Cimzia^® (Solution) Instructions for Use

Marketing Authorization Holder

UCB Pharma, S.A. (Belgium)

Manufactured By

Vetter Pharma-Fertigung, GmbH & Co. KG (Germany)

Packaging and Quality Control Release

UCB Pharma, S.A. (Belgium)

Contact Information

UCB Pharma S.A. (Belgium)

ATC Code

L04AB05 (Certolizumab pegol)

Active Substance

Certolizumab pegol (Rec.INN registered by WHO)

Dosage Form

Cimzia®

Solution for subcutaneous injection 200 mg/1 ml: syringes 1 ml 2 pcs. in a kit with 2 wipes

Dosage Form, Packaging, and Composition

Solution for s.c. injection as a clear to opalescent, colorless to yellow liquid, free from visible particles.

Excipients: sodium acetate – 1.36 mg, sodium chloride – 7.31 mg, water for injections – up to 1 ml.

1 ml – single-dose syringes made of borosilicate glass (type I) (2), equipped with an injection needle – plastic contour packaging (1) – in a kit with individually packaged alcohol wipes (2) – cardboard “Wallet”-type booklet packaging.

Clinical-Pharmacological Group

Selective immunosuppressant. Monoclonal antibodies to TNF

Pharmacotherapeutic Group

Immunosuppressants; tumor necrosis factor-alpha (TNF-alpha) inhibitors

Pharmacological Action

Certolizumab pegol is a tumor necrosis factor alpha (TNFα) inhibitor. TNFα is a key cytokine that sustains the inflammatory process in rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, and axial spondyloarthritis. Certolizumab pegol has high specific activity against human TNFα (IC₉₀ is 4 ng/ml for inhibiting TNFα in vitro in a cytotoxic assay using mouse fibrosarcoma L929 cells), and it does not have activity against lymphotoxin α (TNFβ).

Certolizumab pegol has been shown to neutralize both membrane-bound and soluble human TNFα in a dose-dependent manner. Incubation of human monocytes with certolizumab pegol led to dose-dependent inhibition of LPS (lipopolysaccharide)-induced synthesis of TNFα and interleukin-1 beta (IL-1β).

Certolizumab pegol does not contain the crystallizable fragment (Fc) typically found in a full antibody and therefore does not fix complement and does not lead to antibody-dependent cellular cytotoxicity in vitro.

Certolizumab pegol does not induce apoptosis in vitro of human peripheral blood monocytes and lymphocytes, nor does it lead to neutrophil degranulation.

Tissue susceptibility to certolizumab pegol was studied in ex vivo and in vitro experiments conducted on live tissue to assess potential interactions between the drug and cryosections of frozen normal human tissue. Using a standard panel of human tissues, no evidence of cross-reactivity with certolizumab pegol was obtained.

Elevated concentrations of TNFα are found in the synovial fluid of patients with rheumatoid arthritis and play an important role in the progression of inflammatory, proliferative, and destructive changes in the joints, which are the main manifestations of the disease.

The biological properties of TNFα include activation of cell adhesion molecules and chemokines, activation of class I and II major histocompatibility complex molecules, and direct activation of leukocytes. TNFα stimulates the formation of cellular inflammatory mediators, including IL-1, prostaglandins, platelet-activating factor, and nitric oxide. Increased TNFα concentration plays a key role in the pathophysiological mechanisms of Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis. Certolizumab pegol selectively binds to TNFα, suppressing its role as a key inflammatory mediator. In Crohn’s disease, TNFα is found in significant concentrations in the affected areas of the intestinal wall, and its concentration in the stool of patients with Crohn’s disease reflects the clinical severity of the disease.

After treatment with certolizumab pegol, patients with Crohn’s disease showed a decrease in the concentration of C-reactive protein (CRP) in the blood. During treatment with Cimzia^®, patients with axial spondyloarthritis that developed in adulthood showed a marked reduction in inflammatory symptoms both in the sacroiliac joints and in the intervertebral joints – both in the entire population of patients with axial spondyloarthritis and in subgroups of patients with ankylosing spondylitis and axial spondyloarthritis without radiographic signs.

The use of Cimzia^® was accompanied by a marked improvement in key efficacy parameters, which included spinal mobility and physical function, pain intensity, severity of fatigue, and quality of life. Patients with active psoriatic arthritis, which debuted in adulthood, demonstrated a significant improvement in all key efficacy parameters during treatment with Cimzia^®. At 12 and 24 weeks of treatment with Cimzia^®, patients with psoriatic arthritis showed improvement in parameters characterizing peripheral disease activity (e.g., number of swollen joints, number of tender/stiff joints, severity of dactylitis, and prevalence of enthesitis). There was a significant improvement in physical function, reduction in arthritic pain, and reduction in fatigue compared to placebo. Patients receiving treatment with Cimzia^® reported a significant improvement in quality of life.

Pharmacokinetics

Absorption

After s.c. administration, C_max of certolizumab pegol in plasma is reached within 54-171 hours. The bioavailability of certolizumab pegol is about 80% (from 76% to 88%).

Distribution

In patients with rheumatoid arthritis and Crohn’s disease, according to population pharmacokinetic analysis, the steady-state V_d of certolizumab pegol was estimated to be in the range of 6 to 8 L.

Metabolism

The metabolism of certolizumab pegol has not been studied in clinical trials. Experimental studies in animals have shown that the elimination of certolizumab pegol occurs primarily via the kidneys.

Elimination

PEGylation (covalent attachment of polyethylene glycol (PEG) polymers to proteins) helps slow the elimination of these compounds from the bloodstream through various mechanisms, including reduced renal clearance, reduced proteolysis, and reduced immunogenicity. Thus, conjugation with PEG of certolizumab pegol, which is an Fab’ antibody fragment, helps increase the half-life (T_1/2) of the Fab’ fragment to a value comparable to the Tγ₂ of a whole antibody. The T_1/2 of certolizumab pegol is about 14 days for all studied doses. In healthy individuals, the elimination rate of certolizumab pegol after intravenous administration ranges from 9.21 ml/h to 14.38 ml/h. In Crohn’s disease, the clearance of certolizumab pegol after s.c. administration was 17 ml/h according to population pharmacokinetic analysis.

