Exemptia^® (Solution) Instructions for Use

Marketing Authorization Holder

PSK Pharma, LLC (Russia)

ATC Code

L04AB04 (Adalimumab)

Active Substance

Adalimumab (Rec.INN registered by WHO)

Dosage Form

Exemptia®

Solution for subcutaneous administration 40 mg/0.8 ml: syringes 1 or 2 pcs. with alcohol swabs

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration clear or opalescent, colorless or slightly yellow.

Excipients: sorbitol – 8 mg, sodium chloride – 4.672 mg, L-arginine hydrochloride – 4 mg, succinic acid – 0.944 mg, polysorbate 80 – 0.08 mg, sodium hydroxide – to adjust pH to 5.2, water for injections – to 0.8 ml.

0.8 ml – three-component syringes made of colorless glass (1) – contour cell packaging (1) complete with an alcohol swab (1) – cardboard packs^×.
0.8 ml – three-component syringes made of colorless glass (1) – contour cell packaging (2) complete with alcohol swabs (2) – cardboard packs^×.

^× a tamper-evident label may be applied to the pack.

Clinical-Pharmacological Group

Selective immunosuppressant. Monoclonal antibodies to TNF

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Immunosuppressant. Adalimumab is a recombinant monoclonal antibody whose peptide sequence is identical to human IgG1. Adalimumab selectively binds to TNFα and neutralizes its biological functions by blocking the interaction with the surface cell p55 and p75 TNFα receptors. TNFα is a natural cytokine involved in the regulation of normal inflammatory and immune responses.

Increased concentrations of TNFα are found in the synovial fluid of patients with rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα plays an important role in the development of pathological inflammation and destruction of joint tissue characteristic of these diseases.

Increased concentrations of TNFα are also found in psoriatic plaques. In plaque psoriasis, treatment with adalimumab may lead to a reduction in plaque thickness and a decrease in inflammatory cell infiltrate. The relationship between this clinical effect of adalimumab and its mechanism of action has not been established.

Adalimumab also modulates biological responses that are induced or regulated by TNFα, including changes in the content of adhesion molecules that cause leukocyte migration.

In patients with rheumatoid arthritis, Adalimumab causes a rapid decrease in the concentrations of acute-phase inflammatory markers (C-reactive protein and ESR) and serum cytokine concentrations (interleukin-6). A decrease in C-reactive protein content was also observed in patients with juvenile idiopathic arthritis or Crohn’s disease.

In addition, a decrease in serum activity of matrix metalloproteinases (MMP-1 and MMP-3), which cause tissue remodeling underlying cartilage destruction, is noted.

Pharmacokinetics

Adalimumab is absorbed and distributed slowly and reaches C_max in approximately 5 days. The absolute bioavailability after a single subcutaneous administration of 40 mg of adalimumab is 64%.

In patients with Crohn’s disease who receive Adalimumab at a starting dose of 160 mg at week 0 and a subsequent dose of 80 mg at week 2, C_max of the active substance is reached at week 2 and week 4 and is approximately 12 µg/ml.

V_d after a single intravenous administration ranges from 4.7 to 6 L, indicating nearly equal distribution of adalimumab in the blood and extravascular fluids.

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

C_ss of adalimumab after subcutaneous administration at a dose of 40 mg once every 2 weeks in patients with rheumatoid arthritis at the end of the dosing interval is about 5 µg/ml (without concomitant methotrexate) and 8-9 µg/ml (with concomitant methotrexate).

When the adalimumab dose was increased in the range of 20 mg, 40 mg and 80 mg once every 2 weeks and once weekly subcutaneously, an almost linear increase in serum adalimumab concentrations at the end of the dosing interval was noted.

When using adalimumab at a dose of 40 mg as monotherapy once every 2 weeks, the average C_min of adalimumab 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 weeks 24 and 56 of maintenance therapy with adalimumab at a dose of 40 mg once every 2 weeks.

Adalimumab is eliminated slowly, clearance usually does not exceed 12 ml/h. T_1/2 is, on average, 2 weeks and ranges from 10 to 20 days.

A trend towards an increase in the clearance of adalimumab depending on body weight and the presence of antibodies to adalimumab was noted.

Indications

Adults

Moderate to severe active rheumatoid arthritis (as monotherapy or in combination with methotrexate or other basic anti-inflammatory drugs).

Active ankylosing spondylitis.

Severe axial spondyloarthritis without radiographically confirmed ankylosing spondylitis, but in the presence of objective signs of inflammation based on elevated CRP levels and/or MRI data, in the absence of an adequate response to NSAID treatment or their intolerance.

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

Chronic plaque psoriasis (moderate and severe), nail psoriasis, when systemic therapy is indicated.

Active hidradenitis suppurativa (acne inversa) of moderate or severe degree in adult patients in the absence of an adequate response to standard systemic therapy.

Crohn’s disease (moderate or severe): in case of inadequate response to conventional therapy, as well as intolerance or contraindications to conventional therapy; in case of ineffectiveness (or loss of effectiveness) or intolerance to infliximab.

