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.

Pharmacological properties of the drug Humira

Immunological and biological properties . Humira (adalimumab) is a recombinant monoclonal antibody whose peptide sequence is identical to that of humans. Humira has specificity and high affinity for soluble tumor necrosis factor (TNF-α) but does not bind to lymphotoxin (TNF-β). Adalimumab neutralizes the biological effects of TNF by blocking its interaction with p55 and p75 TNF receptors on the cell surface. TNF is a naturally occurring cytokine involved in physiological inflammatory and immune responses in the body. TNF levels are increased in synovial fluid in rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNF plays an important role in the development of pathological inflammation and destruction of joint tissues characteristic of these diseases. The level of TNF in psoriatic plaques is also increased. The use of Humira for plaque psoriasis can prevent the thinning of the epidermis and its infiltration by inflammatory cells. The relationship between these pharmacodynamic effects and the mechanism(s) by which Humira exerts its clinical effectiveness is unknown. Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the level of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1 and ICAM-1 with an IC50 of 1–2 × 10'''°M). Pharmacodynamics . In patients with rheumatoid arthritis, the use of Humira led to a rapid decrease, compared with initial parameters, in the level of acute phase indicators of inflammation (CRP, ESR) and serum cytokines (IL-6). A rapid decrease in CRP levels was also observed in patients with Crohn's disease. There was also a decrease in the levels of matrix metalloproteinases (MMP-1 and MMP-3) in the blood plasma, which cause tissue remodeling, which underlies the destruction of cartilage. In rheumatoid and psoriatic arthritis and ankylosing spondylitis, mild to moderate anemia and lymphocytopenia, as well as increased numbers of neurophilic granulocytes and platelets, are common. Improvements in these hematologic parameters are typically observed with Humira. Pharmacokinetics . Absorption. Following a single 40 mg subcutaneous dose of Humira, absorption and distribution of adalimumab were slow, with plasma Cmax achieved approximately 5 days after administration. The mean absolute bioavailability of adalimumab was 64%. Distribution and excretion. The pharmacokinetics of adalimumab after a single intravenous dose of 0.25–10 mg/kg body weight have been studied in several studies. The volume of distribution (Vss) was 4.7–6.0 L, indicating approximately equal distribution of adalimumab between the vascular and extravascular spaces. Adalimumab is eliminated slowly; clearance of adalimumab usually does not exceed 12 ml/h. The median final T1/2 of adalimumab was approximately 2 weeks (10–20 days). Clearance and T1/2 of adalimumab were relatively unchanged over the dose range studied, and final T1/2 with IV and SC administration of the drug were similar. Concentrations of adalimumab in synovial fluid in rheumatoid arthritis were 31–96% of plasma levels. Pharmacokinetics of adalimumab at steady state . Adalimumab accumulation was studied based on T1/2 after subcutaneous administration of Humira at a dose of 40 mg once every 2 weeks. Steady-state concentrations ranged from 5 μg/ml (without concomitant use of methotrexate) to 8–9 μg/ml (with methotrexate). The concentration of adalimumab in the blood plasma at steady state increased almost proportionally to the subcutaneously administered dose of 20 mg, 40 mg, 80 mg once every 2 weeks or once a week. Longer studies (2 years) showed no changes in adalimumab clearance over time. In patients with psoriasis, the average steady-state concentration was 5 mcg/ml with monotherapy with adalimumab at a dose of 40 mg once every 2 weeks. Results from a population pharmacokinetic data analysis suggest that concomitant use of methotrexate alters the apparent clearance of adalimumab (see INTERACTIONS ). As expected, there was a trend toward increased apparent clearance of adalimumab with increasing body weight and in the presence of anti-adalimumab antibodies. In healthy volunteers and patients with rheumatoid arthritis, the pharmacokinetic parameters of adalimumab are identical. Pharmacokinetic parameters do not change depending on gender or race.

