Humira® (Humira®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAdalimumabAdalimumab
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  • Humira®
    solution PC 
    EbbVi Ltd.     Russia
  • Humira®
    solution PC 
    EbbVi Ltd.     Russia
    • Dosage form: & nbsphypodermic solution
    Composition:

    The 0.8 ml solution contains:

    Active substance: adalimumab - 40.0 mg.

    Excipients: mannitol - 9.6 mg; citric acid monohydrate - 1,044 mg; sodium citrate - 0.244 mg; sodium hydrogen phosphate dihydrate - 1.224 mg; sodium dihydrogenphosphate dihydrate 0.688 mg; sodium chloride - 4.932 mg; polysorbate 80 - 0.8 mg; water for injection - 759,028-759,048 mg; sodium hydroxide for correction of pH - 0,02-0,04 mg.

    Description:

    Opalescent lightly colored solution.

    Pharmacotherapeutic group:Immunosuppressive remedy
    ATX: & nbsp

    L.04.A.B.04   Adalimumab

    Pharmacodynamics:

    Adalimumab is a recombinant monoclonal antibody whose peptide sequence is identical IgG1 rights. Adalimumab selectively binds to tumor necrosis factor alpha (TNF-α) and neutralizes its biological functions through blockade of interaction with surface cellular p55 and p75 receptors to TNF-α. TNF-α is a natural cytokine that participates in the regulation of the normal inflammatory process and the immune response. Elevated concentrations of TNF-α are found in synovial fluid in patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis.TNF-α plays an important role in the development of the pathological inflammatory process and the destruction of the articular tissue characteristic of these diseases. Elevated concentrations of TNF-α are also found in psoriatic plaques. With plaque psoriasis treatment with adalimumab can lead to a decrease in the thickness of plaques and infiltration by inflammatory cells. The relationship between this clinical effect of adalimumab and its mechanism of action has not been established.

    Also adalimumab modulates biological responses that are enhanced or regulated by TNF-α, including changes in levels of adhesion molecules that cause migration of leukocytes.

    Pharmacodynamics

    In patients with rheumatoid arthritis adalimumab caused a rapid decrease in the concentration of acute phase parameters of inflammation (C-reactive protein (SRV) and erythrocyte sedimentation rate) and serum cytokine concentration (interleukin-6). Reducing the concentration of SRV was also observed in patients with juvenile idiopathic arthritis or Crohn's disease. In addition, there was a decrease in the serum activity of matrix metalloproteinases (MMP-1 and MMP-3), causing tissue remodeling, which underlies the destruction of cartilaginous tissue.


    Pharmacokinetics:

    Suction

    Adalimumab is absorbed and distributed slowly and reaches its maximum serum concentration after about 5 days. Absolute bioavailability of adalimumab with a single subcutaneous injection of 40 mg is 64%.

    Distribution and deduction

    Volume of distribution (Vd) with a single intravenous administration is from 4.7 liters to 6.0 liters, indicating an almost identical distribution of adalimumab in the blood and extravascular fluids. Adalimumab output slowly, clearance (Cl) usually does not exceed 12 ml / h. The half-life (T1/2) is, on average, 2 weeks and varies from 10 to 20 days. FROMl and T1/2 essentially do not change at introduction of doses of 0,25-10 mg / kg, and Т1/2 similar to intravenous and subcutaneous administration of adalimumab. The concentration of adalimumab in synovial fluid in patients with rheumatoid arthritis ranges from 31% to 96% of serum.

    Pharmacokinetics of adalimumab in an equilibrium state

    The equilibrium concentrations of adalimumab when administered subcutaneously at a dose of 40 mg once every two weeks in patients with rheumatoid arthritis at the end of the dosing interval were about 5 μg / ml (without simultaneous administration of methotrexate (MTX)) and 8-9 μg / ml (against simultaneous application MTX).With an increase in the dose of adalimumab in the range of 20 mg, 40 mg and 80 mg once every two weeks and once a week, a close to proportional increase in serum concentrations of adalimumab at the end of the dosing interval was noted subcutaneously. With prolonged use (more than 2 years), the clearance of adalimumab remained unchanged.

    When monotherapy with adalimumab at a dose of 40 mg once every 2 weeks, the average equilibrium minimum concentration (Cmin) of the drug in patients with psoriasis was 5 mcg / ml. There is a tendency to increase Cl adalimumab with an increase in body weight and the presence of antibodies to adalimumab.

    For patients with Crohn's disease, with a starting dose of 160 mg adalimumab at week 0 and followed by a dose of 80 mg at week 2, adalimumab reaches its maximum serum concentration (CmOh) (approximately 12 μg / ml) at the 2 nd and 4 th week.

    In patients with Crohn's disease, an equilibrium concentration (approximately 7 μg / ml) is observed at the 24th and 56th weeks of maintenance therapy with 40 mg adalimumab once every 2 weeks.

    Children

    After the administration of 24 mg / m2 adalimumab (maximum 40 mg) subcutaneously biweekly to patients aged 4 to 17 years with juvenile idiopathic arthritis the mean equilibrium concentration of adalimumab (measured from the 20th week to the 48th)in the serum was 5.6 ± 5.6 μg / ml (102% coefficient of variation (CV)) with monotherapy and 10.9 ± 5.2 μg / ml (47.7% CV) with concomitant therapy with methotrexate. The mean equilibrium serum adalimumab concentration in patients with a body weight of less than 30 kg, after administration of Humira® 20 mg dose subcutaneously once every two weeks, was 6.8 μg / ml with monotherapy and 10.9 μg / ml when applied in combination with methotrexate. The mean equilibrium concentration of adalimumab in the blood serum in patients with a body weight of 30 kg or more after administration of Humira® at a dose of 40 mg subcutaneously every two weeks was 6.6 μg / ml with monotherapy and 8.1 μg / ml when used in combination with methotrexate. In patients aged 2 years to 4 years or 4 years and older with a body weight of less than 15 kg with juvenile idiopathic arthritis, the average equilibrium concentration was 6.0 ± 6.1 μg / ml (101% CV) with monotherapy and 7.9 ± 5.6 μg / ml (71.2 % CV) when used in combination with methotrexate.

