Adalimumab - instructions for use, doses, side effects, contraindications

Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation

Humira®

solution PC

EbbVi Ltd. Russia

Humira®

solution PC

EbbVi Ltd. Russia

Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

VED

ONLS

АТХ:

L.04.A.B.04 Adalimumab

Pharmacodynamics:

Adalimumab is a recombinant monoclonal antibody whose peptide sequence is identical to human IgG1. Adalimumab selectively binds to the tumor necrosis factor alpha and neutralizes its biological functions by blocking interaction with surface cellular p55 and p75 receptors to the tumor necrosis factor alpha.

The tumor necrosis factor alpha is a natural cytokine that takes part in the regulation of a normal inflammatory and immune response. Elevated concentrations of tumor necrosis factor alpha are found in synovial fluid in patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis. The tumor necrosis factor alpha plays an important role in the development of pathological inflammation and destruction of the articular tissue characteristic of these diseases. Elevated concentrations of tumor necrosis factor alpha are also found in psoriatic plaques.With plaque psoriasis treatment with adalimumab can lead to a decrease in the thickness of plaques and a decrease in infiltration in inflammatory cells. The relationship of this clinical effect of adalimumab with the mechanism of its action is not established.

Adalimumab also modulates the biological responses that are induced or regulated by the tumor necrosis factor alpha, including changes in the levels of adhesion molecules that cause migration of leukocytes.

In patients with rheumatoid arthritis adalimumab causes a rapid decrease in the concentrations of acute phase indices of inflammation (C-reactive protein and erythrocyte sedimentation rate) and serum cytokine concentrations (interleukin-6). Reductions in C-reactive protein concentrations have also been observed in patients with juvenile idiopathic arthritis or Crohn's disease. In addition, there is a decrease in the serum activity of matrix metalloproteinases (MMP-1 and MMP-3) that cause tissue remodeling, which underlies cartilage destruction.

Pharmacokinetics:

Adalimumab is absorbed and distributed slowly, and reaches C_max in about 5 days.Absolute bioavailability of the drug with a single subcutaneous injection of 40 mg adalimumab is 64%.

In patients with Crohn's disease who are prescribed a drug at a starting dose of 160 mg at week 0 and a subsequent dose of 80 mg at week 2, C_max Adalimumab is achieved at the 2 nd and 4 th week and is approximately 12 μg / ml.

V_d (volume of distribution) with a single intravenous administration is from 4.7 to 6 liters, indicating an almost identical distribution of adalimumab in the blood and in extravascular fluids.

The concentration of adalimumab in synovial fluid in patients with rheumatoid arthritis is 31% to 96% of serum.

C_ss Adalimumab with subcutaneous application at a dose of 40 mg once in 2 weeks in patients with rheumatoid arthritis at the end of the dosing interval is about 5 μg / ml (without simultaneous administration of methotrexate) and 8-9 μg / ml (against simultaneous use of methotrexate). With an increase in the dose of adalimumab in the range of 20 mg, 40 mg and 80 mg every 2 weeks and once a week, an almost linear increase in serum concentrations of adalimumab at the end of the dosing interval was noted subcutaneously.

When appointing adalimumab at a dose of 40 mg in monotherapy once every 2 weeks, the average C_min of the drug in patients with psoriasis was 5 μg / ml.

In patients with Crohn's disease C_ss is approximately 7 μg / ml and is observed at the 24th and 56th weeks of maintenance therapy with adalimumab at a dose of 40 mg once every 2 weeks.

Adalimumab is excreted slowly, clearance usually does not exceed 12 ml / h. The half-life is on average 2 weeks and varies from 10 to 20 days. Clearance and half-life do not change significantly when the drug is administered at a dose of 0.25-10 mg / kg, and the half-life is similar for intravenous and subcutaneous administration of the drug.

With prolonged use (more than 2 years) the clearance of adalimumab does not change.

There is a tendency to increase the clearance of adalimumab in relation to body weight and the presence of antibodies to adalimumab.

Age has minimal effect on the clearance of adalimumab.

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

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

Indications:

- moderate 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) with an inadequate response to traditional therapy or inefficiency (or a decrease in effectiveness) of infliximab;

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

- Juvenile idiopathic arthritis in patients aged 13 to 17 years in monotherapy or in combination with methotrexate.

