic therapy does not always slow down the progression of the destructive process in the joints.

Humira is an innovative drug of choice for rheumatoid arthritis. Rheumatologists at the Yusupov Hospital use it as monotherapy or as part of a combination treatment. The drug is prescribed after a comprehensive examination of the patient using the latest equipment and modern laboratory research methods. Severe cases of the disease are discussed at a meeting of the Expert Council with the participation of doctors and candidates of medical sciences, doctors of the highest category. Leading specialists in the field of rheumatology collectively develop patient management tactics. Patient reviews of the drug Humira are positive.

Composition and pharmacological action of the drug Humira

Humira comes in glass syringes containing one dose of solution for subcutaneous administration. One syringe contains 40 mg of the main active ingredient adalimumab and auxiliary ingredients:

• Mannitol;
• Sodium citrate;
• Citric acid monohydrate;
• Sodium dihydrogen phosphate dihydrate;
• Disodium hydrogen phosphate dihydrate;
• Sodium chloride;
• Polysorbate 80;
• Water for injections;
• Sodium hydroxide.

The Humira drug solution is slightly colored and opalescent. The drug has an immunosuppressive effect. Adalimumab is a recombinant monoclonal antibody whose peptide sequence is identical to human IgG1. It selectively binds to tumor necrosis factor, which plays an important role in the development of pathological inflammation and destruction of joint tissue, and neutralizes its biological functions.

In patients with rheumatoid arthritis, Humira causes rapid reductions in acute phase markers of inflammation (erythrocyte sedimentation rate, C-reactive protein) and serum levels of cytokines. After administration of the drug, there is a decrease in the serum activity of matrix metalloproteinases, which cause tissue remodeling, which underlies the destruction of cartilage.

Humira®

Infections

Adalimumab should not be started in patients with active infectious diseases, including chronic or focal infections, until the infection has resolved. In patients who have had contact with a tuberculosis pathogen, a patient or carrier of tuberculosis, and patients who have traveled to areas with a high incidence of tuberculosis or endemic mycoses such as histoplasmosis, coccidioidomycosis or blastomycosis, the risk and appropriateness of adalimumab therapy should be assessed before initiating therapy. As with other TNF blockers, patients should be closely monitored for infectious diseases before, during, and after treatment with adalimumab.

Patients who develop an infectious disease during treatment with adalimumab should be identified and fully evaluated. Adalimumab should be withheld if the patient develops a serious infectious complication or sepsis, and appropriate antibacterial and antifungal therapy should be continued until the infection resolves.

Adalimumab should be administered with caution to patients with a history of recurrent infections and in the presence of conditions predisposing to infectious complications.

Tuberculosis

There is a risk of developing active tuberculosis or activation of latent tuberculosis when taking all TNF blockers, incl. adalimumab. The incidence of tuberculosis reactivation was particularly higher at doses of adalimumab that exceeded the recommended values.

Before starting adalimumab therapy, all patients should be assessed for both active and inactive (latent) tuberculosis infection. This assessment should include a detailed medical history, taking into account possible contacts with patients with active forms of tuberculosis and previous or current immunosuppressive therapy, as well as the necessary screening examinations (including chest x-ray, tuberculin test). Treatment of latent tuberculosis infection should be performed before starting adalimumab therapy. If the diameter of the papule after a tuberculin skin test for latent tuberculosis infection is more than 5 mm, then this test is considered positive, even if BCG vaccination was previously performed.

The possibility of an unidentified latent tuberculosis infection should be considered especially in those patients who have immigrated from or traveled to a country with a high incidence of tuberculosis, or who have been in contact with a person with active tuberculosis.

If active tuberculosis is diagnosed, adalimumab therapy should not be initiated. If latent tuberculosis is diagnosed, anti-tuberculosis prophylaxis should be administered before starting treatment with adalimumab. Antituberculosis therapy before starting treatment with adalimumab should also be prescribed to those patients who have been exposed to risk factors for tuberculosis, even with a negative tuberculin test. The decision to provide anti-tuberculosis therapy in such patients should be made only taking into account the risk of both latent tuberculosis infection and the risk of anti-tuberculosis therapy. Treatment is prescribed by a phthisiatrician.