Ulcerative colitis of moderate and severe degree in case of inadequate response to conventional therapy, including corticosteroids and/or 6-mercaptopurine or azathioprine, as well as in case of intolerance or contraindications to conventional therapy.

Non-infectious uveitis (intermediate, posterior and panuveitis) in adults in case of inadequate response to corticosteroid therapy, in situations where dose limitation or discontinuation of corticosteroids is necessary, and also when corticosteroid therapy is contraindicated.

Behçet’s disease (intestinal form) in patients in the absence of an adequate response to standard therapy.

Children

Juvenile idiopathic arthritis in patients from 2 years of age as monotherapy or in combination with methotrexate.

Active enthesitis-related arthritis in patients aged 6 years and older in the absence of an adequate response to standard drug therapy or their intolerance.

Chronic plaque psoriasis (severe) in children from 4 years of age in case of inadequate response to local therapy or phototherapy, as well as in patients for whom local therapy and phototherapy are contraindicated.

Crohn’s disease (moderate or severe) in patients from 6 years of age and older in case of inadequate response to conventional therapy (including complete enteral nutrition and corticosteroids and/or immunosuppressants), as well as intolerance or contraindications to conventional therapy.

Non-infectious anterior uveitis in children from 2 years of age in case of inadequate response to standard therapy or when standard therapy is not suitable for such patients.

Active hidradenitis suppurativa (acne inversa) of moderate or severe degree in children from 12 years of age in the absence of an adequate response to standard systemic therapy.

Ulcerative colitis of moderate and severe degree in children from 5 years of age in case of inadequate response to conventional therapy, including corticosteroids and/or 6-mercaptopurine or azathioprine, as well as in case of intolerance or contraindications to conventional therapy.

ICD codes

Dosage Regimen

Administered subcutaneously.

A single dose for adults is 40-80 mg, the daily dose is up to 160 mg, depending on the indications and the treatment regimen used. A single dose for children aged 4 to 12 years is 24 mg/m², with a maximum dose of 40 mg. The treatment regimen is established individually, depending on the indications.

A single dose for children depending on body weight and indications is 20-80 mg. The treatment regimen also depends on the indications.

Adverse Reactions

Infections: very common – respiratory tract infections (including upper and lower respiratory tract infections, pneumonia, sinusitis, pharyngitis, nasopharyngitis and herpes viral pneumonia); common – generalized infections (including sepsis, candidiasis and influenza), gastrointestinal infections (including viral gastroenteritis), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotizing fasciitis and herpes zoster), ear infections, oral cavity infections (including herpes simplex, oral herpes and dental lesions), genital infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis); uncommon – opportunistic infections and tuberculosis (including coccidioidomycosis, histoplasmosis and Mycobacterium avium complex infections), neurological infections (including viral meningitis), eye infections, bacterial infections, joint infections.

Neoplasms common – benign neoplasms, skin cancer, except melanoma (including basal cell carcinoma and squamous cell carcinoma); uncommon – lymphoma, parenchymal neoplasms, neoplasms (including breast cancer, lung and thyroid neoplasms), melanoma.

From the hematopoietic system very common – leukopenia (including neutropenia and agranulocytosis), anemia; common – thrombocytopenia, leukocytosis; uncommon – idiopathic thrombocytopenic purpura; rare – pancytopenia.

From the immune system common – hypersensitivity reactions, seasonal allergy.

From the metabolism very common – increased lipid levels; common – hypokalemia, increased uric acid levels, pathological changes in sodium content, hypocalcemia, hyperglycemia, hypophosphatemia, increased blood potassium levels; uncommon – dehydration.

From the nervous system very common – headache; common – paresthesia (including hypoesthesia), migraine, sciatic neuralgia, mood changes (including depression), irritability, insomnia, dizziness; uncommon – tremor; rare – multiple sclerosis.

From the sensory organs: common – conjunctivitis, visual disturbances; uncommon – blepharitis, eyelid edema, diplopia, deafness, tinnitus.

From the cardiovascular system: common – arterial hypertension, flushing, hematomas, tachycardia; uncommon – arrhythmia, congestive heart failure; rare – cardiac arrest, arterial occlusion, thrombophlebitis, aortic aneurysm.

From the respiratory system: common – cough, asthma, dyspnea; uncommon – COPD, interstitial lung diseases.

From the digestive system very common – nausea, vomiting, abdominal pain, increased activity of liver enzymes; common – dyspepsia, gastroesophageal reflux, dry mouth (sicca syndrome), gastrointestinal bleeding; uncommon – pancreatitis, dysphagia, facial edema, cholecystitis, cholestasis, increased bilirubin content, hepatic steatosis.

Dermatological reactions very common – rash (including exfoliative); common – itching, urticaria, hemorrhages (including purpura), dermatitis (including eczema), nail brittleness, hyperhidrosis; uncommon – night sweats, scars.