Similarly, in rheumatoid arthritis, the clearance of certolizumab pegol after s.c. administration was 21 ml/h according to population pharmacokinetic analysis.

Comparing patients with rheumatoid arthritis with different body weights showed that in patients with a body weight of 70 kg, the clearance of certolizumab pegol is 29% lower and 38% higher than in patients weighing 40 kg and 120 kg, respectively.

The Fab’ fragment is a protein compound that degrades through proteolysis into simple proteins and amino acids. Deconjugated PEG is rapidly eliminated from plasma, with the renal excretion volume not established. The plasma concentration of certolizumab pegol is definitely proportional to the dose.

Pharmacokinetic parameters in patients with rheumatoid arthritis and Crohn’s disease do not differ from those in healthy volunteers.

Pharmacokinetics in special patient groups

It is assumed that in patients with renal impairment, the clearance of certolizumab pegol decreases; however, no specific clinical studies have been conducted to assess the effect of renal impairment on the pharmacokinetics of certolizumab pegol, so there is insufficient data to recommend a special dosing regimen for moderate and severe renal impairment.

No specific clinical studies have been conducted to study the pharmacokinetics of certolizumab pegol in patients with hepatic impairment.

Results of population pharmacokinetic analysis showed no correlation with patient age.

Patient gender did not affect the pharmacokinetic parameters of certolizumab pegol. Since clearance decreases with decreasing body weight, women may have slightly higher systemic exposure to certolizumab pegol.

Concomitant use of methotrexate and other biological drugs, as well as patient race, did not affect the pharmacokinetic parameters of certolizumab pegol in patients with Crohn’s disease and rheumatoid arthritis.

Only body weight and the presence of antibodies to certolizumab pegol had a significant impact on the pharmacokinetics of the drug. However, pharmacodynamic analysis results did not confirm a therapeutic advantage of using body weight-based dosing regimens. The presence of antibodies to certolizumab pegol increased the clearance of the drug by 3.6 times.

Indications

Rheumatoid arthritis

Treatment of moderate to high disease activity rheumatoid arthritis in adults (from 18 years of age)

• In combination with methotrexate in case of insufficient response to treatment with disease-modifying antirheumatic drugs (DMARDs), including methotrexate;
• As monotherapy in case of intolerance or inappropriateness of continuing methotrexate treatment.

It has been shown that Cimzia^®, when used in combination with methotrexate, reduces the progression of joint damage assessed by radiography and improves physical function.

Crohn’s disease

Treatment of moderate to high disease activity Crohn’s disease in adults when therapy with DMARDs is ineffective.

Axial spondyloarthritis

The drug Cimzia^® is indicated for the treatment of severe active axial spondyloarthritis in adults, including

• Severe active ankylosing spondylitis with insufficient response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or intolerance to them in adults;
• Severe active axial spondyloarthritis without radiographic signs of AS but with objective signs of inflammation, manifested by elevated CRP concentration and/or corresponding changes on magnetic resonance imaging (MRI), with insufficient response to NSAID therapy or intolerance to them.

Psoriatic arthritis

Treatment of active psoriatic arthritis in adults

• In combination with methotrexate in case of insufficient response to DMARD therapy;
• As monotherapy in case of intolerance or inappropriateness of continuing methotrexate treatment.

ICD codes

Dosage Regimen

The drug is administered s.c.

Treatment should be prescribed and monitored by a physician experienced in the diagnosis and treatment of conditions for which Cimzia^® is indicated.

After proper training of the patient in the injection technique, the physician may allow self-administration of the drug (see further instructions for administration) with appropriate medical supervision. Cimzia^® is used as a ready-to-use injection solution at a dose of 200 mg (a single-use syringe containing 1 ml of certolizumab pegol).

Induction dose

The recommended induction dose of Cimzia^® for adult patients is 400 mg as two s.c. injections of 200 mg each on the first day of treatment, and on the second and fourth weeks of treatment.

Maintenance dose

For Crohn’s disease, after the induction dose, the recommended maintenance dose of Cimzia^® for adult patients is 400 mg once every 4 weeks.

For rheumatoid arthritis, after the induction dose, the recommended maintenance dose of Cimzia^® for adult patients is 200 mg once every 2 weeks. For maintenance treatment of the disease, an alternative dosing regimen of 400 mg once every 4 weeks may be used.

For ankylosing spondylitis, after the induction dose, the recommended maintenance dose of Cimzia^® for adult patients is 200 mg once every 2 weeks or 400 mg once every 4 weeks.

For axial spondyloarthritis without radiographic signs of ankylosing spondylitis, after the induction dose, the recommended maintenance dose of Cimzia^® for adult patients is 200 mg once every 2 weeks or 400 mg once every 4 weeks.

For psoriatic arthritis, after the induction dose, the recommended maintenance dose of Cimzia^® for adult patients is 200 mg once every 2 weeks. After response to therapy, an alternative dosing regimen of 400 mg once every 4 weeks may be used.

Data from rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis studies indicate that a clinical response is usually achieved within 12 weeks of treatment. The decision to continue treatment in patients who have not shown a therapeutic effect within the first 12 weeks of therapy should be carefully considered.

Missed dose

Patients who have missed a scheduled dose should be advised to administer the missed dose of Cimzia^® as soon as they remember, and then continue with subsequent doses according to the original treatment plan.

For elderly patients (65 years and older), no dose adjustment is required.

