Actemra^® (Solution, Concentrate) Instructions for Use

ATC Code

L04AC07 (Tocilizumab)

Active Substance

Tocilizumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Specific immunosuppressive drug. Interleukin-6 receptor antagonist

Pharmacotherapeutic Group

Monoclonal antibodies

Pharmacological Action

Mechanism of action

Tocilizumab is a recombinant humanized monoclonal antibody against the human interleukin-6 (IL-6) receptor of the immunoglobulin IgG₁ subclass. Tocilizumab selectively binds to and inhibits both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various cell types and is involved in paracrine regulation, systemic physiological and pathological processes, such as stimulation of Ig secretion, T-cell activation, stimulation of acute-phase protein production in the liver, and stimulation of hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis, and neoplasms.

The possibility of a negative impact of tocilizumab on the body’s anti-tumor and anti-infective defenses cannot be excluded. The role of IL-6 receptor inhibition in tumor development is not known.

Preclinical safety data

Carcinogenicity studies to investigate the carcinogenicity of tocilizumab have not been conducted. Available preclinical data demonstrate the contribution of pleiotropic IL-6 to the progression of malignant neoplasms and resistance to apoptosis in various forms of cancer. These data do not suggest that treatment with tocilizumab leads to a significant risk of cancer development and progression.

Mutagenicity standard genotoxicity tests in both prokaryotic and eukaryotic cells were negative.

Effect on fertility available preclinical data do not suggest an effect of tocilizumab analogs on fertility.

Teratogenicity no direct or indirect adverse effects on pregnancy or intrauterine development were detected with intravenous administration of tocilizumab to cynomolgus monkeys in the early gestational period.

Other a slight increase in cases of spontaneous miscarriage/intrauterine fetal death was noted at high levels of systemic cumulative exposure (more than 100 times that in humans) when administering a dose of 50 mg/kg/day compared to placebo or lower administered doses. The miscarriage rate was within the historical control for captive cynomolgus monkeys; individual cases of miscarriage/intrauterine death did not demonstrate any relationship between these events and the dose or duration of tocilizumab administration.

Although IL-6 does not appear to play a critical role in fetal development or immunological regulation of the mother-fetus system, a relationship between these phenomena and tocilizumab administration cannot be ruled out.

Excretion of a murine analog of tocilizumab into the milk of lactating mice was observed. The use of the murine analog of tocilizumab did not have a toxic effect on juvenile mice. In particular, no impairment of skeletal growth, immune function, or sexual development was observed.

Preclinical safety data for intravenous use of tocilizumab in cynomolgus monkeys do not differ from those for subcutaneous use of tocilizumab.

Pharmacokinetics

Absorption

In patients with rheumatoid arthritis receiving Tocilizumab subcutaneously, the time to reach peak concentration of tocilizumab is about 2.8 days. The bioavailability of tocilizumab with subcutaneous administration is 80%.

Distribution

After subcutaneous administration, Tocilizumab undergoes biphasic elimination from the systemic circulation. In patients with rheumatoid arthritis, V_d in the central compartment is 3.5 L, in the peripheral compartment is 2.9 L, and V_d at steady state is 6.4 L.

Elimination

The total clearance of tocilizumab is concentration-dependent and is the sum of linear and nonlinear clearance. Linear clearance is 12.5 ml/h in patients with rheumatoid arthritis. Nonlinear clearance, which is concentration-dependent, is most significant at low concentrations of tocilizumab. At higher concentrations of tocilizumab, linear clearance predominates due to saturation of the nonlinear clearance pathway.

In rheumatoid arthritis, the concentration-dependent apparent T_1/2 for tocilizumab at steady state with subcutaneous administration at a dose of 162 mg once a week is up to 13 days, and for tocilizumab with subcutaneous administration at a dose of 162 mg once every 2 weeks is up to 5 days.

Pharmacokinetics in special patient groups

Patients with hepatic impairment

The pharmacokinetics of tocilizumab in patients with hepatic impairment have not been studied.