Antituberculosis treatment of patients with latent tuberculosis infection reduces the risk of reactivation of tuberculosis when these patients are treated with adalimumab. However, the risk of developing active tuberculosis or activation of latent tuberculosis exists even in patients who have undergone screening and/or preventive anti-tuberculosis therapy, so careful monitoring of the patient during therapy is necessary in order to promptly detect symptoms of active tuberculosis, especially since tests for latent tuberculosis infection are often false negatives. The risk of false-negative results of intradermal tuberculin tests should be taken into account especially in critically ill or immunocompromised patients.

For this purpose, it is recommended to repeat the Mantoux reaction 7-21 days after the first.

Patients should be informed of the need to consult a doctor if symptoms appear (persistent cough, weight loss, low-grade fever) indicating the development of tuberculosis infection.

Other opportunistic infections

Opportunistic infections, including fungal infections, have been observed in patients receiving adalimumab. These infections require timely diagnosis and adequate treatment.

Patients who develop fever, malaise, weight loss, profuse sweating, cough, shortness of breath and/or pulmonary infiltrates on chest x-ray, or other significant systemic abnormalities with or without shock should immediately seek medical attention for diagnostic evaluation. . In patients who have stayed in areas where various mycoses are endemic, the development of fungal infections should be assumed. Such patients are at risk for developing histoplasmosis or other fungal infection, and clinicians should therefore provide empirical antifungal therapy until the pathogen(s) are identified. Antigen-antibody tests for histoplasmosis may be negative in some patients with active infection. Whenever possible, the decision to initiate empirical antifungal therapy in such patients should be made in consultation with a physician skilled in the diagnosis and treatment of fungal infections, taking into account both the risk of severe fungal infection and the risk of antifungal therapy. Patients who develop a severe fungal infection are advised to stop taking TNF blockers until the infection has resolved.

Hepatitis B reactivation

The use of TNF blockers is associated with a risk of hepatitis B virus (HBV) reactivation in patients who are chronic carriers of the virus. In some cases, HBV reactivation due to use of TNF blockers has been fatal. Most of these cases occurred in patients taking other medications that suppress the immune system, which may also contribute to HBV reactivation. In patients at risk for HBV infection, the primary symptoms of HBV infection should be diagnosed before initiating TNF blocker therapy. TNF blockers should be prescribed with caution to patients who are carriers of HBV. Those patients who are carriers of HBV and require treatment with TNF blockers should be carefully monitored for signs of active HBV infection during therapy and several months after the end of therapy. There are no reliable data on the safety or effectiveness of treating HBV carriers with antivirals combined with TNF blockers to prevent HBV reactivation. In patients who develop HBV reactivation, adalimumab should be withheld and effective antiviral therapy should be initiated with appropriate supportive care.

Neurological complications

The use of TNF blockers, including adalimumab, is associated with rare cases of occurrence or complications of clinical manifestations and/or radiological signs of demyelinating diseases of the central nervous system, including multiple sclerosis and peripheral demyelinating diseases, including Guillain-Barré syndrome. Adalimumab should be prescribed with caution to patients with current or a history of demyelinating diseases of the central and peripheral nervous system.

Malignant neoplasms

There is a higher risk of developing lymphoma in patients with rheumatoid arthritis, which is characterized by long-lasting, severe inflammation, making risk assessment difficult. During long-term, open-label clinical studies of adalimumab, the mean incidence of malignancy was similar to that expected for the general population of a given age, sex, and race. Based on the available data, a possible risk of developing lymphomas or other malignancies in patients using TNF blockers cannot be excluded.

Malignancies, some fatal, have been reported in children and adults treated with TNF blockers. Approximately half of the cases developed lymphomas, both Hodgkin's and non-Hodgkin's. Other cases presented a variety of malignancies, including rare malignancies associated with immunosuppression. Malignant neoplasms occurred after an average of 30 months of therapy. Most patients received concomitant treatment with immunosuppressants.

There have been rare post-marketing reports of hepatosplenic T-cell lymphoma (HSTCL), a rare aggressive lymphoma that has occurred in patients treated with adalimumab and has often been fatal. Most patients were initially treated with infliximab and concomitant therapy for inflammatory bowel disease with azathioprine or 6-mercaptopurine. The cause-and-effect relationship of HSTCL with adalimumab has not been proven.