Instructions for subcutaneous injection technique

Preparing for the injection

Before administering Cimzia^® in the pre-filled syringe, ensure the following:

• The packaging and syringe are labeled with the drug name Cimzia^®;
• The drug’s expiration date has not passed;
• The drug packaging integrity is not compromised, the protective stickers are intact on the bottom and top of the cardboard box;
• The drug in the syringe has not been frozen and has not been exposed to direct sunlight;
• The contents of the pre-filled syringe are a clear, opalescent, colorless to yellow solution, free of visible particles.

The drug must not be used if any of the above requirements are not met.

Each package of Cimzia^® contains a single-use syringe equipped with a needle and two individually packaged alcohol wipes.

For each injection, use 1 syringe and 1 alcohol wipe.

You will also need an additional clean cotton ball (not included in the Cimzia^® kit) and a sharps container for used needles and syringes to prevent needle-stick injuries.

Each pre-filled syringe contains a dose of the drug sufficient for one injection (200 mg). According to the doctor’s prescription, it may be necessary to administer the drug more than once. If Cimzia^® is prescribed at a dose of 400 mg, then 2 s.c. injections (200 mg×2 times) must be performed. The drug is injected under the skin in the abdomen or thigh area. If two injections are needed, they should be administered into anatomically different areas (e.g., right and left side, or abdomen and thigh).

Remove 1 or 2 pre-filled syringes with Cimzia^® and the alcohol wipes from the refrigerator and place them on a clean, flat surface. Before injection, allow the syringe with the drug to warm to room temperature. This will take approximately 30 minutes.

Selecting and preparing the injection site

Wash hands thoroughly with soap and water.

Determine the injection site(s), considering the need to administer the drug into different anatomical areas. The distance from a previously used injection site should be at least 3 cm (injection sites should be noted). Do not inject into areas with bruising, areas where the skin is hardened or reddened, or into scar or stretch mark areas. If the abdominal area is chosen, do not inject within a 5 cm radius of the navel. Alternate injection sites between the abdomen and thighs to avoid the risk of local skin reactions.

Use an alcohol wipe to clean the injection site. Do not touch the cleaned skin area before injection.

Using the pre-filled syringes with Cimzia^®

Ensure that the drug in the syringe is a colorless or pale yellow solution, free of visible mechanical particles. The presence of air bubbles is acceptable. There is no need to remove air bubbles before injection. Subcutaneous administration of a solution containing air bubbles is safe.

Remove the needle cap by pulling up on the plastic ring. Be careful, do not touch the needle. Set the needle cap aside. Do not bend the needle. Perform the injection immediately.

Hold the syringe with the needle pointing down. Do not touch the needle with your fingers or let it touch other surfaces. Hold the syringe in one hand, with the other hand gently pinch the skin fold of the pre-cleaned area and hold it firmly. Position the needle at a 45°C (113°F) angle to the skin surface and with one quick, short movement, insert the needle through the full thickness of the skin fold.

While holding the syringe, slowly pull back the plunger. If blood appears in the syringe, it means the needle has entered a blood vessel. Do not inject Cimzia^®. Withdraw the needle and discard the pre-filled syringe and needle into the sharps container. Do not reuse this syringe.

If no blood appears in the syringe, inject the entire solution under the skin by pressing the plunger.

After no drug remains in the syringe, carefully remove the needle from the skin at the same angle it was inserted, and then press the injection site with a clean cotton ball for 10 seconds. Do not rub the injection site. Slight bleeding may occur; a small pressure bandage can be applied to the injection site if necessary.

If a second injection is prescribed (total dose 400 mg), repeat the steps described above.

Waste Disposal

Never reuse a syringe and needle, and do not recap the needle. Used syringes and needles must be disposed of by placing them in a special protective container for subsequent destruction. When the container is two-thirds full, it should be sealed and sent for destruction in accordance with the doctor’s recommendations.

Adverse Reactions

Rheumatoid Arthritis

The most frequently observed adverse reactions belonged to the group of “Infections and Infestations” – in 14.4% of patients receiving Cimzia^® and in 8% of placebo group patients, “General Disorders and Administration Site Conditions” in 8.8% of patients receiving Cimzia^® and 7.4% – placebo, and also “Skin and Subcutaneous Tissue Disorders” in 7% of patients receiving Cimzia^® and 2.4% – placebo.

Therapy was discontinued due to the development of adverse events in 4.4% of patients receiving Cimzia^® and in 2.7% of patients not receiving the drug (placebo group).

Crohn’s Disease

In patients with Crohn’s disease in controlled studies, serious adverse events were noted in 10.8% of cases receiving treatment with Cimzia^®, and in the placebo group – in 8.6%.

The most common adverse reactions were nasopharyngitis (11.1% and 6.7%, respectively), nausea (8% and 6.7%, respectively), urinary tract infections (5.1% and 4.4%, respectively), abdominal pain (9.3% and 8.8%, respectively), arthralgia (6.7% and 3.9%, respectively), headache (14.8% and 13.8%, respectively).

Due to adverse reactions, therapy was discontinued in 11.3% of patients receiving Cimzia^® and 12.6% receiving placebo. The most common adverse reactions leading to discontinuation of Cimzia^® were: diarrhea (0.5% and 0.2%, respectively), abdominal pain (0.9% and 0.4%, respectively) and nausea (0.4% and 0.2%, respectively).

Axial Spondyloarthritis

A placebo-controlled study evaluated the safety profile in 325 patients with active axial spondyloarthritis who received Cimzia^® for up to 30 months. The safety profile of Cimzia^® when used in patients with axial spondyloarthritis was consistent with that in patients with rheumatoid arthritis and the previous experience of using the drug.

Psoriatic Arthritis

A placebo-controlled study evaluated the safety profile in 409 patients with psoriatic arthritis who received Cimzia^® for up to 30 months.

The safety profile of Cimzia^® when used in patients with psoriatic arthritis was consistent with that in patients with rheumatoid arthritis and the previous experience of using the drug.