Patients with renal impairment

No specific studies have been conducted in patients with renal impairment. Most patients with rheumatoid arthritis included in the population pharmacokinetic analysis had normal renal function or mild renal impairment (Cockcroft-Gault creatinine clearance <80 ml/min and ≥50 ml/min), which did not affect the pharmacokinetics of tocilizumab. Dose adjustment of tocilizumab is not required for patients with mild renal impairment.

Gender, race, elderly age

Population pharmacokinetic analysis in adult patients with rheumatoid arthritis showed that age, gender, and race do not affect the pharmacokinetics of tocilizumab. No dose adjustment of tocilizumab is required.

Indications

• Rheumatoid arthritis with moderate or high activity in adults both as monotherapy and in combination with methotrexate and/or with other basic anti-inflammatory drugs, including for slowing radiographically proven joint destruction.

ICD codes

Dosage Regimen

Concentrate

Administered by intravenous drip infusion.

Adults – 8 mg/kg over at least 1 hour, once every 4 weeks. A dose increase of more than 800 mg per infusion is not recommended for patients weighing more than 100 kg.

Children over 2 years old – 8 mg/kg and depending on the indications, administered once every 2-4 weeks in patients with body weight ≥ 30 kg or 10-12 mg/kg once every 2-4 weeks in patients with body weight < 30 kg.

The dose should be calculated based on the patient’s body weight at each administration. Dose adjustment should be based solely on appropriate changes in the patient’s body weight over time.

Solution

General recommendations

The drug Actemra^® for subcutaneous administration is administered using a single-use syringe tube or autoinjector.

The first injection should be performed under the supervision of a qualified healthcare professional. It is recommended to alternate subcutaneous injection sites (anterior abdominal wall, thigh, or shoulder) each time; the drug should not be injected into moles, scars, areas of increased skin sensitivity, hematomas, redness, damage, or skin induration.

The drug Actemra^® in the dosage form “solution for subcutaneous injection” is not intended for intravenous administration!

Do not use the drug if it is cloudy, contains foreign particles, or has changed color.

Rheumatoid arthritis

The drug Actemra^® for subcutaneous administration is administered subcutaneously at a dose of 162 mg once a week. Actemra^® can be used both as monotherapy and in combination with methotrexate and/or other basic anti-inflammatory drugs (DMARDs).

When switching a patient from intravenous to subcutaneous administration of Actemra^®, the first subcutaneous injection should be administered instead of the next planned intravenous infusion under the guidance of a qualified healthcare professional. The clinical efficacy of tocilizumab with subcutaneous administration is comparable to that with intravenous administration.

The possibility of the patient using Actemra^® independently at home should be assessed. If symptoms of a serious allergic reaction develop, the patient may require immediate medical attention. The patient should be informed of the need to report any symptoms of an allergic reaction that occur to the treating physician before the next injection of the drug.

Recommendations for dose adjustment based on changes in laboratory parameters

Increased activity of “liver” enzymes.

ULN* – upper limit of normal DMARD** – disease-modifying antirheumatic drugs

Low absolute neutrophil count (ANC)

Low platelet count

Instructions for use and disposal of unused drug and expired drug

The release of pharmaceuticals into the environment with waste should be minimized. The drug should not be disposed of via wastewater or with household waste. If possible, special systems for drug disposal should be used.

Dosing in special cases

Elderly patients

No dose adjustment is required in elderly patients (≥65 years).

Patients with renal impairment

No dose adjustment is required in patients with mild renal impairment (see section “Pharmacological properties”, subsection “Pharmacokinetics in special patient groups”). The use of tocilizumab in patients with moderate and severe renal impairment has not been studied.

Patients with hepatic impairment

The safety and efficacy of tocilizumab in patients with hepatic impairment have not been studied (see section “With caution”).

Children

The safety and efficacy of subcutaneous use of tocilizumab in children have not been established.

Instructions for using the syringe tube

The device is for single use only.

Before using the syringe tube, carefully read the instructions.

1. Inspection of the syringe tube

Remove the package with the syringe tube from the refrigerator. Then remove the syringe tube with the drug from the carton. Inspect the syringe tube and the drug inside it.