There have been no studies that included patients with a history of malignancy or in which treatment with adalimumab was continued in patients who had developed a malignancy. Therefore, additional caution should be exercised when using adalimumab in these patients.

All patients, and especially patients who have previously received long-term immunosuppressant therapy or PUVA therapy for psoriasis, should be evaluated for the presence of non-melanoma skin cancer that develops before or during treatment with adalimumab.

Cases of acute or chronic leukemia have been reported in association with post-marketing use of TNF blockers for the treatment of rheumatoid arthritis and other indications. Patients with rheumatoid arthritis have a higher risk of developing leukemia (up to twofold) than the general population, even in the absence of TNF blocker therapy.

Allergy

Serious allergic reactions associated with adalimumab were rare during clinical studies. In post-marketing surveillance, serious allergic reactions, including anaphylactic shock, have been reported very rarely following administration of adalimumab. If an anaphylactic reaction or other serious allergic reaction occurs, adalimumab should be discontinued immediately and appropriate antiallergic therapy should be instituted.

The syringe needle cover contains natural rubber (latex). This may lead to severe allergic reactions in patients sensitive to latex.

Hematological complications

There have been rare reports of pancytopenia, including aplastic anemia, with the use of TNF blockers. Hematologic side effects, including significant cytopenia (including thrombocytopenia, leukopenia), have been rarely reported during treatment with adalimumab. The causal relationship of these reports to adalimumab remains unclear. All patients should be advised to seek immediate medical attention if they develop symptoms suggestive of hematologic abnormalities (including persistent fever, bruising, bleeding, pallor) while receiving adalimumab. If significant hematological abnormalities are confirmed, treatment with adalimumab should be suspended.

Combination with anakinra

Severe infections have been observed in clinical studies with coadministration of anakinra and another TNF blocker, etanercept, with no improvement in clinical effect compared with etanercept used alone. Based on the nature of the adverse events observed with the combination of etanercept and anakinra, similar toxicities may occur when anakinra is combined with other TNF blockers. Therefore, concomitant therapy of adalimumab with anakinra is contraindicated.

Combination with abatacept

Concomitant use of TNF blockers and abatacept is associated with an increased risk of infectious diseases, including severe infections, compared with use of TNF blockers alone. There is no increase in clinical effect when using this combination. Therefore, the combined use of TNF blockers and abatacept is contraindicated.

Vaccination

Patients with juvenile arthritis are recommended to be fully vaccinated, if possible, according to their current immunization schedule before initiating adalimumab therapy. Patients taking adalimumab may receive concomitant vaccinations other than live vaccines.

Congestive heart failure (CHF)

There have been no studies of adalimumab in patients with CHF, but in clinical trials of another TNF blocker, a higher rate of CHF-related adverse reactions, including development of CHF and progression of CHF, was observed. Cases of progression of CHF have also been described in patients taking adalimumab. Adalimumab should be administered with caution to patients with heart failure and such patients should be closely monitored.

Autoimmune processes

Treatment with adalimumab may lead to the formation of autoimmune antibodies. The effect of long-term treatment on the development of autoimmune diseases has not been studied. If a patient develops symptoms suggestive of lupus-like syndrome as a result of treatment with adalimumab, the drug should be discontinued.

Elderly patients

The incidence of serious infections in patients over 65 years of age receiving adalimumab was higher than in patients under 65 years of age. 10.8% of the total number of patients taking adalimumab were over 65 years of age and approximately 2.3% were over 75. Adalimumab should be administered with caution in elderly patients due to the high likelihood of infectious diseases. There were no differences in effectiveness in this group of patients compared to younger patients, and no dose adjustment is required.

Use in pediatrics

Adalimumab has not been studied in children under 4 years of age.

, data on the use of the drug in children weighing less than 5 kg are limited. The effectiveness and safety of adalimumab in children is indicated only for the treatment of juvenile idiopathic arthritis.

Indications and contraindications for the use of Humira

Rheumatologists at the Yusupov Hospital prescribe the drug Humira to patients suffering from the following diseases:

• Moderate and severe active rheumatoid arthritis;
• Active psoriatic arthritis;
• Active ankylosing spondylitis.

In the first two cases, Humira is used as monotherapy or in combination with methotrexate or other basic anti-inflammatory drugs. Reviews for psoriasis are good.