Adverse reactions are grouped by frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Infections and Infestations Common – bacterial infections (including abscess), viral infections (including those caused by herpes virus, influenza, papillomavirus); Uncommon – sepsis (including multiorgan failure and septic shock), tuberculosis, fungal infections (including opportunistic).

Benign Neoplasms, Malignant Neoplasms and Unspecified Neoplasms (including cysts and polyps) Uncommon – malignant diseases of the blood and lymphatic system, including lymphoma and leukemia, solid neoplasms, malignant skin neoplasms, excluding melanoma, precancerous lesions (oral leukoplakia, melanocytic nevus), benign tumors and cysts (including skin papilloma); Rare – gastrointestinal neoplasms, melanoma.

Blood and Lymphatic System Disorders Common – eosinophilia, eosinopenia, leukopenia (lymphopenia and neutropenia); Uncommon – anemia, thrombocytopenia, lymphadenopathy, thrombocytosis; Rare – pancytopenia, splenomegaly, erythrocytosis, morphological changes in leukocytes.

Immune System Disorders Uncommon – vasculitis, SLE (systemic lupus erythematosus), increased drug sensitivity, psoriasis and related diseases, allergic disorders, positive autoantibody test; Rare – angioedema, sarcoidosis, serum sickness, panniculitis (including erythema nodosum).

Endocrine Disorders Rare – thyroid dysfunction.

Metabolism and Nutrition Disorders Uncommon – electrolyte disturbances, dyslipidemia, appetite disorders, changes in body weight; Rare – changes in blood glucose concentration, hypoalbuminemia, hypoproteinemia, hemosiderosis.

Psychiatric Disorders Uncommon – anxiety (including mental stress), mood changes (and related symptoms); Rare – suicide attempts, delirium, reduced mental activity, aggression.

Nervous System Disorders Common – headache (including migraine), sensory disturbances; Uncommon – peripheral neuropathy, dizziness, tremor, optic neuritis; Rare – demyelinating diseases, including cranial neuritis, seizure, extrapyramidal disorders, trigeminal neuralgia, coordination and balance disorders, dysphonia, masked facies, sleep disorder.

Eye Disorders Uncommon – visual perception disorders (including decreased visual acuity), uveitis and blepharitis, dacryoadenitis and dacryocystitis.

Ear and Labyrinth Disorders Uncommon – vertigo, tinnitus; Rare – hearing loss.

Cardiac Disorders Common – increased blood pressure; Uncommon – cardiomyopathy, heart failure, ischemic heart disease, arrhythmias (including atrial fibrillation), palpitations, hemorrhages, bleeding, venous thromboembolism (pulmonary embolism, thrombophlebitis), syncope, decreased blood pressure, edema (face, limbs), ecchymoses (hematomas, petechiae); Rare – pericarditis, AV block, shock, stroke, atherosclerosis, Raynaud’s syndrome, livedo reticularis, telangiectasias.

Respiratory, Thoracic and Mediastinal Disorders Uncommon – pleural effusion (and related symptoms), bronchial asthma and its manifestations, dyspnea, congestive and inflammatory changes in the lungs, cough; Rare – interstitial lung diseases, pneumonitis, nasal mucosa ulcerations.

Gastrointestinal Disorders Common – nausea, vomiting; Uncommon – ascites, symptoms of Crohn’s disease (stenosis), ulceration and perforation (of various parts of the gastrointestinal tract), inflammation of the gastrointestinal mucosa, dyspepsia, stomatitis, abdominal bloating, dryness of the oral and pharyngeal mucosa; Rare – intestinal obstruction, painful swallowing, anal fissures, increased intestinal motility.

Hepatobiliary Disorders Common – hepatitis, increased liver enzyme activity; Uncommon – liver diseases, including liver cirrhosis, cholestasis, increased plasma bilirubin concentration; Rare – cholelithiasis.

Skin and Subcutaneous Tissue Disorders Common – rash; Uncommon – alopecia, onset or worsening of psoriasis symptoms, dermatitis, eczema, sweat gland dysfunction, skin ulcerations, increased photosensitivity, acne, skin pigmentation disorders, dry skin, nail plate and nail bed lesions; Rare – acute febrile neutrophilic dermatosis, skin exfoliation and desquamation, bullous dermatitis, skin ulcerations, pityriasis rosea, striae, rosacea, hair structure disorder.

Musculoskeletal and Connective Tissue Disorders Uncommon – arthritis, muscle function impairment; Rare – tendon function impairment.

Renal and Urinary Disorders Uncommon – renal function impairment, hematuria, nephrolithiasis, urethritis, cystitis; Rare – nephropathy, nephritis.

Reproductive System and Breast Disorders Uncommon – menstrual cycle disorders, uterine bleeding, amenorrhea, breast dysfunction, azoospermia; Rare – premature birth, vaginal discharge, sexual dysfunction, balanitis.

General Disorders and Administration Site Conditions Common – hyperthermia, pain (unspecified location), asthenia, pruritus (unspecified location), injection site reactions; Uncommon – fistula formation (unspecified location), chills, flu-like syndrome, temperature sensitivity disorder, night sweats, “hot flashes”; skin lesions, slow wound healing.

Investigations Uncommon – increased creatine phosphokinase (CPK) activity, alkaline phosphatase, total bilirubin, increased blood clotting time, changes in urinalysis; Rare – increased blood uric acid concentration.

The following adverse reactions are associated with the use of drugs from the class of TNFα antagonists: Merkel cell carcinoma, multiple sclerosis, Guillain-Barré syndrome, but the frequency of their occurrence with the use of Cimzia^® is unknown.

Infections

In controlled studies in patients with rheumatoid arthritis, new cases of infectious diseases were observed with a frequency of 1.03 per patient-year in those receiving treatment with Cimzia^® and with a frequency of 0.92 per patient-year in those receiving placebo. Infections were mainly represented by diseases of the upper and lower respiratory tract, urinary tract diseases and viral herpes diseases.