Indications for use of Humira

• rheumatoid arthritis (to reduce the severity of symptoms of the disease, induce a major clinical response and clinical remission, to slow the progression of structural joint damage and improve functional status in adult patients with moderate and highly active rheumatoid arthritis). Humira can be used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs);
• juvenile rheumatoid arthritis (to reduce the severity of symptoms of the disease in children over 4 years of age with a polyarticular variant of moderate and high activity). Humira can be used in combination with methotrexate or as monotherapy;
• psoriatic arthritis (to reduce the severity of symptoms of arthritis in the active phase of the disease, to slow the progression of damage to peripheral joints in patients with a symmetrical polyarticular form of the disease and to improve the functional state of the joints). Humira can be used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs).
• ankylosing spondylitis (to reduce the severity of symptoms in the active phase of the disease);
• Crohn's disease (to reduce the severity of symptoms of the disease, to induce and maintain clinical remission in adult patients with Crohn's disease of moderate and high activity when traditional therapy is ineffective, as well as in the absence of clinical effect when using infliximab or if it is intolerant);
• plaque psoriasis (for the treatment of adult patients with moderate to severe disease who require systemic therapy or phototherapy in the absence of indications for other types of systemic treatment).

Using Humira

rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: the recommended dose is 40 mg once every 2 weeks subcutaneously. You may continue to use methotrexate, corticosteroids, salicylates, analgesics, and other NSAIDs or other disease-modifying antirheumatic drugs (DMARDs) during Humira therapy. When monotherapy with adalimumab (without methotrexate), it may be necessary to increase the frequency of drug administration to 40 mg once a week, s.c. Juvenile rheumatoid arthritis: the recommended dose (EMEA data) for children over 13 years of age is 40 mg once every 2 weeks, administered subcutaneously. The recommended dose (FDA data) for children over 4 years of age depends on body weight: 15–30 kg - use 20 mg 1 time every 2 weeks subcutaneously, for a body weight of 30 kg - 40 mg 1 time every 2 weeks subcutaneously /To. The dosage form of the drug Humira at a dose of 20 mg is not registered in Ukraine. According to available data, clinical effect usually occurs within 12 weeks of treatment; if there is no effect within this time, the need to extend therapy should be considered. During therapy with Humira, you can continue to use methotrexate, corticosteroids, salicylates, analgesics and other NSAIDs. Crohn's disease: for induction of remission, the recommended initial dose is 80 mg (day 1), followed by a dose reduction to 40 mg after 2 weeks (day 15), s.c. If a faster clinical effect is needed, initially 160 mg is used on the 1st day (administered subcutaneously 40 mg of the drug 4 times a day or 40 mg 2 times a day for 2 days), after 2 weeks (15th day ) apply 80 mg of the drug subcutaneously (it should be borne in mind that with such a scheme for inducing remission, the risk of developing adverse reactions increases). After 2 weeks (day 29), maintenance treatment begins - subcutaneous administration of 40 mg once every 2 weeks. During therapy with Humira, you can continue to use aminosalicylates, corticosteroids and/or immunosuppressive drugs (6-mercaptopurine and azathioprine). If the clinical effect decreases, in some cases it may be necessary to increase the frequency of drug administration - 40 mg once a week subcutaneously. If there is no clinical effect at the 4th week of treatment, maintenance therapy is continued for up to 12 weeks. The need to extend therapy for 12 weeks should be considered if the patient's condition does not improve. During maintenance therapy, the dose of GCS is reduced. Plaque form of psoriasis: the recommended initial dose is 80 mg, after 1 week 40 mg s.c. is used. Maintenance therapy - 40 mg 1 time every 2 weeks s.c. The need to extend therapy for 16 weeks should be considered if there is no positive dynamics in the patient’s condition. Interruption of treatment . Existing data suggest that re-administration of Humira after a treatment break of 70 days or more results in a return to the same clinical effect and does not affect the safety of the drug. Introduction . Humira is used under medical supervision. On the recommendation of a doctor, the patient can independently administer the drug after training in the technique of subcutaneous administration. Recommended areas for self-administration are the thighs and abdomen. Injection sites should be constantly changed. The drug should not be injected into areas with sensitive skin, bruising, hyperemia or infiltration of the skin. Like other drugs for parenteral use, the solution must be inspected before administration for the presence of foreign particles, changes in color and transparency. Humira should not be mixed in the same syringe with other medications. Unused solution and syringe are disposed of after use.