    In pediatric patients with Crohn's disease (moderate to severe) after administration of a starting dose of adalimumab 160/80 mg at week 0 and with a subsequent dose of 80/40 mg at week 2 (depending on body weight) and further with using maintenance doses of 40/20 mg or 20/10 mg once every 2 weeks (depending on body weight),the mean serum concentration of adalimumab (taking into account the standard deviation) at the 4th week of use was 15.7 ± 6.6 μg / ml (in patients with a body weight of 40 kg and more) and 10.6 ± 6.1 μg / ml (in patients with body weight less than 40 kg).

    Elderly patients

    Age has a minimal effect on Cl adalimumab.

    Sex, race

    Differences in pharmacokinetics (adjusted for body weight) in patients of different sex and race were not revealed.

    Hepatic and renal insufficiency

    Information about the pharmacokinetics of adalimumab in patients with impaired liver or kidney function.

    Indications:

    Adults

    - Severe and severe active rheumatoid arthritis (in monotherapy or in combination with methotrexate or other basic anti-inflammatory drugs).

    - Active psoriatic arthritis (in monotherapy or in combination with methotrexate or other basic anti-inflammatory drugs).

    - Active ankylosing spondylitis.

    - Crohn's disease (moderate or severe):

    1. with an inadequate response to traditional therapy, as well as intolerance or contraindications to traditional therapy;

    2. with inefficiency (or a decrease in efficacy) or intolerance to infliximab.

    - Chronic plaque psoriasis (moderate to severe) when systemic therapy or phototherapy is indicated and when other options for systemic therapy are not optimal.

    Children

    - Juvenile idiopathic arthritis in patients 4 years to 17 years of age in monotherapy or in combination with methotrexate.

    - Crohn's disease (moderate to severe) in patients 6 years and older with an inadequate response to traditional therapy, as well as intolerance or contraindications to conventional therapy.

    Contraindications:

    - Hypersensitivity to adalimumab or any of its auxiliaries.

    - Pregnancy.

    - Breastfeeding period.

    - Children under 18 years of age, except for patients from 4 years to 17 years with juvenile idiopathic arthritis and patients 6 years and older with Crohn's disease (moderate or severe).

    - Infectious diseases, including tuberculosis.

    - Joint reception with other genetically engineered biological antirheumatic drugs (for example, anakinra and abatacept), including TNF antagonists.

    Carefully:

    - Recurrent infections in the anamnesis.

    - The carrier of the hepatitis B virus.

    - Malignant neoplasms, including in the anamnesis.

    - Heart failure.

    - Demyelinating diseases of the nervous system, including in the anamnesis.

    - Patients over 65 years of age.

    Pregnancy and lactation:

    In studies on animals in doses up to 100 mg / kg, the signs of the damaging effect of adalimumab on the fetus were not revealed. However, in evidence-based controlled trials in pregnant women, the drug has not been studied, therefore adalimumab it is contraindicated to apply during pregnancy. Women of reproductive age should avoid pregnancy during treatment with adalimumab.

    Information on the excretion of adalimumab with breast milk or its absorption after ingestion is not present.

    Many human immunoglobulins penetrate into breast milk. Given the risk of developing serious adverse reactions in the newborn, breastfeeding is contraindicated during treatment with adalimumab for at least five months after the last injection of adalimumab. It is advisable to stop breastfeeding or abolish the drug, taking into account its importance for the mother.

    Childbirth

    The effect of adalimumab on labor and delivery is unknown.

    Dosing and Administration:

    Subcutaneously.

    Treatment with Humira® is carried out under the supervision of a doctor. If the doctor considers this possible, then after appropriate training in the hypodermic injection technique, patients can independently administer the drug themselves.

    The drug Humira® is administered subcutaneously in the region of the thigh or abdomen. The solution should be inspected before introduction for the presence of foreign particles and discoloration.

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

    If another injection of Humira® was accidentally missed, it is necessary to inject immediately as soon as it is detected. The next injection should be carried out in accordance with the schedule previously planned.

    Adults

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

    The recommended dose of Humira preparation in adults with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) is 40 mg subcutaneously once every two weeks.With the appointment of Humira®, glucocorticosteroid therapy, 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 who do not receive methotrexate, an additional effect can be achieved with an increase in the frequency of administration of Humira® to 40 mg once a week.

    Crohn's disease

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

    Patients who observe a decrease in response to drug treatment may receive an additional effect from an increase in the frequency of administration of Humira® to 40 mg once a week.

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

    Chronic plaque psoriasis

    The initial dose for adult patients is 80 mg.

    The maintenance dose is 40 mg once every two weeks, starting one week after the initial dose.

    Children

    Juvenile idiopathic arthritis

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

    With 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 every 2 weeks. The volume of injection is determined based on the height and weight of the patient (see Table 1).

    For patients who require the administration of less than 40 mg of the drug, it is necessary to use the Humira® preparation in the vial.