In controlled studies, more cases of serious infectious diseases were noted in the group receiving treatment with Cimzia^® (0.07 per patient-year) than in those receiving placebo (0.02 per patient-year). The most common serious infectious diseases were pneumonia and tuberculosis. No increase in the risk of infections with increasing duration of Cimzia^® use was established. The frequency of infections in controlled studies in patients with Crohn’s disease was 38.6% in those receiving treatment with Cimzia^® and 30.6% in patients receiving placebo. Mainly, respiratory tract infectious diseases were noted (18.9% in patients receiving treatment with Cimzia^® and 12.4% – placebo). The frequency of clinically significant serious infections during controlled studies was 2.6% per patient-year among those receiving treatment with Cimzia^® and 1.3% – placebo. Serious infections included both bacterial and viral diseases, pneumonia and pyelonephritis.

Tuberculosis

The use of drugs from the group of TNFα inhibitors may be accompanied by the development of active tuberculosis. There are reports of severe and fatal cases of tuberculosis during treatment with Cimzia^®. In completed and ongoing clinical studies for all known indications among 5118 patients who received treatment with Cimzia^®, the frequency of tuberculosis detection was approximately 0.61 per 100 patient-years. The largest number of cases was observed in countries endemic for tuberculosis. Reports included cases of pulmonary and disseminated tuberculosis and, in rare cases, opportunistic infections. Rare cases of fatal outcome in patients with tuberculosis and opportunistic infections have been noted.

Malignant and Lymphoproliferative Disorders

In controlled studies of TNFα inhibitors, more cases of malignant neoplasms and lymphoma were registered in the group of patients receiving Cimzia^® compared to the control group.

Out of 4049 patients with rheumatoid arthritis who received Cimzia^®, lymphoma was diagnosed in 5 patients. In patients with rheumatoid arthritis, especially with high disease activity, the risk of developing lymphoma is increased.

Out of 2657 patients who received Cimzia^® for Crohn’s disease, 1 patient was diagnosed with lymphoma; also, 1 case of lymphoma was observed in the control group of patients, which included 1319 people. The frequency of development of malignant neoplasms and lymphoma in clinical studies of Cimzia^® cannot be compared with the results of studies of other TNFα inhibitors and cannot serve as a basis for predicting the frequency of these diseases when using Cimzia^® in a wider population of patients. In patients with Crohn’s disease who require long-term therapy with immunosuppressants, the risk of developing lymphoma is increased compared to the general population, even if they are not treated with TNFα inhibitors.

In a clinical study, one patient with psoriatic arthritis was diagnosed with lymphoma.

Chronic Heart Failure

During treatment with Cimzia^®, both new cases of CHF and progression of pre-existing CHF symptoms were noted. Most of these cases were mild or moderate in severity and were diagnosed within the first year of treatment with the drug.

Immunogenicity

Rheumatoid Arthritis

The total number of patients with rheumatoid arthritis with antibodies to Cimzia^®, which were determined at least once, was 9.6% in placebo-controlled studies of the drug. Approximately one third of these patients had antibodies that exhibited neutralizing activity in vitro. In patients who were simultaneously taking immunosuppressants (methotrexate), the rate of antibody formation was lower than in patients who were not initially receiving them. Antibody formation was associated with a lower plasma concentration of Cimzia^®, and in some patients – with its lower efficacy.

Crohn’s Disease

In Crohn’s disease, 8% of patients receiving long-term treatment with Cimzia^® had antibodies to the drug, approximately 6% of them had antibodies that were neutralized in vitro. No obvious relationship between antibody formation and the efficacy of Cimzia^® was established. In patients simultaneously taking immunosuppressants, the level of antibody formation was lower than in patients not taking them (3% and 11%, respectively).

Psoriatic Arthritis

The total number of patients with psoriatic arthritis in a placebo-controlled study who, at least once during 24 weeks, had antibodies to Cimzia^® was 11.7%. Antibody formation was associated with a lower plasma concentration of the drug. The number of patients with antibodies to Cimzia^® was insufficient to give a definite assessment of the relationship between antibody titer and drug efficacy.

Axial Spondyloarthritis

During a placebo-controlled study in axial spondyloarthritis, the total number of patients who, at least once during 24 weeks, had antibodies to Cimzia^® was 4.4%. Antibody formation was associated with a lower plasma concentration of the drug. The number of patients with antibodies to the drug was insufficient to give a definite assessment of the relationship between antibody titer and drug efficacy.

Antibody Formation

In clinical studies, 4% of patients with Crohn’s disease receiving Cimzia^® and 2% of patients receiving placebo had antinuclear antibody (ANA) formation. In studies of TNFα inhibitor drugs, including Cimzia^®, some patients with rheumatoid arthritis also had antinuclear antibody (ANA) formation. In clinical studies of Cimzia^® in rheumatoid arthritis and Crohn’s disease, some patients developed symptoms similar to lupus-like syndrome. The effect of long-term treatment with Cimzia^® on the development of the autoimmune process has not been established.

Hypersensitivity Reactions

The following symptoms, which are similar to hypersensitivity reactions, were observed in rare cases after administration of Cimzia^® to patients: angioedema, allergic dermatitis, pruritic rash, dyspnea, “hot flashes”, decreased blood pressure, injection site reactions, malaise, hyperthermia, rash, serum sickness and syncope.

Injection Site Reactions

In some patients during treatment with Cimzia^®, the following injection site reactions were observed: erythema, itching, subcutaneous hematoma, pain, swelling or bruising.

No cases of drug discontinuation due to the development of local reactions were noted.