Do not use the syringe tube if

• The solution is cloudy or contains foreign visible particles;
• The color has changed (the solution has a color different from that indicated in the section “Description of the dosage form”);
• Any parts of the syringe tube are damaged;
• The expiration date (expires on…) indicated on the carton and on the syringe tube label has passed.

Do not remove the syringe tube cap until Step 5.

2. Bringing the syringe tube to room temperature

Leave the syringe tube at room temperature for approximately 25-30 minutes. Do not warm the syringe tube in any other way.

3. Hand hygiene

Wash your hands with soap and water.

4. Selection and preparation of the injection site

Injections are recommended in the front and middle surface of the mid-thigh, in the lower abdomen, excluding an area five centimeters in diameter directly around the navel. If the injection is given by a healthcare professional or a caregiver, injections can also be given in the outer surface of the upper arm. The injection site should be changed each time (when giving an injection, it is recommended to step back at least three centimeters from the area of the previous injection). Areas that may be irritated by clothing belts or waistbands should be avoided. Do not inject the drug into birthmarks, scar tissue, hematomas, areas with induration, damage, areas with sensitive skin, redness and/or reaction from previous injections.

Thoroughly clean the intended area with an alcohol wipe. Wait for the cleaned area to dry. Do not touch this area until the injection is performed. Do not fan or blow on the cleaned area.

5. Preparation of the syringe tube

Holding the syringe tube gently and without pressing the plunger, carefully remove the protective cap from the needle. After removing the cap, the syringe tube should be used immediately. If the syringe tube is not used within 5 minutes after cap removal, it must be disposed of and a new syringe tube should be used instead. Do not put the protective cap back on after removal.

6. Administration of the drug

Pinch the skin at the intended injection site with two fingers. Holding the syringe tube comfortably with the other hand and without pressing the plunger, insert the needle into the skin fold at a 45-90° angle (the injection angle depends on the thickness of the subcutaneous fold).

By pressing the plunger smoothly, slowly inject the entire drug.

Do not stop pressing the syringe tube plunger until you have completely removed the needle from the skin!

After administering the entire dose, remove the needle from the skin without releasing the syringe tube plunger.

When the plunger is released, the trigger mechanism is activated and the spring located above the needle in a compressed state is released (uncompressed) and ensures the needle is retracted inside the protective housing.

Press a cotton swab on the drug administration site. If necessary, cover the injection site with a bandage.

7. Disposal of the syringe tube

It is not necessary to put the protective cap back on the syringe tube. The used syringe tube and cap must be placed in a puncture-resistant container. This container should be stored in places inaccessible to children. The filled container should be disposed of in accordance with the recommendations of healthcare professionals. The release of pharmaceuticals into the environment with waste should be minimized. The drug should not be disposed of via wastewater or with household waste. If possible, special systems for drug disposal should be used.

Instructions for using the autoinjector

The device is for single use only.

Before using the autoinjector, carefully read the instructions.

1. Inspection of the autoinjector

Remove the package with the autoinjector from the refrigerator. Then remove the autoinjector from the carton. Inspect it and the drug inside it through the inspection window.

Do not use the autoinjector if

• The solution is cloudy or contains foreign visible particles;
• The color has changed (the solution has a color different from that indicated in the section “Description of the dosage form”);
• Any parts of the autoinjector are damaged;
• The expiration date (expires on…) indicated on the carton and on the autoinjector label has passed.

Do not remove the autoinjector cap until Step 5.

2. Bringing the autoinjector to room temperature

Leave the autoinjector at room temperature for no more than 45 minutes. Do not warm the autoinjector in any other way.

3. Hand hygiene

Wash your hands with soap and water.

4. Selection and preparation of the injection site

Injections are recommended in the front and middle surface of the mid-thigh, in the lower abdomen below the navel, excluding an area five centimeters in diameter directly around the navel. If the injection is given by a healthcare professional or a caregiver, injections can also be given in the outer surface of the upper arm. The injection site should be changed each time (when giving an injection, it is recommended to step back at least three centimeters from the area of the previous injection). Areas that may be irritated by clothing belts or waistbands should be avoided. Do not inject the drug into birthmarks, scar tissue, hematomas, areas with induration, damage, areas with sensitive skin, redness and/or reaction from previous injections.