ICD-10

XI.K50-K52.K50 Crohn's disease [regional enteritis]

XII.L40-L45.L40 Psoriasis

XIII.M05-M14.M06.9 Rheumatoid arthritis, unspecified

XIII.M05-M14.M05 Seropositive rheumatoid arthritis

XIII.M05-M14.M08 Juvenile [juvenile] arthritis

XIII.M45-M49.M45 Ankylosing spondylitis

XIII.M05-M14.M07 * Psoriatic and enteropathic arthropathies

Contraindications:

Infectious diseases, including tuberculosis; pregnancy, lactation (breastfeeding); children and adolescents under the age of 18, except for patients aged 13 to 17 years with juvenile idiopathic arthritis; joint reception with drugs anakinra and abatacept (risk of developing severe infections, increased sensitivity to adalimumab, hypersensitivity (including latex).

Carefully:

Use with caution in case of recurrent infections in the history, carrier of hepatitis B virus, malignant neoplasms (including history), with heart failure, demyelinating diseases of the nervous system (including in the anamnesis), especially active rheumatoid arthritis (increased risk of developing lymphoma , the effect of blockers of tumor necrosis factor alpha on the development of lymphoma is not known), patients older than 65 years.

Pregnancy and lactation:

The action category for fetus by FDA is B.

Adequate and well-controlled studies on humans have not been conducted. Animals have no toxic effects. There is no information on the penetration of breast milk, but immunobiological agents generally penetrate into the milk. The drug is contraindicated during pregnancy and lactation.

In animal studies, the damaging effect of adalimumab on the fetus has not been revealed, however, no controlled studies have been conducted in pregnant women, therefore, women of reproductive age should be treated with reliable contraceptive methods during treatment.

Dosing and Administration:

Subcutaneously in the abdominal region or anterolateral region of the thigh 40 mg once every 1-2 weeks.

In appointing the drug glucocorticosteroid therapy, NSAIDs (including salicylates), analgesics (narcotic and non-narcotic), methotrexate and other basic antirheumatic drugs can be continued.

In some patients who do not receive methotrexate, an additional effect can be achieved with an increase in the frequency of administration of the drug to 40 mg once a week.

In Crohn's disease the recommended dosage regimen - 160 mg day 1 (40 mg 4 times a day or 40 mg 2 times a day consecutively for two days), 2 weeks (on day 15) - 80 mg , after 2 weeks (the 29th day) a maintenance dose is prescribed - 40 mg once every 2 weeks.

Patients who observe a decrease in response to drug treatment may receive an additional effect from increasing the dose of the drug to 40 mg once a week.

Some patients may not respond to adalimumab therapy within the first 4 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 there is no therapeutic effect during this period.

In chronic plaque psoriasis, the initial dose for adult patients is 80 mg. The maintenance dose is 40 mg once every 2 weeks, starting one week after the initial dose.

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

If the next injection of the drug 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.

Side effects:

Infections: very often - an infection of the upper respiratory tract; often - infection of the lower respiratory tract (including pneumonia and bronchitis), urinary tract infection, herpetic infection (including simple and herpes zoster), influenza, superficial fungal infection (including skin and nail lesions); infrequently - sepsis, joint and wound infections, abscess, skin infection (including impetigo), infection of the hair follicle (including boils and carbuncles), paronychia, pustular rash,infection of teeth and periodontal disease, ear infection, gastroenteritis, candidiasis of the oral cavity and pharynx, vaginal infections (including fungal infection), viral infection.

Neoplasms: infrequently - papilloma of the skin.

From the nervous system: frequent - headache, dizziness, paresthesia; infrequent - migraines, drowsiness, fainting, neuralgia, tremor, neuropathy, depression, anxiety disorders (including nervousness and agitation), insomnia, confusion.

From the sense organs: infrequent - conjunctivitis, blepharitis; pain, redness, dry eyes; edema of the eyelids, glaucoma; pain, stuffiness, tinnitus; perversion of taste.

From the cardiovascular system: frequent - increased blood pressure; infrequent - "hot flashes", hematoma, tachycardia, palpitations.

From the respiratory system: frequent - cough, sore throat, nasal congestion; infrequent - dyspnea, bronchospasm, dysphonia, pulmonary crepitus, ulceration of the mucous membrane of the nasal cavity, edema of the upper respiratory tract, hyperemia of the throat.

From the digestive system: frequent - nausea, abdominal pain, diarrhea, dyspepsia, ulceration of the oral mucosa; infrequent - vomiting, flatulence, constipation, gastroesophageal reflux, gastritis, dysphagia, colitis, hemorrhoids,hemorrhoidal bleeding, vesicular rash in the oral cavity, toothache, dry mouth, gingivitis, ulceration of the tongue, stomatitis (including aphthous).