Increased Creatine Phosphokinase (CPK) Activity

The frequency of cases of increased CPK activity in patients with axial spondyloarthritis (axSpA) was, in general, higher than in the population of patients with rheumatoid arthritis (RA). This frequency was also higher in patients with axSpA and RA receiving placebo, 2.8% and 0.4%, respectively, and during treatment with Cimzia^®, 4.7% and 0.8%, respectively.

Increased CPK activity in patients with axSpA was in most cases transient, clinically insignificant, and was not the reason for discontinuation of participation in the study in any patient.

Contraindications

• Sepsis or risk of sepsis, as well as severe chronic or localized infections in the active stage (including tuberculosis, abscess, other opportunistic infections, including fungal (histoplasmosis, candidiasis, aspergillosis, blastomycosis, coccidioidomycosis, nocardiosis, listeriosis, etc.)), pneumocystis and viral infections, including viral hepatitis B in the reactivation stage;
• Heart failure of NYHA functional class III-IV;
• Children and adolescents under 18 years of age;
• Concomitant use of anakinra, abatacept and etanercept;
• Hypersensitivity to certolizumab pegol or other components included in the drug.

Use in Pregnancy and Lactation

Women of reproductive age should use reliable methods of contraception during treatment and for at least 10 weeks after its completion.

Active transplacental transfer of immunoglobulins (IgG) occurs due to the binding of the Fc fragment of the antibody to the neonatal Fc receptor (FcRn). Certolizumab pegol consists only of the Fab fragment of the antibody and does not contain an Fc fragment. In a reproductive study in rats, it was shown that during pregnancy, TN3 γ1 (a complete surrogate antibody to certolizumab pegol, including the Fc fragment) was transferred to the fetus. However, TN3 PF (a surrogate Fab fragment of the antibody to certolizumab pegol without the Fc fragment) was transferred to the fetus in insignificant or unmeasurable amounts compared to the concentration of the Fc fragment in the maternal plasma, which indicates the important role of the Fc fragment in transplacental transfer.

In addition, data confirming these observations were obtained in vitro using a closed-loop model of human placental transport. It was shown that the concentration of certolizumab pegol in the fetal loop was below or near the lower limit of its quantification.

As part of an independent clinical study in 10 patients with Crohn’s disease receiving Cimzia^® during pregnancy, the concentration of certolizumab pegol was measured in maternal blood, cord blood, and in newborn blood (n=12) on the day of delivery. The concentration of certolizumab pegol was very low in cord blood (<0.41-1.66 µg/ml) and newborn blood (<0.41-1.58 µg/ml) compared to the concentration in maternal blood (1.87 – 59.57 µg/ml). The PEG (polyethylene glycol) concentration was below the limit of detection in all cord blood and newborn blood samples.

Preclinical and clinical data indicate the absence of active FcRn-dependent transplacental transfer of certolizumab pegol.

Since there are no data from well-controlled studies of the drug Cimzia^® in pregnant women, it should not be used during pregnancy except in cases of clear necessity.

Due to the inhibition of tumor necrosis factor (TNFα), the drug Cimzia^® used during pregnancy may affect the parameters of the normal immune response of the newborn. Although the concentration of certolizumab pegol in infant blood is low, the clinical significance of these data is unclear.

The risk/benefit ratio for the use of live vaccines during the first 12 weeks of an infant’s life should be assessed by pediatricians. However, the drug Cimzia^® does not suppress the humoral immune response when using non-live vaccines in adults.

In male rodents, decreased sperm motility and a tendency to decrease sperm count were found without a visible effect on animal fertility.

In a clinical study evaluating the effect of certolizumab pegol on qualitative sperm parameters (semen volume, sperm count and concentration, progressive motility, percentage of total motility, viability, and sperm morphology), 20 healthy men were examined who were randomized to receive a single s.c. injection of 400 mg of certolizumab pegol or placebo. During the 14-week observation period, no effect of certolizumab pegol on qualitative sperm parameters compared to placebo was revealed.

It has not been established whether Certolizumab pegol is excreted in breast milk. However, it is known that immunoglobulins can pass into breast milk, so the risk to the breastfed child cannot be eliminated. If treatment with the drug Cimzia^® is necessary during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Before prescribing the drug Cimzia^®, patients should be tested for hepatitis B virus. Patients with positive test results for hepatitis B virus should be recommended to consult a specialist in the treatment of hepatitis B.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Clinical studies have noted a higher frequency of infectious diseases in patients aged 65 years and older compared to younger patients, although these data are limited. Caution is recommended when using the drug Cimzia^® in elderly patients; patients in this group require special attention regarding the possible development of infection.

Special Precautions

Infections

Patients should be thoroughly examined for the presence of infections, including chronic and local foci of infection, before prescribing the drug Cimzia^®, during treatment, and after its completion. Taking into account the long T_1/2 of the drug Cimzia^®, patients should be monitored throughout this entire period.

Patients with a newly diagnosed infection during treatment with the drug Cimzia^® should be under careful observation. When using TNF antagonists, including Cimzia, cases of sepsis, tuberculosis, and other severe infections with bacterial, mycobacterial, invasive fungal, viral, and/or parasitic pathogens have been reported.

Among opportunistic infections, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, nocardiosis, listeriosis, and pneumocystosis were most frequently reported.

In case of development of a severe infection, treatment with the drug Cimzia^® should be discontinued.

Before prescribing the drug Cimzia^®, the benefit-risk ratio of this therapy should be carefully assessed in patients with a history of chronic or recurrent or opportunistic infections; in patients receiving concomitant immunosuppressive therapy; in patients with conditions predisposing to the development of infections, as well as when changing residence or traveling to areas with a high incidence of tuberculosis, mycoses, histoplasmosis, and other infections.

In patients with rheumatoid arthritis, symptoms of an infectious disease may be blurred. Therefore, early detection of any infectious disease, especially atypical clinical manifestations of a severe infection, is extremely important for timely diagnosis and immediate initiation of treatment.