Thoroughly clean the intended area with an alcohol wipe. Wait for the cleaned area to dry. Do not touch this area until the injection is performed. Do not fan or blow on the cleaned area.

5. Preparation of the autoinjector

Holding the autoinjector firmly with one hand, remove the protective cap with the other hand, after which the part of the needle shield cylinder with the purple rim becomes visible. The protective cap contains a movable metal tube.

Do not put the protective cap back on. Discard the cap in a puncture-resistant container or sharps container.

Note: after removing the cap, the autoinjector should be used immediately. If the autoinjector is not used within 5 minutes after cap removal, it must be disposed of and a new autoinjector should be used instead.

6. Positioning the autoinjector to the intended injection site

Pinch the skin at the intended injection site with two fingers. Without pressing the activation button, holding the autoinjector with the other hand, firmly press the needle shield cylinder against the top of the skin fold at a right angle (90°).

Press the autoinjector firmly against the skin until the needle shield cylinder is completely retracted into the autoinjector. Only after this the autoinjector is activated and ready to perform the injection.

7. Administration of the drug

Holding the autoinjector firmly, press the activation button with your thumb and release it immediately. An audible click indicates the start of the injection. During the injection, the inspection window gradually fills with the purple indicator.

Do not release the autoinjector for 20 seconds to complete the injection. When the activation button returns to its original position, a second click may be heard. After the injection is completed, the inspection window will become completely purple.

Make sure your thumb is removed from the autoinjector activation button. After 20 seconds, holding the autoinjector at a right angle (90°) to the skin, remove it. The needle shield will automatically cover the needle, preventing possible needle-stick injuries.

Caution: if the purple indicator does not completely fill the inspection window

• It is possible that the needle-protecting cylinder is not fully closed – in this case, do not touch the tip of the autoinjector, as needle-related injuries are possible in this situation;
• Incomplete administration of the drug is possible – do not attempt to reuse the autoinjector, do not repeat the injection, contact your healthcare professional. After administering the drug, wipe the injection site with an alcohol wipe.

8. Autoinjector Disposal

It is not required to put the protective cap back on the autoinjector. The used autoinjector and cap should be placed in a puncture-resistant container. This container should be stored in places inaccessible to children. The filled container should be disposed of in accordance with the recommendations of healthcare professionals.

The release of medicinal products into the environment with waste must be minimized. The drug should not be disposed of via wastewater or with household waste. Whenever possible, special systems for the disposal of medicinal products should be used.

Adverse Reactions

The following categories are used to describe the frequency of adverse reactions: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000, including isolated cases).

Table 1. Summary of adverse reactions reported in patients with rheumatoid arthritis receiving Actemra^® as monotherapy or in combination with methotrexate or other disease-modifying anti-rheumatic drugs (the entire controlled population)

Additional information on specific adverse reactions is provided below. The safety and immunogenicity profile observed with subcutaneous administration of tocilizumab correlates with the known safety profile of intravenous tocilizumab, with no new adverse reactions identified. A higher frequency of injection site reactions was observed with subcutaneous use of tocilizumab compared to subcutaneous placebo injections.

Infections

The following serious infectious diseases were reported: pneumonia, cellulitis, infections caused by Herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis, some of which were fatal. Cases of opportunistic infections have been reported.

Gastrointestinal Perforations

Cases of gastrointestinal perforation were mainly reported as complications of diverticulitis and included generalized purulent peritonitis, lower gastrointestinal perforation, fistula, and abscess.

Injection Site Reactions

Injection site reactions to tocilizumab (including erythema, pruritus, pain, and hematoma) were mild or moderate in severity, resolved in most cases without treatment, and did not lead to drug discontinuation.

Immunogenicity

Antibodies to tocilizumab were detected in 0.8% of tested patients, of which 0.2% had immunoglobulin E (IgE) antibodies. All patients had neutralizing antibodies.