Contraindications to the use of the drug Humira are hypersensitivity to adalimumab or any auxiliary components of the drug, infectious diseases, including tuberculosis, pregnancy and breastfeeding. The drug is not prescribed to children and adolescents under 16 years of age. Use the drug with caution in demyelinating diseases. Doctors recommend that women of reproductive age avoid conceiving while taking Humira. If there is a need to treat women who are breastfeeding with Humira, the baby is transferred to artificial feeding for the duration of the entire course of therapy.

Adalimumabum

During treatment with adalimumab, cases of tuberculosis, fungal and other opportunistic infections, including deaths, have been observed. Before starting treatment, an examination is necessary to identify active and inactive tuberculosis (presence of contacts with patients, immunosuppressive therapy; chest x-ray, tuberculin test). In patients with immunodeficiency, false-negative tuberculin tests are possible. In case of active tuberculosis, treatment with adalimumab is not started; in case of latent tuberculosis, preventive anti-tuberculosis treatment is first carried out. If signs of tuberculosis infection appear during treatment (persistent cough, weight loss, low-grade fever), you should consult a doctor.

While taking adalimumab in carriers of the hepatitis B virus, reactivation of the virus is possible, and cases of death have been described. The decision to initiate therapy is made after examination (presence of hepatitis B virus) taking into account the possible risk to the patient. During treatment and several months after the end of treatment, medical supervision is carried out. If the virus is reactivated, treatment with adalimumab is stopped and antiviral therapy is administered.

In rare cases, the appearance or exacerbation of demyelinating diseases may occur.

A possible risk of developing lymphoma or other malignancies cannot be excluded during treatment with tumor necrosis factor blockers.

During treatment, pancytopenia (thrombocytopenia, leukopenia, aplastic anemia) may be observed. If symptoms such as persistent fever, bruises, bleeding, or pale skin appear, you should consult a doctor.

When anakinra was used concomitantly with the tumor necrosis factor antagonist etanercept, the development of severe infections was observed (compared to etanercept monotherapy), which can be expected when anakinra is used in combination with other tumor necrosis factor blockers, including adalimumab.

During treatment, vaccinations are possible, with the exception of live vaccines.

If signs of lupus-like syndrome develop, treatment is discontinued.

If an anaphylactic reaction or other serious allergic reaction occurs, adalimumab should be discontinued immediately and appropriate antiallergic therapy should be instituted. It must be remembered that the syringe needle cover contains natural rubber (latex). This may lead to severe allergic reactions in patients sensitive to latex.

If significant hematological abnormalities are confirmed, treatment with adalimumab should be suspended.

Cases of progression of congestive heart failure have been described in patients receiving adalimumab. Adalimumab should be administered with caution to patients with heart failure and such patients should be closely monitored.

The incidence of serious infections in patients over 65 years of age receiving adalimumab was higher than in patients under 65 years of age. 12% of the total number of patients receiving adalimumab were over 65 years of age and approximately 2.5% were over 75. Adalimumab should be used with caution in elderly patients due to the high likelihood of infectious diseases. There were no differences in effectiveness in this group of patients compared to younger patients, and no dose adjustment is required.

Adalimumab has not been studied in children under 4 years of age; data on the use of the drug in children weighing less than 5 kg are limited. The effectiveness and safety of adalimumab in children is indicated only for the treatment of juvenile idiopathic arthritis.

Side effects of the drug Humira

During clinical studies on the safety of the drug Humira, it was found that during treatment with the drug, patients very often developed infectious diseases of the upper respiratory tract. Infections of the lower respiratory tract, including bronchitis and pneumonia, of the urinary system, and herpes infections (including herpes simplex and herpes zoster) often developed. When using Humira, patients are at increased risk of developing influenza and superficial fungal infections, including skin and nail lesions.

The following complications from the hematopoietic system are possible:

• Anemia;
• Lymphopenia;
• Leukopenia, leukocytosis;
• Neutropenia;
• Thrombocytopenia.

Sometimes patients' lymph nodes become enlarged. Hypersensitivity reactions rarely occur. When using the drug Humira, undesirable metabolic reactions rarely develop: hypercholesterolemia, hyperuricemia, decreased appetite, anorexia, hyperglycemia, weight loss or increase.