Tuberculosis

As with the use of other TNFα inhibitors, cases of tuberculosis reactivation or new cases of tuberculosis (including miliary pulmonary tuberculosis, extrapulmonary tuberculosis, and disseminated form of the disease) have been observed during treatment with the drug Cimzia^®. Before prescribing the drug Cimzia^®, the benefit-risk ratio of this therapy should be assessed, taking into account risk factors for the development of tuberculosis. Before starting treatment with the drug Cimzia^®, all patients must be examined to exclude active or latent tuberculosis. This examination should include a detailed study of the patient’s history to rule out previous tuberculosis, identify possible contacts with tuberculosis patients, and obtain data on ongoing or previous immunosuppressive therapy. All patients undergo appropriate screening tests, for example, a tuberculin skin test (or other test to detect latent tuberculosis) and chest X-ray. It must be taken into account that in some cases, false-negative results of the tuberculin test are possible, especially in patients with severe clinical condition and reduced immune status. When performing a tuberculin test, a papule size of 5 mm or more is considered positive, even if BCG (Bacillus Calmette-Guérin) vaccination has been previously administered. The need for a preventive course of tuberculosis treatment before prescribing the drug Cimzia^® should be considered in those patients who, with indications of previously suffered tuberculosis or signs of its latent course, cannot confirm previous adequate anti-tuberculosis therapy, as well as in patients with risk factors for the development of tuberculosis, despite a negative test result for latent tuberculosis. To decide on the need for a course of anti-tuberculosis therapy for each specific patient, consultation with a phthisiatrician is necessary.

The condition of patients should be carefully monitored, paying attention to the occurrence of symptoms such as persistent cough, sputum production, weight loss, low-grade fever, which may indicate the presence of tuberculosis. If active tuberculosis is diagnosed before the start of therapy or during treatment, treatment with the drug Cimzia^® should not be started or continued, and appropriate anti-tuberculosis therapy should be initiated.

Reactivation of viral hepatitis B (HBV)

Cases of reactivation of viral hepatitis B have been reported in patients who are chronic carriers of this virus (including those with a positive surface antigen) who received TNFα inhibitors, including the drug Cimzia^®. In some cases, the disease was fatal. Before prescribing the drug Cimzia^®, patients should be tested for hepatitis B virus. Patients with positive test results for hepatitis B virus should be recommended to consult a specialist in the treatment of hepatitis B.

Patients who are carriers of the hepatitis B virus and for whom treatment with the drug Cimzia^® is indicated should be under constant observation for the timely detection of signs and symptoms of active HBV infection throughout the entire course of therapy and for several months after the end of treatment. There is no relevant data on the treatment of HBV carrier patients with antiviral drugs simultaneously with TNF antagonists to prevent HBV reactivation.

If patients develop symptoms of hepatitis B virus reactivation, the use of the drug Cimzia^® should be discontinued and effective antiviral and appropriate supportive therapy should be prescribed.

Vaccination

Vaccination of patients receiving treatment with the drug Cimzia^® is allowed, except for the use of live or live attenuated vaccines.

There are no data on the response to vaccination or secondary transmission of infection through a live vaccine in patients receiving the drug Cimzia^®. Live vaccines and live attenuated vaccines are not recommended to be administered during treatment with the drug Cimzia^®. All necessary vaccination measures should be carried out in accordance with the current national vaccination schedule, if possible, before starting treatment with the drug Cimzia^®. Cimzia^® does not suppress the humoral immune response to pneumococcal polysaccharide vaccine or influenza vaccine.

Malignant and lymphoproliferative diseases

In clinical studies, lymphoma and malignant neoplasms were more common in patients treated with the drug Cimzia^® compared with patients in the placebo group. However, the limited number of patients in the control group and the short duration of their treatment do not allow definitive conclusions to be drawn. No studies have been conducted involving patients with a history of malignant neoplasms, or studies in which treatment with the drug Cimzia^® was continued after the detection of malignant neoplasms. Therefore, in this group of patients, treatment with the drug Cimzia^® is recommended to be prescribed with caution. In patients with rheumatoid arthritis, especially in the subgroup with very high disease activity, the risk of developing lymphoma is increased.

In patients with Crohn’s disease and other diseases for which long-term immunosuppressive therapy is prescribed, the risk of developing lymphoma, compared with the general patient population, may also be increased, even if therapy with TNFα inhibitors is not carried out. Cases of acute and chronic leukemia have been reported with the use of TNFα inhibitors in rheumatoid arthritis and for other indications. Even in the absence of TNF inhibitor therapy, the risk of developing leukemia in patients with rheumatoid arthritis is higher (approximately 2 times) than in the general population. There have been reports of malignant neoplasms, including fatal ones, in adults and children treated with TNFα inhibitors (when treatment was started at the age of 18 years and under). Approximately half of these cases were diagnosed with lymphomas (including Hodgkin’s lymphoma and non-Hodgkin’s lymphomas). The remaining cases included various malignant neoplasms, including rare ones, which are usually associated with immunosuppressive therapy. Malignant neoplasms developed on average after 30 months of treatment (from 1 to 84 months). The majority of patients received concomitant immunosuppressive therapy. These cases were published in the post-marketing period and were obtained from various safety information sources, including registries and spontaneous post-marketing reports.

During post-marketing surveillance, cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma with an extremely aggressive disease course and usually fatal outcome, have been registered in patients receiving TNF inhibitor therapy. Most cases associated with the use of TNF antagonists were observed in adolescents and young men with Crohn’s disease and ulcerative colitis. Almost all of these patients received treatment with immunosuppressants, azathioprine and/or 6-mercaptopurine, in combination with TNF inhibitors at the time of or before diagnosis.

Skin cancer

Cases of melanoma and Merkel cell carcinoma have been reported with the use of TNF inhibitors, including the drug Cimzia^®. Periodic skin examination of all patients is recommended, especially those patients who have risk factors for the development of skin cancer.