Of all 434 patients receiving Tocilizumab every 2 weeks at a dose of 163 mg, 1.6% of patients had antibodies to tocilizumab, of which 1.4% had neutralizing antibodies to tocilizumab. Immunoglobulin E (IgE) antibodies were detected in 0.9% of patients.

No correlation was found between the presence of antibodies to tocilizumab and clinical response or the development of adverse events.

Changes in Laboratory Parameters

The following changes were noted during routine monitoring of laboratory parameters

• A decrease in neutrophil count below 1×10⁹/L was observed in 2.9% of patients receiving Actemra^® subcutaneously at a dose of 162 mg once weekly; no clear association was observed between a decrease in neutrophil count below 1×10⁹/L and the development of serious infectious diseases;
• A decrease in platelet count ≤50×10³/µL was not observed;
• An increase in ALT or AST activity to ≥3 times the upper limit of normal was recorded in 6.5% and 1.4% of patients, respectively;
• An increase in total cholesterol >6.2 mmol/L (240 mg/dL) was observed in 19% of patients, and a persistent increase in LDL ≥4.1 mmol/L (160 mg/dL) was observed in 9% of patients.

Post-Marketing Experience

The safety profile of the drug in post-marketing use is consistent with clinical trial data, except for cases of fatal anaphylaxis reported with intravenous use of Actemra^®. In post-marketing use of intravenous Actemra^®, serious hypersensitivity events, including anaphylaxis, occurred in patients receiving various doses of Actemra^® regardless of concomitant therapy for rheumatoid arthritis, premedication, and/or history of hypersensitivity reactions.

Contraindications

• Hypersensitivity to tocilizumab, any component of the drug in history;
• Active infectious diseases (including tuberculosis);
• Combination with TNFα inhibitors or use within 1 month after treatment with anti-TNF antibodies;
• Age under 18 years.

With caution

Infections in patients receiving immunosuppressants (including Actemra^®), serious cases of infectious diseases (sometimes fatal) have been observed (see section “Adverse Reactions”). Treatment with Actemra^® should not be initiated in patients with active infectious diseases. If serious infections develop, therapy with Actemra^® should be interrupted until the infection is resolved. Caution should be exercised when using Actemra^® in patients with a history of recurrent infectious diseases, as well as with comorbidities predisposing to the development of infections (e.g., diverticulitis, diabetes mellitus). Particular caution should be exercised for the early detection of serious infectious diseases in patients with moderate to high disease activity rheumatoid arthritis, as signs or symptoms of acute inflammation may be masked due to suppression of the acute phase response.

Complications of diverticulitis: cases of diverticular perforation have been reported in patients with rheumatoid arthritis. Caution should be exercised when using Actemra^® in patients with a history of gastrointestinal ulceration or diverticulitis. Patients with signs possibly indicating complicated diverticulitis (abdominal pain) should be examined immediately for early detection of gastrointestinal perforation.

Active Liver Disease and Hepatic Insufficiency therapy with Actemra^®, especially concurrently with methotrexate, may be associated with an increase in “hepatic” transaminase activity, therefore caution should be exercised in patients with active liver disease or hepatic insufficiency.

Demyelinating Diseases particular caution should be exercised for the early detection of symptoms possibly indicating the development of CNS demyelinating diseases. The ability of tocilizumab to cause CNS demyelinating diseases is currently unknown.

Increased “Hepatic” Transaminase Activity mild or moderate increases in “hepatic” transaminase activity without signs of hepatic insufficiency were observed (see section “Adverse Reactions”). The frequency of such changes increased when Actemra^® was used concomitantly with drugs with potential hepatotoxicity (e.g., methotrexate). Caution should be exercised when deciding to initiate therapy with Actemra^® in patients with ALT or AST levels exceeding the upper limit of normal (ULN) by more than 1.5 times. Therapy with Actemra^® is not recommended if ALT or AST levels exceed ULN by more than 5 times. In rheumatoid arthritis, ALT and AST should be monitored once between weeks 4 and 8 after initiation of therapy, and thereafter according to clinical practice. Dosing recommendations based on “hepatic” transaminase activity are provided in the “Dosage Regimen” section.