    Growth

    Total body weight (kg)

    (cm)

    10

    15

    20

    25

    30

    35

    40

    45

    50

    55

    60

    65

    70

    80

    0,2

    0,3

    0,3

    0,3










    90

    0,2

    0,3

    0,3

    0,4

    0,4

    0,4








    100

    0,3

    0,3

    0,3

    0,4

    0,4

    0,4

    0,5

    0,5






    110

    0,3

    0,3

    0,4

    0,4

    0,4

    0,5

    0,5

    0,5

    0,5

    0,6

    0,6



    120

    0,3

    0,4

    0,4

    0,4

    0,5

    0,5

    0,5

    0,6

    0,6

    0,6

    0,6

    0,7

    0,7

    130


    0,4

    0,4

    0,5

    0,5

    0,5

    0,6

    0,6

    0,6

    0,6

    0,7

    0,7

    0,7

    140


    0,4

    0,4

    0,5

    0,5

    0,6

    0,6

    0,6

    0,7

    0,7

    0,7

    0,7

    0,8*

    150



    0,5

    0,5

    0,6

    0,6

    0,6

    0,7

    0,7

    0,7

    0,7

    0,8*

    0,8*

    160



    0,5

    0,5

    0,6

    0,6

    0,7

    0,7

    0,7

    0,8*

    0,8*

    0,8*

    0,8*

    170




    0,6

    0,6

    0,6

    0,7

    0,7

    0,8*

    0,8*

    0,8*

    0,8*

    0,8*

    180




    ...

    0,6

    0,7

    0,7

    0,8*

    0,8*

    0,8*

    0,8*

    0,8*

    0,8*

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

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

    Clinical response is usually achieved within 12 weeks of treatment. The decision to discontinue therapy can be made if the patient does not receive the effect of treatment during this period.

    Crohn's disease

    Patients weighing less than 40 kg: 80 mg on the first day (two injections of 40 mg per day are used), after 2 weeks (on the 15th day) - 40 mg, after 2 weeks (29th day) they begin to use the maintenance dose for the next scheme - 20 mg once every 2 weeks (moderate to severe).

    Patients with a body weight of 40 kg and more: 160 mg on day 1 (four injections of 40 mg per day or two injections of 40 mg per day, successively for two days),

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

    maintaining the dose according to the following scheme:

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

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

    Patients who have a reduced response to treatment with the drug may receive an additional effect from an increase in the frequency of administration of the drug Humira® up to 1 st time a week.

    Clinical response is usually achieved within 12 weeks of treatment. The decision to discontinue therapy can be made if the patient does not receive the effect of treatment during this period.

    The use of Humira® in children younger than 6 years with Crohn's disease has not been studied.


    Instructions for the preparation and injection of the drug Humira® look in the information sheet, enclosed in a cardboard box.

    INSTRUCTION FOR THE PREPARATION AND INDUCTION OF THE INJECTION OF THE PREPARATION HUMIRA® IN ONE-DAY SYRINGE

    Preparation

    - Wash your hands thoroughly.

    - Remove from the package and put on a clean surface one syringe with the drug Humira® and one alcohol-soaked napkin.

    - Ensure that the shelf life of the Humira® preparation indicated on the syringe has not expired.

    Selection and preparation of injection site

    - Choose a place on the abdomen or the front surface of the thigh.

    - Place injection and side should be changed.

    - Each next injection site should deviate at least 3 cm from the previous one.

    - Do not administer the drug to a place on the skin where there is soreness, redness, tightness, or bruising. These signs may indicate an infection.

    - Place the injection site with an alcoholic napkin in circular motions.

    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, fold the treated skin.

    - In the other hand, take the syringe, holding it at an angle of 45 ° to the surface of the skin, graduated with the surface upwards.

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

    - After inserting the needle, release the skin fold.

    - Enter the entire solution within 2-5 seconds.

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

    - With a piece of gauze, squeeze the injection area lightly for 10 seconds, but do not rub the surface. A small amount of blood can be released from the injection site. If you want, you can use a band-aid.

    - After the injection, the syringe should not be reused.

    INSTRUCTION FOR THE PREPARATION AND INDUCTION OF THE INJECTION OF THE PREPARATION HUMIRA® IN THE FLOAT

    Preparation

    - Make sure that you know how much (volume) of the drug you need to enter.

    - Wash your hands thoroughly.

    - Take from a carton box one box containing one syringe, one nozzle per vial, one bottle, two alcohol napkins and one needle.If there is another box in the carton with the kit for the next injection, immediately remove it to the refrigerator.

    - Check the shelf life of the product on the box. DO NOT USE the kit after the expiration date.

    - Put the following items on a clean surface, at this stage DO NOT pull them out of the individual package.

    - One 1 ml syringe (1)

    - One nozzle per vial (2)

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

    - Two alcohol wipes (4)

    - One needle (5)

    The drug Humira® is a clear, colorless liquid. Do not use the drug if the liquid is cloudy, contains flakes or particles, or changes its color.

    Preparation of a dose of Humira® preparation for administration

    The general rule: do NOT throw anything away until the end of the injection.

    - Prepare the needle, partially removing the packaging from the side closest to the yellow connecting cap of the needle. Remove the packaging exactly enough so that open the yellow connecting cap. Keep the package open end up.

    - Remove the white plastic cap from the bottle so as to see the top of the vial plug.

    - One of the alcohol wipes wipe the stopper bottle. After that, DO NOT touch the vial.

    - Open the packing of the nozzle on the bottle, but do not remove it from the package.

    - Keep the bottle upside down.

    - Without taking out the nozzle on the bottle from the package, connect it to the stopper of the bottle, pressing the nozzle onto the stopper until it clicks into place.