Some patients experience reactions from the following body systems:

• Central and peripheral nervous system (headache, dizziness, paresthesia, depression, anxiety disorders, insomnia, confusion, taste disturbance, fainting, migraine, drowsiness, neuralgia, neuropathy, tremor);
• Sense organs (conjunctivitis, blepharitis, redness, pain, dry eye, eyelid swelling, glaucoma, ringing and congestion in the ears);
• Cardiovascular system: (arterial hypertension, hot flashes, increased heart rate, palpitations);
• Respiratory system (cough, sore throat, nasal congestion, shortness of breath, redness of the pharynx, swelling of the upper respiratory tract);
• Digestive system (nausea, abdominal pain, diarrhea, diarrhea, ulceration of the oral mucosa, increased activity of liver enzymes).

Patients may experience skin rash, itching, and hair loss during treatment with Humira. Rarely, skin ulcers, angioedema, skin peeling, and photosensitivity reactions occur. Patients may experience pain in the joints, muscles, shoulder girdle and back. Muscle cramps, bursitis, synovitis, and tendonitis rarely occur. The following undesirable reactions are possible from the genitourinary system:

• Dysuria (urination disorder);
• Hematuria (blood in urine);
• Nocturia (increased frequency of urination at night).

In women, the menstrual cycle may be disrupted. Sometimes patients experience increased fatigue and increased body temperature. They are worried about feeling hot, chills, and chest pain. Wound healing may be impaired.

Humira®

Subcutaneously.

Treatment with Humira® is carried out under the supervision of a physician. If the doctor considers this possible, then after appropriate training in the technique of subcutaneous injections, patients can self-administer the drug.

Humira® is injected subcutaneously into the thigh or abdomen. The solution should be inspected before administration for the presence of foreign particles and discoloration.

Adalimumab should not be mixed in the same syringe or vial with any other medicines. The remaining solution and used materials should be disposed of.

If your next injection of Humira® is accidentally missed, you should take the injection as soon as it is discovered. The next injection should be carried out according to the previously planned schedule.

Adults

Rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS)

The recommended dose of Humira for adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) is 40 mg subcutaneously once every two weeks. When prescribing Humira®, therapy with glucocorticosteroids, non-steroidal anti-inflammatory drugs (including salicylates), analgesics (narcotic and non-narcotic), methotrexate and other basic antirheumatic drugs can be continued.

In some patients with rheumatoid arthritis not receiving methotrexate, additional benefit may be achieved by increasing the frequency of Humira to 40 mg once a week.

Crohn's disease

The recommended dosing regimen for adults with Crohn's disease is 160 mg on day 1 (four injections of 40 mg per day or two injections of 40 mg per day consecutively for two days), after 2 weeks (at 15th day) - 80 mg, after another 2 weeks (29th day) they begin to use a maintenance dose - 40 mg once every 2 weeks. When prescribing Humira®, therapy with aminosalicylates, glucocorticosteroids, and/or immunomodulators (for example: 6-mercaptopurine and azathioprine) can be continued.

Patients experiencing a decreased response to drug treatment may receive additional benefit by increasing the frequency of Humira® dosing to 40 mg once weekly.

Some patients may not respond to Humira® therapy within the first four weeks, but treatment should be continued because a positive effect can be achieved within 12 weeks. A decision to discontinue therapy may be made if the patient does not benefit from treatment during this period.

Chronic plaque psoriasis

The starting dose for adult patients is 80 mg.

Maintenance dose: 40 mg every two weeks, starting one week after the initial dose.

Children

Juvenile idiopathic arthritis

Humira has not been studied in children younger than 2 years of age with juvenile idiopathic arthritis.

For juvenile idiopathic arthritis in children aged 4 to 12 years, Humira® is prescribed at a dose of 24 mg/m2 body surface area, with a maximum dose of 40 mg. The drug is administered subcutaneously once every 2 weeks. The injection volume is determined based on the patient's height and weight (see Table 1).

For patients requiring less than 40 mg of the drug, the Humira® vial must be used.

* - the maximum dose for a single administration is 40 mg (0.8 ml)

Children from 13 years to 17 years are prescribed 40 mg once every 2 weeks, regardless of body surface area.

Clinical response is usually achieved within 12 weeks of treatment. A decision to discontinue therapy may be made if the patient does not benefit from treatment during this period.