Changes in Lipid Metabolism Parameters increases in lipid metabolism parameters (total cholesterol, LDL, triglycerides) were observed (see section “Adverse Reactions”). In rheumatoid arthritis, lipid metabolism parameters should be assessed once between weeks 4 and 8 after initiation of Actemra^® therapy. Patient management should be guided by national guidelines for the treatment of hyperlipidemia.

Use in Pregnancy and Lactation

The safety and efficacy of Actemra^® during pregnancy have not been sufficiently studied. Studies in monkeys did not reveal a dysmorphogenetic potential of Actemra^®. However, administration of the drug in high doses revealed an increased risk of spontaneous abortion/intrauterine death. The significance of this information for humans is unknown (see section “Pharmacological Properties”, subsection “Pharmacodynamics”).

Tocilizumab should not be used during pregnancy, except in cases of clear clinical necessity.

It is not known whether Actemra^® is excreted in human breast milk. Although endogenous IgG is excreted in breast milk, systemic absorption of the drug during breastfeeding is unlikely due to rapid proteolytic degradation of such proteins in the digestive system.

The decision to continue/discontinue breastfeeding or to continue/discontinue tocilizumab therapy should take into account the benefit of breastfeeding for the child and the benefit of continued therapy for the mother.

Use in Hepatic Impairment

Use the drug with caution, especially concurrently with methotrexate, in patients with active liver disease or hepatic insufficiency.

The safety and efficacy of tocilizumab in patients with hepatic impairment have not been studied.

Use in Renal Impairment

No dose adjustment is required in patients with mild renal impairment. The use of tocilizumab in patients with moderate and severe renal impairment has not been studied.

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required in elderly patients (≥65 years).

Special Precautions

The trade name of the drug (Actemra^®) should be indicated in the patient’s medical records.

Switching from Actemra^® for subcutaneous administration to any other biological medicinal product requires consultation with the attending physician.

Hypersensitivity reactions. serious hypersensitivity reactions, including anaphylaxis, have been observed in post-marketing use of intravenous Actemra^® (see section “Adverse Reactions”). These serious events can be severe and potentially fatal in patients who have previously had hypersensitivity reactions to Actemra^® even when combined with corticosteroid and antihistamine premedication.

A set of necessary measures for the treatment of a possible anaphylactic reaction must be provided during the administration of Actemra^®. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, the administration of Actemra^® should be stopped immediately, appropriate treatment initiated, and therapy with the drug should not be resumed in the future.

Tuberculosis: before prescribing Actemra^®, as with other biological drugs for the treatment of rheumatoid arthritis, patients should be screened for latent tuberculosis. If latent tuberculosis is detected, a standard course of antimycobacterial therapy should be administered before starting treatment with Actemra^®.

Immunization: immunization with live and live attenuated vaccines should not be carried out concurrently with Actemra^® therapy, as the safety of such a combination has not been established. There are no data on secondary transmission of infection from patients receiving live vaccines to patients receiving Tocilizumab. In patients with rheumatoid arthritis receiving tocilizumab/methotrexate therapy, the response to the 23-valent pneumococcal polysaccharide vaccine and tetanus toxoid was comparable to that in patients receiving methotrexate monotherapy.

It is recommended that all patients be vaccinated according to the national immunization schedule before starting treatment with Actemra^®. An interval (in accordance with current immunization guidelines) should be observed in patients receiving immunosuppressive therapy between immunization with live vaccines and the start of Actemra^® therapy.

Reactivation of viral infections: cases of viral infection reactivation (e.g., viral hepatitis B) have been observed in patients with rheumatoid arthritis treated with biological drugs. Patients with a positive screening result for hepatitis were not included in the clinical trials of Actemra^®.

Changes in Laboratory Parameters

Neutropenia: therapy with Actemra^® was associated with a higher frequency of neutropenia. Caution should be exercised when prescribing Actemra^® to patients with neutropenia, i.e., with ANC <2.0×10⁹/L. Treatment with Actemra^® is not recommended for ANC <0.5×10⁹/L.