    - When you make sure that the nozzle is connected to the bottle, remove the packing 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, partially taking off the packaging, open from the side closest to the white rod-piston.

    - Remove the package exactly enough to open the white piston rod, but do not pull the syringe out of the package.

    - Hold the syringe packing and SLOWLY pull out the white rod-piston, so that the volume exceeds the required dose by 0.1 ml. (For example, if the prescribed dose is 0.5 ml, pull out the white piston rod to 0.6 ml). NIKODA does not extend the piston beyond the position corresponding to 0.9 ml, regardless of the prescribed dose.

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

    - DO NOT PULL the white stem-piston from the syringe completely.

    NOTE:

    If the white rod-piston is completely removed from the syringe, the syringe can not be used. DO NOT try to insert a white piston rod back.

    DO NOT use a white plunger-piston to remove the syringe from the package. Remove the syringe from the package, while the piston rod must remain in the set position. Never tip the syringe.


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

    - While holding the bottle, press the piston rod and fully lower it. This step is important for obtaining the correct dose of the drug. Hold the white piston rod inside and flip the syringe with the vial.

    - SLOWLY pull the white piston rod to the mark, 0.1 ml higher than the required dose. This is important for getting the right dose. You will adjust the dose in step 4 (Dose preparation). If the prescribed dose is 0.5 ml, pull out the white piston rod to 0.6 ml. You will see how the liquid from the vial fills the syringe.

    - Press down on the white piston rod, so that the liquid is returned to the bottle.Again SLOWLY pull the white piston rod to the mark, 0.1 ml higher than the required dose, this is important for obtaining the correct dose and preventing the formation of air bubbles and air gaps. You will adjust the dose in step 4 (Dose preparation).

    - If you see that air bubbles or air gaps remain in the syringe, you can repeat this procedure up to three times. DO NOT rush the syringe.

    NOTE:

    If the white rod-piston is completely removed from the syringe, the syringe can not be used. DO NOT try to insert a white piston rod back.


    - While still holding the syringe upright, disconnect the nozzle from the syringe on the vial with the vial, turning the bottle adapter with the other hand. Make sure that, together with the vial, you are disconnected from the syringe and the nozzle. DO NOT touch the tip of the syringe.

    - If large bubbles of air or air gaps are visible near the tip of the syringe, SLOWLY push the white piston rod until the liquid begins to fill the tip of the syringe. DO NOT PRESS on the white piston rod after reaching the required dose mark.

    - For example, if the prescribed dose is 0.5 ml, DO NOT PRESS ON the white plunger after reaching 0.5 ml.

    - Make sure that the volume of fluid remaining in the syringe is at least not less than 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.

    - While holding the syringe pointing upwards, insert the tip of the syringe into the yellow connecting cap of the needle and turn the syringe until it stops, as indicated by the arrow in the picture below. Now the needle is connected to the syringe.

    - Remove the packing from the needle, but DO NOT REMOVE the protective cap of the needle.

    - Place the syringe on a clean work surface. Immediately go to the selection of the area for injection and dose preparation.

    Selection and preparation of the area for injection

    - Select the area on the hip or abdomen.

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

    - Do not administer the drug to a place on the skin where there is soreness, redness, tightness, or bruising. These signs may indicate an infection.

    - To reduce the risk of infection, treat the injection area with a second alcohol sponge.Do not touch the area of ​​injection before injection.

    Preparation of the dose

    - Take the syringe so that the needle is pointing upwards.

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

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

    - DO NOT touch the needle.

    - DO NOT place the syringe after removing the cap from the needle.

    - DO NOT try to put a protective cap on the needle.

    - Hold the syringe at eye level, with the needle pointing upwards. You should clearly see the amount of the drug in the syringe. Be careful that the product does not get in your eyes.

    - Once again, check how much of the drug you need to measure.

    - Gently push the white piston rod so that the prescribed amount of the drug remains in the syringe. Excess of the drug can exit the needle. DO NOT PROMOT the needle or syringe.

    Introduction of the drug Humira®

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

    - With the other hand, take the syringe and hold it at an angle of 45 ° to the skin.

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

    - Release the skin fold.

    - Press on the white rod-piston to insert the drug. Enter the entire medicine.

    - When the syringe is empty, remove the needle from the skin.Be careful, remove the needle at the same angle as it was injected.

    - Carefully place the pink cap on the needle until it clicks. Place the syringe with the needle on the work surface.

    - DO NOT take the protective cap off the needle.

    - After the injection, the syringe, vial, needle, needle cap and nozzle on the bottle should not be reused.

    - With a piece of gauze, press the injection area for 10 seconds.

    - There may be a slight bleeding. DO NOT rub the injection site. The area of ​​injection can be sealed with a patch.

    Side effects:

    Clinical Trials Data

    Approximately 14% of patients can be expected to develop reactions at the injection site (one of the most common adverse reactions with adalimumab administration in controlled clinical trials).

    Adverse reactions may be causally related to the use of the drug, both clinical and laboratory, are given below with frequency (very often> 1/10, often> 1/100, but <1/10, infrequently> 1/1000, but < 1/100, rarely> 1/10000, but <1/1000). The highest frequency observed among the various indications was included.

    Infections

    Very often: respiratory tract infections (including upper and lower respiratory tract infections, pneumonia, sinusitis, pharyngitis, nasopharyngitis and herpesvirus pneumonia).

    Often: generalized infections (including sepsis, candidiasis and influenza), gastrointestinal infections (including viral gastroenteritis), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotizing fasciitis and shingles), ear infections, oral infections (including herpes simplex, oral herpes and dental lesions), infections of the genital area (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, infection of joints.