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.

Side effects of Humira

In table Table 1 shows side effects observed in clinical studies in patients with rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and Crohn's disease. Adverse reactions, possibly associated with the use of adalimumab, are distributed by organs and systems and by frequency of occurrence (10% - very common; 1-10% - often; 0.1-1% - rare; 0.01-0.1% - Sometimes). Table 1

In psoriasis, the safety profile of Humira was similar to that of rheumatoid arthritis, with the exception of a higher incidence of arthralgia compared with the control group (3% vs. 1%). Humira was studied in 171 patients aged 4–17 years with juvenile rheumatoid arthritis. As a rule, adverse reactions occurring in children were similar in frequency and nature to those observed in adult patients. The development of severe infections (rarely fatal) - tuberculosis (including miliary and extrapulmonary localization) and invasive opportunistic infections (disseminated histoplasmosis, Pneumocystis pneumonia, aspergillosis, listeriosis) has been reported. Two of 3,989 patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis treated with Humira during clinical trials developed new-onset lupus-like syndrome that resolved after discontinuation of treatment. There were no cases of lupus nephritis or central nervous system damage. The effect of long-term use of Humira on the development of autoimmune diseases is unknown. The resulting increase in ALT activity was transient, was not accompanied by the appearance of other symptoms and disappeared with continued treatment. In patients with juvenile rheumatoid arthritis, the increase in ALT activity was small and similar to placebo and primarily occurred when Humira was combined with methotrexate. Additional side effects reported during post-marketing surveillance or during phase IV clinical trials are presented in Table. 2. Since this information is provided voluntarily, it is not always possible to estimate the incidence of side effects and cause-and-effect relationships. table 2

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.