Chronic obstructive pulmonary disease (COPD)

In a study of another drug from the TNFα inhibitor group in patients with moderate and severe COPD, an increased risk of malignant neoplasms (mainly localized in the lungs, as well as in the head and neck area) was noted in the group of patients treated with the TNFα inhibitor compared with the control group. All patients were active smokers. In this regard, caution should be exercised when treating patients with COPD with TNFα inhibitors, as well as patients who have an increased risk of developing malignant neoplasms due to active smoking.

Chronic heart failure (CHF)

During treatment with TNFα inhibitors, including the drug Cimzia^®, there have been reports of cases of chronic heart failure (CHF) and its progression. The drug should be used with caution in patients with CHF of functional class I-II according to the NYHA classification.

The drug Cimzia^® should be discontinued if CHF is newly diagnosed or symptoms of its progression are detected. Symptomatic therapy is recommended.

Hypersensitivity reactions

The following symptoms, which may resemble hypersensitivity reactions, have been rarely observed in patients after administration of the drug Cimzia^®: angioedema, shortness of breath, decreased blood pressure, skin rash, serum sickness, and urticaria.

Some of these reactions were noted after the first use of the drug Cimzia^®.

If the above reactions occur, administration of the drug Cimzia^® should be immediately stopped and appropriate treatment initiated.

Neurological disorders

The use of TNF antagonists has been rarely associated with the new development or worsening of the severity of pre-existing clinical symptoms and/or radiological signs of demyelinating disease, including multiple sclerosis.

In patients with pre-existing or recently developed demyelinating disease, the risk/benefit ratio should be carefully weighed before starting therapy with the drug Cimzia^®. Rare cases of neurological diseases, including seizure disorders, neuritis, and peripheral neuropathies, have been observed during treatment with the drug Cimzia^®.

Immunosuppression

Since TNFα is a mediator of the inflammatory process and modulates the cellular immune response, the possibility of suppression of the immune system and a decrease in the body’s resistance to infections and malignant neoplasms cannot be excluded during treatment with the drug Cimzia^®.

Antibody formation

Treatment with the drug Cimzia^® may be accompanied by the formation of antinuclear antibodies (ANA) and, infrequently, the development of a lupus-like syndrome.

If a patient develops symptoms similar to a lupus-like syndrome during treatment with the drug Cimzia^®, treatment should be discontinued. The effect of long-term therapy with the drug Cimzia^® on the development of autoimmune diseases is unknown. Special studies of the drug Cimzia^® in systemic lupus erythematosus have not been conducted.

Hematological reactions

Rare cases of pancytopenia and very rare cases of aplastic anemia have been reported with the use of TNFα inhibitors. Caution should be exercised when prescribing the drug Cimzia^® to patients with a history of significant changes in blood test parameters. All patients and their relatives should be informed of the need for immediate medical attention if the patient develops signs and symptoms characteristic of hematological disorders or infection (e.g., prolonged fever, sore throat, bruising, bleeding, pale skin) during treatment with the drug Cimzia^®. Such patients are recommended to undergo a medical examination, including a complete blood count. If the diagnosis of pancytopenia or other significant hematological disorders is confirmed, treatment with the drug should be discontinued.

Combination therapy

Reports of severe infections and neutropenia were received in clinical studies with the combined use of the drug Cimzia^® with other TNFα inhibitors: anakinra (interleukin-1 antagonist) or abatacept (T-cell surface CD28 activity modulator), as well as with etanercept. Concomitant use of the drug Cimzia^® with these drugs or with other biological DMARDs did not show additional clinical benefit and is therefore not recommended.

Elderly patients

Clinical studies have noted a higher frequency of infectious diseases in patients aged 65 years and older compared to younger patients, although these data are limited. Caution is recommended when using the drug Cimzia^® in elderly patients; patients in this group require special attention regarding the possible development of infection.

Effect on blood clotting parameters

During the use of the drug Cimzia^®, a false-positive increase in aPTT (activated partial thromboplastin time) is possible in patients without coagulation disorders. An increase in aPTT was observed when using various methods, including the lupus anticoagulant test. No data have been obtained on the effect of therapy with the drug Cimzia^® on blood clotting in vivo.

In patients receiving treatment with the drug Cimzia^®, blood clotting parameters that are outside the normal range should be interpreted with particular care, regardless of the analytical method.

No effect on other blood clotting parameters (thrombin time, prothrombin time, etc.) has been established.

Surgical interventions

There are limited data on the safety of surgical operations in patients receiving the drug Cimzia^®. When planning a surgical operation, it must be taken into account that the T_1/2 of certolizumab pegol is 14 days. If a patient requires surgical intervention during treatment with the drug Cimzia^®, constant monitoring of the patient must be ensured for the timely detection of signs of infections and taking appropriate measures.

Effect on the ability to drive vehicles and mechanisms

After administration of the drug Cimzia^®, dizziness, visual disturbances, and a feeling of fatigue may occur, which may adversely affect the ability to engage in activities requiring concentration and high speed of psychomotor reactions. Therefore, if these symptoms occur, one should refrain from driving vehicles and complex mechanisms.

Overdose

No relationship between toxicity manifestations and drug dose was registered within the framework of clinical studies. With s.c. administration of the drug Cimzia^® at a dose of up to 800 mg and i.v. administration at a dose of 20 mg/kg, no symptoms of overdose were noted.

Treatment in case of overdose symptoms requires careful monitoring of the patient’s condition and symptomatic therapy.

Drug Interactions

Concomitant use of the drug Cimzia^® with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, salicylates, antibacterial, antiviral drugs, as well as immunosuppressants (azathioprine, mercaptopurine, methotrexate) did not affect the pharmacokinetic parameters of the drug.

Storage Conditions

The medication should be stored in a place protected from light and out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The medication is dispensed by prescription.

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.