    Infrequently: opportunistic infections and tuberculosis (including coccidiomycosis, Histoplasmosis and a complex of infections caused by Mycobacterium avium), neurological infections (including viral meningitis), eye infections, bacterial infections.

    Neoplasms

    Often: benign neoplasms, skin cancer, except melanoma (including basal cell carcinoma and scaly-cell carcinoma).

    Infrequently: lymphoma, parenchymal neoplasms (including breast cancer, lung and thyroid malignancy), melanoma.

    On the part of the blood and lymphatic system

    Very often: leukopenia (including neutropenia and agranulocytosis), anemia.

    Often: thrombocytopenia, leukocytosis.

    Infrequently: idiopathic thrombocytopenic purpura.

    Rarely: pancytopenia.

    From the immune system

    Often: hypersensitivity reactions, allergic reactions (including seasonal allergy).

    From the side of metabolism

    Very often: an increase in the concentration of lipids.

    Often: hypokalemia, increased concentration of uric acid, abnormal sodium concentrations, hypocalcemia, hyperglycemia, hypophosphatemia, dehydration.

    Disorders of the psyche

    Often: mood changes (including depression), anxiety disorders, insomnia.

    From the nervous system

    Very often: headache.

    Often: paresthesia (including hypoesthesia), migraine, neuralgia of the sciatic nerve, vestibular dizziness.

    Infrequently: tremor, neuropathy.

    Rarely: multiple sclerosis.

    From the sense organs

    Often: conjunctivitis, visual impairment, blepharitis, edema of the eyelid.

    Infrequently: diplopia, deafness, ringing in the ears.

    From the side of the cardiovascular system

    Often: increased blood pressure, hot flashes, bruises, tachycardia.

    Infrequently: arrhythmia, chronic heart failure, arterial occlusion, thrombophlebitis, aortic aneurysm.

    Rarely: cardiac arrest.

    On the part of the respiratory system

    Often: cough, asthma, dyspnoea.

    Infrequent: chronic obstructive pulmonary disease, interstitial lung diseases, pneumonitis.

    From the side of the digestive system

    Very often: nausea, vomiting, abdominal pain, increased activity of hepatic enzymes.

    Often: dyspepsia, gastroesophageal reflux, dry mouth, gastrointestinal bleeding.

    Infrequently: pancreatitis, dysphagia, edema of the face, cholecystitis, cholelithiasis, increased bilirubin concentration, hepatic steatosis.

    From the skin and subcutaneous tissues

    Very often: a rash (including exfoliative).

    Often: itching, hives, hemorrhages (including purpura), dermatitis (including eczema), brittle nails, hyperhidrosis.

    Infrequently: night sweats, scars.

    From the musculoskeletal system

    Very often: musculoskeletal pain.

    Often: muscle spasms.

    Infrequently: rhabdomyolysis, systemic lupus erythematosus.

    From the genitourinary system

    Often: hematuria, renal insufficiency.

    Infrequently: nocturia, erectile dysfunction.

    Other, including reactions at the site of administration

    Very often: reactions at the injection site (including erythema).

    Often: pain in the chest, swelling, worsening of wound healing.

    Infrequently: inflammation.

    Laboratory indicators

    Often: disorders in the blood coagulation system (including increased activated partial thromboplastin time), positive tests for autoantibodies (including antibodies to the double helix DNA), increased lactate dehydrogenase concentration.

    Clinical trials with JIA

    In general, the adverse reactions in children were the same in type and frequency with those observed in adults.

    Reactions at the injection site

    In baseline studies, 13.6% of patients who received adalimumab, reactions at the site of administration (erythema and / or itching, bleeding, pain, swelling) developed in the control group, such reactions developed in 7.6% of patients. Most of the reactions at the injection site were assessed as weak and did not require discontinuation of the drug.

    Infections

    In controlled studies, the level of infectious complications was 1.52 per patient per year for adalimumab treatment and 1.45 per patient per year in the control group of patients (adult and pediatric ages). The incidence of serious infectious complications was 0.04 per patient per year with adalimumab treatment and 0.03 per patient per year in the control group of patients.Infectious complications were in most cases presented by infections of the upper respiratory tract, bronchitis and urinary tract infections. Most patients continued to take adalimumab after resolving the infection.

    In controlled open trials of the use of adalimumab, serious infections (including infrequently occurring fatal infections) have been reported, in particular tuberculosis (including miliary and extrapulmonary), legionellosis and invasive opportunistic infections (including disseminated histoplasmosis, PCP, aspergillosis and listeriosis).

    Malignant neoplasms and lymphoproliferative disorders

    In clinical trials, 203 patients with JIA had no malignant neoplasms observed during 605.3 patient-years.

    In clinical studies, 192 children with childhood with Crohn's disease did not have malignant tumors observed during 258.9 patient-years.

    During controlled trials of baseline trials of adalimumab lasting at least 12 weeks in patients with RA, PsA, AC, Crohn's disease,ulcerative colitis and psoriasis with activity ranging from mild to severe malignant neoplasms, except for lymphoma and non-melanoma skin cancer, were observed with a frequency (with 95% confidence) 6.0 (3.7, 9.8) per 1000 patient-years among 4622 patients who took adalimumab, compared with 5.1 (2.4, 10.7) per 1000 patient-years among the 2828 patients in the control group (median duration of treatment was 5.1 months with adalimumab and 4 months in the control group). The frequency (with a certainty of 95%) of the appearance of lymphomas in patients using adalimumab was 0.7 (0.2, 3.0) per 1000 patient-years, while in the control group the frequency was 1.5 (0.4, 5.8).