Crohn's disease

Patients weighing less than 40 kg: 80 mg on day 1 (two injections of 40 mg per day are used), after 2 weeks (on the 15th day) - 40 mg, after another 2 weeks (on the 29th day ) begin to use a maintenance dose according to the following regimen - 20 mg once every 2 weeks (moderate and severe).

Patients weighing 40 kg or more: 160 mg on day 1 (use four injections of 40 mg per day or two injections of 40 mg per day consecutively for two days),

after 2 weeks (on the 15th day) - 80 mg, after another 2 weeks (on the 29th day) they begin to use

maintenance dose according to the following schedule:

severe Crohn's disease - 40 mg once every 2 weeks;

moderate Crohn's disease - 20 mg once every 2 weeks.

Patients who experience a decrease in response to treatment with the drug may receive additional benefit from increasing the frequency of Humira® administration to 1 time per week.

Clinical response is usually achieved within 12 weeks of treatment. A decision to discontinue therapy may be made if the patient does not benefit from treatment during this period.

Humira has not been studied in children under 6 years of age with Crohn's disease.

For instructions on preparing and administering an injection of Humira ® , see the information leaflet included in the carton.

INSTRUCTIONS FOR PREPARATION AND INJECTION OF HUMIRA® IN A SINGLE-DOSE SYRINGE

Preparation

- Wash your hands thoroughly.

— Remove one syringe of Humira® and one alcohol-soaked wipe from the package and place it on a clean surface.

— Make sure that the expiration date on the syringe for Humira® has not expired.

Selection and preparation of the injection site

- Choose a place on the stomach or front of the thigh.

- Injection sites and sides should be changed.

— Each subsequent injection site must deviate from the previous one by at least 3 cm.

- Do not inject the drug into a place on the skin where there is pain, redness, thickening or bruising. These signs may indicate an infection.

— The injection site must be treated with an alcohol wipe in a circular motion.

Introduction of Humira®

- Do not shake the syringe.

— Remove the cap from the needle without touching the needle and avoiding touching other surfaces.

- With one hand, take the treated skin into the fold.

- Take the syringe in your other hand, holding it at an angle of 45° to the surface of the skin, graduated surface up.

- In one quick movement, insert the needle completely into the skin fold.

— After inserting the needle, release the skin fold.

- Inject the entire solution within 2-5 seconds.

- After injecting the solution (when the syringe is empty), remove the needle from the skin at the same angle.

- Using a piece of gauze, lightly press the injection area for 10 seconds, but do not rub the surface under any circumstances. A small amount of blood may come out from the injection site. If desired, you can use a patch.

— After the injection, do not reuse the syringe.

INSTRUCTIONS FOR PREPARATION AND INJECTION OF HUMIRA® IN A VIAL

Preparation

— Make sure you know what amount (volume) of the drug needs to be administered.

- Wash your hands thoroughly.

- Take one box from the carton containing one syringe, one vial tip, one vial, two alcohol wipes and one needle. If there is another box of kit left in the carton for your next injection, put it in the refrigerator immediately.

— Check the expiration date of the drug indicated on the box. DO NOT use the kit after its expiration date.

- Place the following items on a clean surface, DO NOT remove them from their individual packaging at this time.

— One 1 ml syringe (1)

— One nozzle per bottle (2)

— One bottle of Humira®, solution for injection (3)

— Two alcohol wipes (4)

— One needle (5)

Humira® is a clear, colorless liquid. Do not use the product if the liquid is cloudy, contains flakes or particles, or has changed color.

Preparing the dose of Humira® for administration

As a general rule, DO NOT throw away anything until the injection is complete.

— Prepare the needle by partially removing the packaging that is open on the side closest to the yellow needle connector cap. Remove the packaging just enough to expose the yellow connection cap. Hold the package with the open end facing up.

- Remove the white plastic cap from the bottle so that you can see the top of the bottle stopper.

— Use one of the alcohol wipes to wipe the stopper of the bottle. After this, DO NOT touch the stopper of the bottle.

— Open the packaging of the bottle attachment, but do not remove it from the packaging.

— Keep the bottle with the cap facing up.

— Without removing the bottle attachment from the package, connect it to the bottle stopper, pressing the attachment onto the stopper until it clicks into place.