From the musculoskeletal system very common – musculoskeletal pain; common – muscle spasms; uncommon – rhabdomyolysis; rare – systemic lupus erythematosus.

From the urinary system: common – hematuria, renal failure; uncommon – nocturia.

From the reproductive system uncommon – nocturia, erectile dysfunction.

From laboratory parameters common – blood coagulation disorders (including increased APTT), positive tests for autoantibodies (including antibodies to double-stranded DNA), increased LDH level.

Local reactions very common – injection site reactions (including erythema).

Other common – chest pain, edema; uncommon – inflammation, impaired wound healing.

Contraindications

Hypersensitivity to adalimumab.

Children under 18 years of age (except for patients from 2 years of age with juvenile idiopathic arthritis, patients from 6 years of age with Crohn’s disease (moderate or severe), patients from 6 years of age with active enthesitis-related arthritis, patients from 4 years of age with chronic plaque psoriasis, patients from 12 years of age with active hidradenitis suppurativa, patients from 2 years of age with non-infectious anterior uveitis, patients from 5 years of age with ulcerative colitis of moderate and severe degree).

Infectious diseases, including tuberculosis.

Concomitant use with TNF antagonists or other genetically engineered biological antirheumatic drugs (for example, anakinra and abatacept).

Moderate or severe heart failure NYHA class III-IV).

With caution

History of recurrent infections; hepatitis B virus carriers; malignant neoplasms, including history; mild heart failure (NYHA class I-II); demyelinating diseases of the nervous system, including history; patients over 65 years of age.

Use in Pregnancy and Lactation

The use of adalimumab during pregnancy may affect the immune response in newborns. Adalimumab should be used during pregnancy only if clearly necessary.

Adalimumab can cross the placenta into the serum of newborns from women who received the drug during pregnancy. Consequently, these children may have an increased risk of developing infection. Infants who have been exposed to adalimumab in utero are not recommended to receive live vaccines for 5 months after the last injection of adalimumab in the mother during pregnancy.

The benefit of breastfeeding for the development and health of the child should be considered along with the clinical need for adalimumab treatment in the mother and the likelihood of adverse effects due to exposure to adalimumab on the breastfed child or due to the mother’s underlying disease.

Pediatric Use

Contraindication: children under 18 years of age (except for patients from 2 years of age with juvenile idiopathic arthritis, patients from 6 years of age with Crohn’s disease (moderate or severe), patients from 6 years of age with active enthesitis-related arthritis, patients from 4 years of age with chronic plaque psoriasis, patients from 12 years of age with active hidradenitis suppurativa, patients from 2 years of age with non-infectious anterior uveitis, patients from 5 years of age with ulcerative colitis of moderate and severe degree).

Geriatric Use

Use with caution in elderly patients over 65 years of age. Dose adjustment is not required.

Special Precautions

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

Before starting therapy with adalimumab, all patients should be examined for both active and inactive (latent) tuberculosis infection. If active tuberculosis is diagnosed, therapy with adalimumab should not be started. In the case of diagnosed latent tuberculosis, anti-tuberculosis prophylaxis should be carried out before starting treatment with adalimumab.

Anti-tuberculosis therapy before starting treatment with adalimumab should also be prescribed to those patients who have been exposed to tuberculosis risk factors, even with a negative tuberculin test. The decision to conduct anti-tuberculosis therapy in such patients should be made only taking into account the risk of both latent tuberculosis infection and the risk of anti-tuberculosis therapy. Treatment is prescribed by a phthisiatrician.

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

The use of adalimumab should not be started in patients with active infectious diseases, including chronic or focal infections, until the infection is resolved. In patients who have visited areas with endemic mycoses, such as histoplasmosis, coccidioidomycosis or blastomycosis, the risk and advisability of adalimumab therapy should be assessed before starting therapy.

Patients who develop 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, and appropriate antibacterial and antifungal therapy should be carried out until the infectious disease is cured.

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

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

If an anaphylactic reaction or other serious allergic reactions occur, administration of adalimumab should be discontinued immediately and appropriate anti-allergic therapy should be administered.

In case of confirmed significant hematological abnormalities, treatment with adalimumab should be discontinued.

Patients with juvenile idiopathic arthritis are recommended to complete all vaccinations according to the current immunization schedule prior to initiating adalimumab therapy, if possible. Patients receiving Adalimumab may receive concomitant vaccinations, except for live vaccines.

Treatment with adalimumab may lead to the formation of autoantibodies. The effect of long-term treatment on the development of autoimmune diseases is unknown. If a patient develops symptoms suggestive of a lupus-like syndrome due to treatment with adalimumab, the use of adalimumab should be discontinued.

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

Use in Pediatrics

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

Drug Interactions

Antibody formation was lower with the concomitant use of adalimumab and methotrexate compared with monotherapy. Administration of adalimumab without methotrexate resulted in increased antibody formation, accelerated clearance, and reduced efficacy of adalimumab.

It is contraindicated to use Adalimumab in combination with anakinra, or with abatacept.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.