    The frequency (with 95% confidence) of skin cancer, except for melanoma, was 9.7 (6.6, 14.3) per 1000 patient-years among patients taking adalimumab, and 5.1 (2.4, 10.7) per 1000 patient-years among patients in the control group. Of the total number of skin cancers, scaly-cell carcinomas occurred with a frequency (with 95% confidence) of 2.6 (1.2, 5.5) per 1000 patient-years among patients taking the drug adalimumab, and 0.7 (0.1, 5.2) per 1000 patient-years among patients in the control group.

    The observed incidence of malignant neoplasms, with the exception of lymphomas and non-melanoma skin cancers,was about 8.8 per 1000 patient-years in the controlled part of the clinical trial and in ongoing and completed open trials. The observed incidence of skin cancer (except melanoma) was about 10.3 per 1000 patient years, the observed incidence of lymphoma was about 1.4 per 1000 patient-years. The average duration of these studies was about 3.4 years and included 5727 patients who took adalimumab at least 1 year or who developed malignant neoplasm within 1 year of initiation of therapy, covering 24568 patient-years.

    Autoantibodies

    On I-V During the RA study, the patient's blood serum was analyzed for autoantibodies. In reliable controlled trials, it was reported that 11.9% of patients who took the drug adalimumab, and in 8.1% of placebo-treated patients and control patients who had initially negative antinuclear antibody titers, positive titers appeared at week 24. In two of the 3989 patients who took adalimumab in the studies of RA, PsA and AS, the clinical manifestations of the lupus-like syndrome developed. The condition of patients improved after the treatment was withdrawn.None of the patients developed lupus nephritis or symptoms of central nervous system damage. The effect of prolonged use of adalimumab on the development of autoimmune diseases remains unexplored.

    Psoriasis: development or deterioration

    Describes cases of the appearance of psoriasis, including pustular psoriasis and palmar dyspnoea psoriasis, and cases of worsening of existing psoriasis with all TNF blockers, including adalimumab. Many of these patients took immunosuppressants (including MTX, corticosteroids) as a concomitant medication. Some of these patients required hospitalization. Most patients experienced an improvement after withdrawal of TNF blockers. Some patients experienced a relapse of psoriasis after re-starting the administration of various TNF blockers. The abolition of adalimumab should be carried out in severe cases and when there is no improvement, or there is a deterioration in response to ongoing local treatment.

    The following are the adverse reactions indicated by organ systems, the frequency and the relationship of which with the administration of the drug is not proven.

    Post-marketing research data

    Infections and invasions

    Diverticulitis.

    Neoplasms are benign, malignant and unclassified (including cysts and polyps)

    Hepatospheric T-cell lymphoma, leukemia, Merkel's carcinoma (neuroendocrine cutaneous carcinoma).

    From the immune system

    Anaphylaxis, sarcoidosis.

    From the nervous system

    Demyelinating diseases (including optic neuritis, Hyena-Barre syndrome), cerebrovascular disorders.

    From the side of the cardiovascular system

    Pulmonary embolism, myocardial infarction.

    On the part of the respiratory system

    Pleural effusion, pulmonary fibrosis.

    From the side of the digestive system

    Perforation of the intestine, reactivation of the hepatitis B virus, hepatic insufficiency, hepatitis.

    From the skin and subcutaneous tissues

    Cutaneous vasculitis, Stevens-Johnson syndrome, Quincke's edema (angioedema), the appearance or deterioration of psoriasis (including palmar-plantar pustular psoriasis), erythema multiforme, alopecia.

    From the musculoskeletal system and connective tissue

    Lupus-like syndrome.

    Other, including reactions at the site of administration

    Increased body temperature.

    Overdose:

    The maximum tolerated dose of adalimumab in humans is not established. Repeated use of adalimumab in doses up to 10 mg / kg was not accompanied by toxic effects, which required a dose reduction. In case of an overdose, it is necessary to monitor adverse reactions and immediately begin adequate symptomatic treatment.

    Interaction:

    In patients with rheumatoid arthritis receiving methotrexate there is no need to adjust the dose of adalimumab or methotrexate. At the same time methotrexate with a single and repeated application reduces the clearance of adalimumab by 29% and 44%, respectively. The interaction of adalimumab with other drugs, in addition to methotrexate, has not been studied in pharmacokinetic studies. No signs of interaction of adalimumab with other basic agents have been observed in clinical studies (sulfasalazine, hydrochloroquine, leflunomide and parenteral preparations of gold), glucocorticosteroids, salicylates, nonsteroidal anti-inflammatory drugs and analgesics.

    Combined use with azathioprine / 6-mercaptopurine

    In clinical studies involving adults with Crohn's disease,increasing the frequency of malignancies and serious adverse reactions associated with infections, were observed in the group of patients who applied the combined use of adalimumab with azathioprine / 6-mercaptopurine, compared to a monotherapy adalimumab.

    Simultaneous application with genetically engineered biological antirheumatic drugs, including TNF antagonists

    Severe infections have been observed in clinical trials with the simultaneous use of anakinra and another TNF antagonist, etanercept, with no improvement in the clinical effect compared to the use of etanercept in the form of monotherapy. Based on the nature of the adverse reactions observed with the simultaneous use of etanercept and anakin, it is possible to assume the appearance of similar toxic effects with the simultaneous use of anakinr with other TNF antagonists. Thus, the simultaneous use of adalimumab with an anakin is contraindicated.

    Simultaneous use of adalimumab with other biological basic antirheumatic drugs (for example, anakinra,abatacept) or other antagonists of TNF is associated with an increased risk of infections and other adverse reactions, and is therefore contraindicated.