— When you are sure that the nozzle is connected to the bottle, remove the packaging from it.

— Carefully place the bottle with the nozzle on a clean work surface. Be careful, the bottle should not fall. DO NOT touch the nozzle.

— Prepare the syringe by partially removing the packaging that is open on the side closest to the white plunger rod.

— Remove the packaging just enough to expose the white plunger rod, but do not remove the syringe from the packaging.

— Hold the syringe package and SLOWLY pull out the white plunger rod until the volume exceeds the required dose by 0.1 ml. (For example, if the prescribed dose is 0.5 ml, pull out the white plunger rod 0.6 ml). NEVER pull the plunger past the 0.9 ml position, regardless of the prescribed dose.

- You will adjust the volume according to the prescribed dose later.

- DO NOT pull the white plunger rod out of the syringe completely.

NOTE:

If the white plunger rod is completely removed from the syringe, the syringe cannot be used. DO NOT attempt to put the white piston rod back in.

DO NOT use the white plunger rod to remove the syringe from its packaging. Remove the syringe from the packaging, while the piston rod should remain in the installed position. Never lower the syringe.

— Hold the nozzle firmly on the bottle. Insert the tip of the syringe into the nozzle and turn the syringe clockwise with one hand until it stops. Do not use excessive force when turning the syringe clockwise until it stops.

— Holding the bottle, press the piston rod and lower it completely. This step is important to ensure you receive the correct dose of the drug. Hold the white plunger rod inside and invert the syringe with the vial.

- SLOWLY pull the white plunger rod towards you until the mark is 0.1 ml higher than the required dose. This is important to ensure you receive the correct dose. You will adjust your dose in step 4 (Prepare your drug dose). If the prescribed dose is 0.5 ml, pull out the white plunger rod 0.6 ml. You will see the liquid from the bottle fill the syringe.

- Press down on the white piston rod to return the liquid to the bottle. Again, SLOWLY pull the white plunger rod towards you until the mark is 0.1 ml above the required dose, this is important to obtain the correct dose and prevent the formation of air bubbles and air gaps. You will adjust your dose in step 4 (Prepare your drug dose).

- If you see that there are still air bubbles or air gaps in the syringe, you can repeat the described procedure up to three times. DO NOT shake the syringe.

NOTE:

If the white plunger rod is completely removed from the syringe, the syringe cannot be used. DO NOT attempt to put the white piston rod back in.

- Still holding the syringe vertically, remove the vial attachment from the syringe along with the vial by turning the vial adapter with your other hand. Make sure that you have removed the nozzle from the syringe along with the bottle. DO NOT touch the tip of the syringe.

— If large air bubbles or air gaps are visible near the tip of the syringe, SLOWLY push down on the white plunger rod until liquid begins to fill the tip of the syringe. DO NOT press the white plunger rod after the required dose mark has been reached.

- For example, if the prescribed dose is 0.5 ml, DO NOT press the white plunger rod after the 0.5 ml mark is reached.

— Make sure that the volume of liquid remaining in the syringe is at least as large as the prescribed dose. If the remaining volume is less than the prescribed dose, do not use this syringe.

— With your free hand, take the package with the needle so that the yellow connecting cap is pointing down.

— Keeping the syringe pointed upward, insert the tip of the syringe into the yellow connector cap of the needle and turn the syringe until it stops, as shown by the arrow in the picture below. The needle is now connected to the syringe.

— Remove the packaging from the needle, but DO NOT remove the needle cap.

— Place the syringe on a clean work surface. Proceed immediately to selecting the injection site and preparing the dose.

Selection and preparation of the injection area

- Select an area on the thigh or stomach.

- The new injection site should be at least 3 cm from the previous injection site.

- Do not inject the drug into a place on the skin where there is pain, redness, thickening or bruising. These signs may indicate an infection.

— To reduce the risk of infection, treat the injection area with a second alcohol wipe. DO NOT TOUCH the injection area before injection.

Dose preparation

- Take the syringe so that the needle points upward.

- With your other hand, transfer the pink needle cap to the syringe.

— Remove the protective cap by pulling it up with your other hand.

- DO NOT TOUCH the needle.

- DO NOT put the syringe down after removing the cap from the needle.

- DO NOT attempt to put the protective cap back on the needle after it has been removed.