Special instructions for the use of Humira

Infections . It is possible to develop severe bacterial, mycobacterial, invasive fungal (disseminated or extrapulmonary histoplasmosis, aspergillosis, coccidioidomycosis), viral or other opportunistic infections when using TNF blockers. There is also evidence of the development of sepsis, and rarely - tuberculosis, candidiasis, listeriosis and Pneumocystis pneumonia when using TNF antagonists, including Humira. Other severe infections observed in clinical studies include pneumonia, pyelonephritis, septic arthritis and septicemia. There are data on cases of hospitalization of such patients (including deaths). Most severe infections developed against the background of the underlying disease and the use of immunosuppressive drugs. Humira should not be used in patients with an active infectious process, including chronic or focal infections, until the process has stabilized. In patients exposed to tuberculosis or returning from countries with a high incidence of tuberculosis or areas where mycosis is endemic (histoplasmosis, coccidioidomycosis, or blastomycosis), the benefit/risk ratio should be assessed before using Humira. As with the use of other TNF antagonists, the patient should be monitored for the development of infections (including tuberculosis) before, during and after treatment with Humira for 5 months (the elimination time of adalimumab). Patients who develop a new infection during treatment with Humira require special attention. Treatment is stopped if severe infection or sepsis develops and appropriate antimicrobial or antimycotic drugs are used until the infectious process has stabilized. Humira should be used with extreme caution in patients with recurrent infections, premorbid conditions, or when using immunosuppressants due to an increased tendency to develop infections. Tuberculosis . In clinical studies of Humira and other similar drugs, cases of tuberculosis were reported, but the incidence of reactivation of tuberculosis increased primarily when Humira was used in doses higher than recommended. Before starting treatment with Humira, all patients should be examined to exclude active and inactive (latent) forms of tuberculosis. The examination should include a detailed medical history, including information about possible contacts with tuberculosis patients and previous or concomitant immunosuppressive therapy. It is mandatory for all patients to undergo an intravenous tuberculin test (Mantoux test) and chest x-ray before starting therapy. In case of a negative result of the Mantoux test, it is recommended to repeat it after 1–3 weeks. A positive result of an intravenous tuberculin test is considered to be the appearance of an infiltrate (papule) with a diameter of ≥5 mm (excluding previous BCG vaccination). The possibility of undetected latent tuberculosis should be considered in patients returning from countries with a high incidence of tuberculosis or in contact with a patient with active tuberculosis. Humira therapy is not carried out for active tuberculosis. In the case of latent tuberculosis, specific preventive treatment is carried out before starting Humira therapy. The need for anti-tuberculosis treatment should be considered before initiating Humira therapy in patients who have risk factors for developing tuberculosis infection but who have tested negative for latent tuberculosis. The decision to initiate anti-tuberculosis therapy in these patients is made after consultation with a TB specialist and assessment of the risk of developing latent tuberculosis and the safety of anti-tuberculosis treatment. Specific treatment of latent tuberculosis reduces the risk of reactivation of tuberculosis during therapy with Humira. However, active tuberculosis also developed in patients screened negative for latent tuberculosis infection who received Humira, and in some patients previously treated for latent or active tuberculosis, active tuberculosis developed during treatment with TNF blockers. While using Humira, patients should be monitored for symptoms of active tuberculosis, taking into account the possibility of false-negative test results for latent tuberculosis (in severely ill and immunocompromised patients). All patients should be warned about the need to consult a doctor when initial symptoms of tuberculosis appear (persistent cough, weight loss, low-grade fever). Opportunistic infections . Opportunistic infections have been reported during treatment with Humira. Sometimes such infections were not diagnosed in a timely manner, which led to late initiation of treatment and sometimes to death. When treated with TNF blockers, patients are more susceptible to developing severe fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, etc.). All patients who develop fever, malaise, weight loss, hyperhidrosis, cough, shortness of breath and/or pulmonary infiltrates, or other signs of severe systemic illness (with or without shock) should be immediately evaluated for opportunistic infections. Due to the increased risk of developing histoplasmosis or other invasive fungal infections, empirical antifungal therapy is administered until the pathogen is identified. It is recommended to discontinue use of the TNF blocker if a severe fungal infection develops until the infection is controlled. Hepatitis B reactivation . The use of TNF blockers may be accompanied by reactivation of hepatitis B virus (HBV) in infected patients carrying this virus. Several cases of death due to reactivation of the hepatitis B virus have been described when using TNF blockers. In most cases, HBV activation was observed in patients receiving concomitant immunosuppressive therapy in addition to TNF blockers. Patients at risk for hepatitis B should be carefully screened for HBV infection before anti-TNF monoclonal antibodies are prescribed. The question of prescribing TNF blocker therapy to HBV carriers should be decided taking into account the possible risk to the patient. If a carrier of HBV is prescribed therapy with monoclonal antibodies to TNF, the patient should be closely monitored throughout the course of therapy and for several months after its completion. If reactivation of the hepatitis B virus occurs while using Humira, treatment with Humira should be discontinued and appropriate antiviral therapy should be initiated. Neurological disorders . Isolated cases of onset or exacerbation of clinical symptoms and/or radiographic signs of demyelinating diseases, including multiple sclerosis, have been reported with the use of Humira and other TNF blockers. Before using Humira for demyelinating diseases of the central nervous system, the benefit/risk ratio should be assessed. Malignant