    Special instructions:

    Infections

    Adalimumab should not be started in patients with active infectious diseases, including chronic or focal infections, until the infection is stopped. In patients who have had contact with tuberculosis, as well as patients who have visited places with high incidence of tuberculosis or endemic mycoses such as histoplasmosis, coccidiomycosis or blastomycosis, the risk and effectiveness of adalimumab treatment should be assessed prior to initiation of therapy (see Other opportunistic infections) .

    As with other TNF antagonists, patients should be carefully screened for infectious diseases before, during and after treatment with adalimumab.

    Patients who developed an infectious disease during treatment with adalimumab should be identified and fully examined. The use of adalimumab should be suspended if the patient develops a serious infectious complication or sepsis, with the appropriate antibacterial and antifungal therapy to be carried out before the infectious disease is cured.

    Caution should be given adalimumab patients with recurrent infections in the anamnesis and in the presence of conditions predisposing to infectious complications.

    Tuberculosis

    The risk of developing active tuberculosis or the activation of latent tuberculosis is available with the admission of all TNF blockers, including adalimumab. The frequency of reactivation of tuberculosis was especially higher with doses of adalimumab exceeding the recommended values.

    Prior to the initiation of adalimumab therapy, all patients should be examined for active as well as inactive (latent) tuberculosis infection. This evaluation should include a detailed history of the disease, taking into account possible contacts with patients with active forms of tuberculosis and previous or current immunosuppressive therapy, as well as the necessary screening tests (including chest x-ray, tuberculin test). Treatment for latent tuberculosis infection should be performed prior to the initiation of adalimumab therapy. If the diameter of the papule after the cutaneous tuberculin test for latent tuberculosis infection is greater than 5 mm, then this test is considered positive, even if before the vaccination was carried out with a bacillus Calmette- Guerin (BCG or BCG).

    The possibility of an unidentified latent tuberculosis infection should be taken into account especially in those patients who immigrated from a country with a high incidence of tuberculosis or traveled to such a country, or those who were in contact with an active tuberculosis patient.

    If active tuberculosis is diagnosed, adalimumab therapy should not be started.

    In the event that latent tuberculosis is diagnosed, antituberculous prophylaxis should be performed before adalimumab treatment begins. Anti-TB therapy before treatment with adalimumab should also be given to those patients who have been exposed to risk factors for tuberculosis, even with a negative tuberculin test. The decision to conduct antituberculous 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 appointed by the phthisiatrist. Antituberculous treatment of patients with latent tuberculosis infection reduces the risk of reactivation of tuberculosis in the treatment of these patients with adalimumab. However, the risk the development of active tuberculosis or the activation of latent tuberculosis exists even in patients who underwent screening and / or anti-tuberculosis therapy, so careful monitoring of patients during therapy is necessary in order to timely detect symptoms of active tuberculosis, especially since tests for latent tuberculosis infection are often false negative. The risk of falsely negative results of intradermal tuberculin samples should be taken into account especially in patients with severe or immunocompromised patients.

    For this purpose, it is recommended to re-react Mantou 7-21 days after the first.

    Patients should be informed about the need to see a doctor if symptoms appear (persistent cough, weight loss, subfebrile fever), indicating the development of tuberculosis infection.

    Other opportunistic infections

    In patients who received adalimumab, opportunistic infections, including fungal infections, were observed. These infections require timely diagnosis and adequate treatment.

    Patients who develop fever, malaise, weight loss, profuse sweating, cough, dyspnea and / or lung infiltrates on a radiograph, or other severe systemic disorders with or without a shock, should immediately seek medical advice for diagnostic activities . Patients who stayed in zones endemic for various mycoses should be expected to develop fungal infections. Such patients are at a risk for developing a histoplasmosis or other fungal infection, and physicians therefore must conduct empirical antifungal therapy before determining the pathogen (s). Antigen-antibody assays for histoplasmosis may be negative in some patients with active infection. If possible, the decision to prescribe empirical antifungal therapy in such patients should be taken after consultation by a physician with expertise in the diagnosis and treatment of fungal infections, while taking into account both the risk of severe fungal infection and the risk of antifungal therapy.Patients who developed a severe fungal infection are advised to stop taking TNF blockers until the infection is healed.

    Reactivation of hepatitis B

    The use of blockers is associated with the reactivation of the hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some cases, the reactivation of HBV, resulting from the administration of TNF blockers, led to death. Most of these cases occurred in patients taking other medications that suppressed the immune system, which could also contribute to the reactivation of HBV. Patients at risk of HBV infection should be diagnosed with primary symptoms of HBV infection prior to initiating therapy with TNF blockers. Caution should be used to prescribe TNF blockers to patients who are carriers of HBV. Those patients who are carriers of HBV and who need treatment with TNF blockers should be carefully examined to identify signs of active HBV infection during therapy and a few months after the end of therapy. There are no reliable data on the safety or efficacy of treating HBV carriers with antiviral drugs in conjunction with TNF blockers to prevent the reactivation of HBV.In patients who develop HBV reactivation, the use of adalimumab should be stopped, and effective antiviral therapy with appropriate supportive treatment should be initiated.

    Neurological complications

    The use of TNF antagonists, including adalimumab, is associated with the rare occurrence or complication of clinical manifestations and / or radiographic signs of demyelinating diseases of the central nervous system, including multiple sclerosis and peripheral demyelinating diseases, including Guillain-Barre syndrome. It should be used with caution adalimumab patients with demyelinating diseases of the central and peripheral nervous system (ongoing or in history).