— Hold the syringe at eye level, with the needle pointing upward. You should clearly see the amount of drug in the syringe. Be careful not to get the drug into your eyes.

— Check again how much of the drug you need to measure.

— Gently press the white plunger rod so that the prescribed amount of drug remains in the syringe. Excess drug may come out of the needle. DO NOT blot the needle or syringe.

Introduction of Humira®

- Using your free hand, gently gather the fold of skin of the treated area and hold it firmly.

- Take the syringe with your other hand and hold it at a 45° angle to the skin.

- In one quick, short movement, insert the needle completely into the skin.

- Release the skin fold.

— Press down on the white plunger rod to inject the drug. Give all the medicine completely.

- When the syringe is empty, remove the needle from the skin. Be careful to remove the needle at the same angle at which it was inserted.

— Carefully place the pink cap on the needle until it clicks. Place the syringe and needle on the work surface.

— DO NOT put the removed protective cap back on the needle.

— After injection, DO NOT reuse the syringe, bottle, needle, needle cap and bottle attachment.

— Using a piece of gauze, press on the area where the drug is injected for 10 seconds.

- There may be some bleeding. DO NOT RUB the injection site. The injection area can be covered with a bandage.

Description of the drug HUMIRA® (HUMIRA®)

Use with caution in patients with a history of recurrent infections, carriage of the hepatitis B virus, malignant neoplasms (including a history), heart failure, demyelinating diseases of the nervous system (including a history), in patients over 65 years of age.

Before starting adalimumab therapy, all patients should be assessed for both active and inactive (latent) tuberculosis infection. If active tuberculosis is diagnosed, adalimumab therapy should not be initiated. If latent tuberculosis is diagnosed, anti-tuberculosis prophylaxis should be administered before starting treatment with adalimumab. Antituberculosis therapy before starting treatment with adalimumab should also be prescribed to those patients who have been exposed to risk factors for tuberculosis, even with a negative tuberculin test. The decision to provide anti-tuberculosis therapy in such patients should be made only taking into account the risk of both latent tuberculosis infection and the risk of anti-tuberculosis therapy. Treatment is prescribed by a phthisiatrician.

Patients should be carefully monitored for infectious diseases before, during and after treatment with adalimumab.

Adalimumab should not be started in patients with active infectious diseases, including chronic or focal infections, until the infection has resolved. In patients with travel history of endemic mycoses such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and appropriateness of adalimumab therapy should be assessed before initiating therapy.

Patients who develop an infectious disease during treatment with adalimumab should be identified and fully evaluated. Adalimumab should be withheld if the patient develops a serious infectious complication or sepsis, and appropriate antibacterial and antifungal therapy should be continued until the infection resolves.

The use of TNF antagonists is associated with a risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In patients who develop HBV reactivation, adalimumab should be withheld and effective antiviral therapy should be initiated with appropriate supportive care.

All patients, and especially patients who have previously received long-term immunosuppressant therapy or PUVA therapy for psoriasis, should be evaluated for the presence of non-melanoma skin cancer that develops before or during treatment with adalimumab.

If an anaphylactic reaction or other serious allergic reaction occurs, adalimumab should be discontinued immediately and appropriate antiallergic therapy should be instituted.

If significant hematological abnormalities are confirmed, treatment with adalimumab should be suspended.

Patients with juvenile arthritis are recommended to be fully vaccinated, if possible, according to the current immunization schedule before initiating adalimumab therapy. Patients taking adalimumab may receive concomitant vaccinations other than live vaccines.

Treatment with adalimumab may lead to the formation of autoimmune antibodies. The effect of long-term treatment on the development of autoimmune diseases has not been studied. If a patient develops symptoms suggestive of lupus-like syndrome as a result of treatment with adalimumab, adalimumab should be discontinued.

The incidence of serious infections in patients over 65 years of age receiving adalimumab was higher than in patients under 65 years of age. 12% of the total number of patients treated with adalimumab were over 65 years of age and approximately 2.5% were over 75. Adalimumab should be used with caution in elderly patients due to the high likelihood of infectious diseases.

Use in pediatrics

The effectiveness and safety of adalimumab has been proven only for the treatment of idiopathic juvenile arthritis in children and adolescents aged 4 to 17 years and Crohn's disease (moderate to severe) in patients aged 6 years and older.