In rheumatoid arthritis, neutrophil count should be monitored. The first determination of neutrophil count is recommended between weeks 4 and 8 after initiation of therapy, and thereafter according to clinical practice. Dosing recommendations based on ANC are provided in the “Dosage Regimen” section.

Thrombocytopenia: therapy with Actemra^® was associated with a decrease in platelet count and was not associated with serious bleeding events. Treatment-related decrease in platelet count was not associated with serious bleeding events (see section “Adverse Reactions”). Caution should be exercised when deciding to initiate therapy with Actemra^® with a platelet count below 100×10³/µL. Treatment is not recommended for platelet count <50×10³/µL. In rheumatoid arthritis, platelet count should be monitored for the first time between weeks 4 and 8 after initiation of therapy, and thereafter according to clinical practice. Dosing recommendations based on platelet count are provided in the “Dosage Regimen” section.

Features of the drug action upon first administration or upon its withdrawal: studies on the potential of Actemra^® to cause dependence have not been conducted. Based on available data, Actemra^® does not have such an effect.

Effect on ability to drive vehicles and machinery

Studies on the effect of the drug on the ability to drive vehicles and machinery have not been conducted. However, given the fact that dizziness was frequently observed during therapy with Actemra^®, patients experiencing this adverse reaction should be advised to refrain from driving vehicles and operating machinery until the dizziness subsides.

Overdose

Data on overdose of Actemra^® are limited. In one case of unintentional overdose of the drug at a dose of 40 mg/kg IV in a patient with multiple myeloma, no adverse reactions were noted. No serious adverse reactions were also noted in healthy volunteers who received a single dose of Actemra^® up to 28 mg/kg, although neutropenia requiring dose reduction was observed.

Drug Interactions

Population pharmacokinetic analysis of clinical trials did not reveal any effect of methotrexate, NSAIDs, or corticosteroids on the clearance of tocilizumab.

The pharmacokinetic parameters of tocilizumab remain unchanged with the concomitant use of other drugs for the treatment of rheumatoid arthritis (such as antimalarials (chloroquine and its derivatives), immunosuppressants (azathioprine, leflunomide), folic acid and its derivatives, COX-2 inhibitors (celecoxib) and analgesics (paracetamol, tramadol, codeine and their derivatives)).

Concomitant single administration of tocilizumab at a dose of 10 mg/kg and methotrexate at a dose of 10-25 mg once weekly did not have a clinically significant effect on methotrexate exposure.

Studies on the combined use of tocilizumab with other biological DMARDs have not been conducted.

Since the expression of hepatic CYP450 isoenzymes is suppressed by the action of cytokines (e.g., IL-6, which stimulates chronic inflammation), therapy with agents that inhibit cytokine action (e.g., Tocilizumab) may disrupt the expression of CYP450 isoenzymes.

In vitro studies conducted on human hepatocyte cultures have shown that IL-6 causes a decrease in the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 isoenzymes. The use of tocilizumab normalizes the expression of these isoenzymes.

The effect of Actemra^® on CYP isoenzymes (except CYP2C19 and CYP2D6) is clinically significant for drugs that are CYP450 substrates with a narrow therapeutic index and/or for which doses are individually selected.

In patients with rheumatoid arthritis, the concentration of simvastatin (a CYP3A4 substrate) decreased by 57% one week after a single administration of tocilizumab, meaning it was slightly elevated or similar to that in healthy volunteers.

At the initiation or completion of a course of therapy with Actemra^®, patients receiving medicinal products in individually selected doses that are metabolized via the CYP450 3A4, 1A2, or 2C9 isoenzymes (e.g., atorvastatin, slow calcium channel blockers, theophylline, warfarin, phenytoin, cyclosporine, or benzodiazepines) should be carefully monitored.

To ensure the therapeutic effect of these drugs, an increase in their dose may be required.

Given the long T_1/2 of Actemra^®, its effect on CYP450 isoenzyme activity may persist for several weeks after therapy discontinuation.

Storage Conditions

The drug should be stored in a place protected from light and out of the reach of children at a temperature of 2°-8°C (17.6°F). Do not freeze.

Shelf Life

Shelf life – 2 years 6 months.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug 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.