    Malignant neoplasms

    There is a higher risk of developing lymphoma in patients with rheumatoid arthritis, which is characterized by a prolonged, severe inflammation, which complicates the assessment of the degree of risk. During long open trials of adalimumab, the average level of malignant tumors was similar to that expected for the general population of a given age, gender, and race.Based on the available data, it is impossible to exclude the possible risk of developing lymphomas or other malignant neoplasms in patients using the TNF blocker.

    Malignant neoplasms have been reported, some of which lead to death in children and adults receiving treatment with TNF blockers. About half of the cases developed lymphomas, both Hodgkin's and non-Hodgkin's. In other cases, various malignant neoplasms, including rare malignant neoplasms associated with immunosuppression, were presented. Malignant neoplasms appeared on average after 30 months of therapy. Most patients received concomitant treatment with immunosuppressants.

    There are rare post-marketing reports of hepatosplenic T-cell lymphoma (GSTL), a rare aggressive lymphoma that occurs in patients receiving adalimumab, and often led to death. Most patients initially received infliximab therapy, as well as concomitant therapy for inflammatory bowel disease with azathioprine or 6-mercaptopurine.The cause-and-effect relationship of GSTCL with adalimumab administration has not been proven.

    There were no studies including patients with anamnesis of malignant neoplasms, or during which treatment with adalimumab continued in patients with developed malignant neoplasm. Therefore, caution should be exercised when using adalimumab in such patients.

    All patients, and in particular patients who previously received long-term therapy with immunosuppressants or PUVA-therapy of psoriasis, should be examined for the presence of non-melanoma-associated skin cancer that developed before or during treatment with adalimumab.

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

    Allergy

    Serious allergic reactions associated with adalimumab intake were rare during clinical trials.In post-marketing observations, severe allergic reactions, including anaphylactic shock, after adalimumab administration were described very rarely. If an anaphylactic reaction or other serious allergic reaction occurs, immediately stop using adalimumab and prescribe appropriate anti-allergic therapy.

    Hematologic complications

    There were rare reports of the development of pancytopenia, including aplastic anemia with the use of blockers. Occasionally, adverse reactions from the blood system have been reported, including significant cytopenia (including thrombocytopenia, leukopenia) in the treatment with adalimumab. The causal relationship of these reports with adalimumab administration remains unclear. All patients should be advised to consult a doctor immediately if they develop symptoms that indicate a violation of the blood system (including persistent fever, bruises, bleeding, pallor) when treated with adalimumab. With confirmed significant hematologic abnormalities, treatment with adalimumab should be stopped.

    Vaccination

    Patients of pediatric age are recommended, if possible, to undergo a full vaccination according to the current immunization schedule before adalimumab therapy begins.

    Patients receiving adalimumab, can receive vaccination in passing, with the exception of live vaccines.

    Chronic heart failure (CHF)

    There have been no studies of the use of adalimumab in patients with chronic heart failure (CHF), however, in the clinical trials of another antagonist of FIO, a higher level of adverse events associated with CHF, including development of CHF and progression of CHF, was observed. Cases of progression of CHF were also described in patients taking adalimumab. It should be used with caution adalimumab patients with heart failure, and carefully monitor such patients.

    Autoimmune processes

    Treatment with adalimumab can lead to the formation of autoimmune antibodies.

    The effect of prolonged treatment on the development of autoimmune diseases has not been studied.

    If the patient develops symptoms suggesting a lupus-like syndrome as a result of treatment with adalimumab, the drug should be discontinued.

    Elderly patients

    The incidence of serious infections among patients over 65 years of age who took adalimumab, was higher than in patients younger than 65 years. 10.3% of the total number of patients taking adalimumab was over 65 years of age and approximately 2.2% were older than 75 years. Adalimumab should be administered with caution in elderly patients due to the high likelihood of infectious diseases. Differences in efficacy in this group of patients compared with younger patients were not detected, dose adjustment is not required.

    Children

    The effectiveness and safety of adalimumab in children is indicated only for the treatment of idiopathic juvenile arthritis from 4 years to 17 years and Crohn's disease (moderate or severe) in patients 6 years and older.

    Form release / dosage:

    A solution for subcutaneous administration of 40 mg / 0.8 ml.

    Packaging:

    The drug in a single-dose syringe

    By 0.8 ml into single-dose syringes from colorless glass. 1 syringe together with 1 napkin, impregnated with 70% isopropyl alcohol, in laminated polyethylene paper, in a blister of PVC and laminated paper. For 1 or 2 blisters together with instructions for use in a pack of cardboard.

    The drug in the vial

    By 0,8 ml in bottles of colorless glass, sealed with a rubber stopper and an aluminum cap with a polypropylene lid.

    A kit for single-dose administration contains the components necessary for one subcutaneous injection:

    - one bottle of colorless glass containing 0.8 ml of the preparation;

    - one plastic syringe with a Luer compound in the blister;

    - one nozzle per bottle in the blister;

    - one injection needle with Luer compound, with polypropylene protective cap and polypropylene protective cover in blister;

    - two napkins, impregnated with 70% isopropyl alcohol, in laminated polyethylene paper.

    One set together with instructions for use in a pack of cardboard.

    Two packs of cardboard, each containing 1 set for single-dose administration and instructions for use, in a pack of cardboard.

    Storage conditions:

    At a temperature of 2 ° C to 8 ° C in a dark place. Do not freeze. Store in inaccessible to children.

    Shelf life:

    2 years. Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-002422
    Date of registration:28.02.2011
    The owner of the registration certificate:EbbVi Ltd.EbbVi Ltd. Russia
    Manufacturer: & nbsp
    Representation: & nbspEbbVi Ltd.EbbVi Ltd.Russia
    Information update date: & nbsp20.08.2014
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