From the hematopoiesis: frequent - anemia, lymphopenia; infrequent - leukopenia, leukocytosis, lymphadenopathy, neutropenia, thrombocytopenia.

From the side of metabolism: infrequent - hypercholesterolemia, hyperuricemia, anorexia, decreased appetite, hyperglycemia, increased or decreased body weight.

From the skin: frequent - a rash (including erythematous and itchy), itching, alopecia; infrequent - macular or papular rash, dry skin, sweating, eczema, dermatitis, psoriasis, urticaria, ecchymosis, purpura, acne, skin ulceration, angioedema, nail plate change, photosensitivity, skin peeling, rheumatoid nodules.

From the musculoskeletal system: infrequent - arthralgia, pain in the extremities, in the back and shoulder girdle, muscle cramps, myalgia, swelling of the joints, synovitis, bursitis, tendonitis.

From the genitourinary system: infrequent - hematuria, dysuria, nocturia, pollakiuria, pain in the kidney; Menorrhagia.

Local reactions: very frequent - pain, swelling, redness, itching at the injection site.

Other: frequent - increased fatigue (including asthenia), flu-like syndrome; infrequent - allergic reactions (including anaphylaxis, seasonal allergies), fever, heat, chills, chest pain, worsening of wound healing.

Laboratory indicators: frequent - increased activity of "liver" enzymes; infrequent - increased triglycerides, alkaline phosphatase, creatine kinase, lactate dehydrogenase, urea and creatinine in the blood, increased activated partial thromboplastin time, hypokalemia, formation of autoantibodies, proteinuria.

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.

Severe infections have been observed in clinical trials with the combined use of anakin and other blockers of tumor necrosis factor, etanercept, with no improvement in the clinical effect compared to the use of etanercept as monotherapy. Based on the nature of the undesirable phenomena observed with the combination of etanercept and anakin, similar intoxications may occur with the combination of anakinra with other tumor necrosis factor blockers. Thus, simultaneous therapy of adalimumab with anakinra is contraindicated.

The combined use of tumor necrosis factor and abatacept blockers is associated with an increased risk of infectious diseases, including severe infections, compared with the use of only tumor necrosis factor blockers. An increase in the clinical effect with this combination is not observed. Thus, the combined use of blockers of tumor necrosis factor and abatacept is contraindicated.

Adalimumab should not be mixed in one syringe or vial with any other medications. Remains of the solution and used materials should be destroyed.

Special instructions:

In the treatment with adalimumab, there have been cases of tuberculosis, fungal and other opportunistic infections, including fatal ones. Before the start of treatment, a check should be performed to identify active and inactive tuberculosis (contact with patients, immunosuppressive therapy, chest radiography, tuberculin test). In patients with immunodeficiency, false-negative tuberculin tests are possible. With active tuberculosis, adalimumab treatment does not begin, with latent tuberculosis preliminary preventive anti-tuberculosis treatment is preliminarily performed. If signs of tuberculosis infection appear during the treatment period (persistent cough, weight loss, subfebrile temperature), consult a doctor.

Against the background of adalimumab administration in carriers of hepatitis B virus, the virus can be reactivated, cases of death are described. The decision to initiate therapy is taken after the examination (the presence of the 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 conducted. In case of reactivation of the virus, adalimumab treatment is stopped and antiviral therapy is performed.

In rare cases, the appearance or exacerbation of demyelinating diseases is possible.

It is impossible to exclude the possible risk of developing lymphoma or other malignant neoplasms during treatment with tumor necrosis factor blockers.

During the treatment, there may be pancytopenia (thrombocytopenia, leukopenia, aplastic anemia). When symptoms such as persistent fever, bruising, bleeding, pale skin, you should consult a doctor.

With the simultaneous use of anakinra with an antagonist of tumor necrosis factor, etanercept showed the development of severe infections (compared to etanercept monotherapy), which can be expected with anakinr in combination with other blockers of tumor necrosis factor, including adalimumab.

During the treatment, vaccination is possible, except for live vaccines.

With the development of signs of lupus-like syndrome, treatment is canceled.

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

With confirmed significant hematologic abnormalities, treatment with adalimumab should be stopped.

Cases of progression of congestive heart failure have been described in patients receiving adalimumab. It should be used with caution adalimumab patients with heart failure and carefully monitor these patients.

The incidence of serious infections among patients older than 65 years who received adalimumab, was higher than in patients younger than 65 years. 12% of the total number of patients taking adalimumab, were older than 65 years and approximately 2.5% were over 75. Adalimumab should be used 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.

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

Instructions

Adalimumab (Adalimumabum)