neoplasms . In controlled studies, the incidence of malignancy in patients receiving anti-TNF monoclonal antibodies was higher than in control groups. The total number of patients receiving placebo and the duration of their follow-up were less than the number and duration of follow-up of patients receiving TNF blockers, which does not allow definite conclusions to be drawn. In addition, the risk of developing lymphoma is increased in highly active rheumatoid arthritis, which makes it difficult to assess the risk of its development during treatment. During long-term, open-label clinical studies of Humira, the overall incidence of malignancies was similar to what would be expected in the general population matched for age, sex, and race. However, a possible risk of developing lymphomas or other malignancies cannot be excluded when using TNF antagonists. In clinical studies of adalimumab for juvenile rheumatoid arthritis, no malignancies were identified. Hepatolienal T-cell lymphoma has been reported very rarely with adalimumab in post-marketing experience, with most patients previously treated with infliximab in combination with azathioprine or 6-mercaptopurine for Crohn's disease. The causal relationship between the development of hepatolienal T-cell lymphoma and adalimumab use remains unclear. There are no clinical studies on the use of Humira in patients with a history of malignancy or on continuation of therapy if malignancy occurs, which should be considered when deciding whether to use Humira in such patients. In all patients, especially those with a history of extensive immunosuppressive therapy or patients with psoriasis who have received phototherapy, the presence of a malignant skin disease should be excluded before and during use of Humira. Allergy . During clinical studies, severe allergic reactions were rare with Humira. Severe allergic reactions, including anaphylaxis, have been reported very rarely during post-marketing use of the drug. If an anaphylactic or other severe allergic reaction occurs, Humira should be discontinued immediately and appropriate therapy initiated. The syringe needle cap contains latex, which can cause a severe allergic reaction. Hematological disorders . Rare cases of pancytopenia, including aplastic anemia, have been described during treatment with TNF blockers. When prescribing Humira, adverse events from the hematopoietic system, including clinically significant thrombocytopenia, leukopenia, were recorded infrequently; their connection to Humira remains unclear. Patients should immediately consult a doctor if symptoms of blood disorders (persistent fever, bruising, bleeding, pale skin) appear during treatment with Humira. If pronounced changes in blood composition are confirmed, discontinuation of Humira should be considered. Immunosuppression . During clinical trials of Humira in patients with rheumatoid arthritis, there was no evidence of inhibition of delayed-type hypersensitivity reactions, decreases in Ig levels, or changes in the number of effector T cells, B cells and NK cells, monocytes/macrophages and neutrophil granulocytes. Vaccination . Vaccinations may be administered while using Humira, with the exception of live vaccines. There is no data on the possibility of infection during vaccination with live vaccines during treatment with Humira. For juvenile rheumatoid arthritis, it is recommended, if possible, to carry out all necessary vaccinations according to the schedule before starting Humira therapy. Chronic heart failure . The use of Humira has not been studied, but in clinical trials of another TNF antagonist, an increase in the incidence of progression of chronic heart failure and the development of new cases was noted. Cases of progression of heart failure have also been described in patients receiving Humira. Humira should be administered with caution and under close medical supervision to patients with heart failure. Autoimmune processes . Humira therapy may cause the development of autoantibodies. The effect of long-term use of Humira on the development of autoimmune diseases is unknown. If symptoms of lupus-like syndrome occur, treatment with Humira should be discontinued. Elderly patients . No dose adjustment is required. Impaired liver or kidney function . Humira has not been studied and no dosage adjustments are recommended. During pregnancy and breastfeeding . There is no clinical data on the use of Humira during pregnancy, so it is not recommended to use the drug unless absolutely necessary. In women of reproductive age, contraceptive methods are used during the treatment period and for at least 5 months after the last injection of Humira. It is unknown whether adalimumab is excreted into breast milk or absorbed after oral administration. Given that Ig passes into breast milk, it is recommended that breastfeeding be discontinued during and after treatment with Humira (given the importance of therapy for the mother). Breastfeeding is permitted no earlier than 5 months after the last Humira injection. Children . Humira has not been studied in children younger than 4 years of age. There are limited data on the use of Humira in children weighing ≤15 kg. The safety and effectiveness of Humira in children for indications other than juvenile rheumatoid arthritis have not been established.

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.

Humira drug interactions

Use with anakinra . In clinical studies with the combined use of anakinra and the TNF blocker etanercept, the development of severe infections was noted with no additional clinical effect compared to etanercept monotherapy. Given the nature of the adverse events that developed during combination therapy with anakinra and etanercept, similar effects can be expected when treating anakinra in combination with other TNF blockers. Therefore, combination therapy with adalimumab and anakinra is not recommended. Use with abatacept . The combined use of a TNF antagonist and abatacept increased the risk of developing infections, including severe infections, compared with TNF antagonist monotherapy, without any therapeutic benefit. Therefore, the combined use of TNF antagonists and abatacept is not recommended. With the combined use of Humira and methotrexate, no statistically significant changes in the plasma concentration profiles of methotrexate were detected, so there is no need for dose adjustment of Humira or methotrexate. The interaction between Humira and drugs other than methotrexate has not been studied. In clinical studies, no interactions were observed when using Humira with sulfasalazine, hydrochloroquine, leflunomide, gold preparations, corticosteroids, salicylates, analgesics and other NSAIDs.