Kevzara^® (Solution) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis Groupe, JSC (France)

Manufactured By

Sanofi Winthrop Industrie (France)

Packaging and Quality Control Release

SANOFI WINTHROP INDUSTRIE (France)

Or

SANOFI-AVENTIS DEUTSCHLAND, GmbH (Germany)

Or

SANOFI-AVENTIS EAST, CJSC (Russia)

ATC Code

L04AC14 (Sarilumab)

Active Substance

Sarilumab (Rec.INN registered by WHO)

Dosage Forms

	Kevzara®	Solution for subcutaneous injection 131.6 mg/ml: syringes or pen-injectors 1.14 ml 2 pcs.
		Solution for subcutaneous injection 175 mg/ml: syringes or pen-injectors 1.14 ml 2 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection clear or opalescent, colorless or brownish-yellow.

Excipients: L-histidine and L-histidine hydrochloride monohydrate (calculated as L-histidine) – 3.71 mg, L-arginine hydrochloride (calculated as L-arginine) – 8.94 mg, sucrose – 57 mg, polysorbate 20 – 2.28 mg, water for injections – up to 1.14 ml.

1.14 ml – single-use syringes made of clear glass (type I) with a fixed needle (2) – cardboard packs^× with sealed valves.
1.14 ml – single-use syringes made of clear glass (type I) with a fixed needle (1) – pen-injectors (2) – cardboard packs^× with sealed valves.

Solution for subcutaneous injection clear or opalescent, colorless or brownish-yellow.

Excipients: L-histidine and L-histidine hydrochloride monohydrate (calculated as L-histidine) – 3.71 mg, L-arginine hydrochloride (calculated as L-arginine) – 8.94 mg, sucrose – 57 mg, polysorbate 20 – 2.28 mg, water for injections – up to 1.14 ml.

1.14 ml – single-use syringes made of clear glass (type I) with a fixed needle (2) – cardboard packs^× with sealed valves.
1.14 ml – single-use syringes made of clear glass (type I) with a fixed needle (1) – pen-injectors (2) – cardboard packs^× with sealed valves.

^× Each cardboard pack has an anti-counterfeit sticker applied.

Clinical-Pharmacological Group

Specific immunosuppressive drug. Interleukin-6 receptor antagonist

Pharmacotherapeutic Group

Immunosuppressants, interleukin inhibitors

Pharmacological Action

Mechanism of action

Sarilumab is a human monoclonal antibody (subtype IgG1) directed against the interleukin-6 (IL-6) receptor. Sarilumab specifically binds to both soluble and membrane-bound IL-6 receptors (IL-6Rα) and inhibits IL-6-mediated signal transduction involving the ubiquitous signaling protein glycoprotein 130 (gp130) and STAT-3 proteins (signal transducers and activators of transcription-3).

In functional studies on human cells, Sarilumab was shown to be capable of blocking the IL-6 signaling pathway, as measured by the degree of STAT-3 protein suppression, only in the presence of IL-6.

IL-6 is a pleiotropic cytokine that stimulates various cellular responses such as cell proliferation, differentiation, survival, and apoptosis; it activates the release of acute-phase inflammatory proteins in hepatocytes, including C-reactive protein (CRP) and serum amyloid A. The elevated level of IL-6 detected in the synovial fluid of patients with rheumatoid arthritis plays an important role in both the development of pathological inflammation and the development of joint destruction, which are hallmarks of rheumatoid arthritis. IL-6 is involved in various physiological processes such as the migration and activation of T- and B-lymphocytes, monocytes, and osteoclasts, leading to the development of systemic inflammation, synovial membrane inflammation, and the development of bone erosions in patients with rheumatoid arthritis. The action of sarilumab leads to a reduction in inflammation and is accompanied by changes in laboratory parameters, such as a decrease in the absolute neutrophil count (ANC) and an increase in lipid concentrations.

Pharmacodynamic effects

After subcutaneous administration of sarilumab in single doses of 150 mg and 200 mg in patients with rheumatoid arthritis, a rapid decrease in CRP levels was observed. CRP levels decreased to normal values as early as 4 days after the start of treatment. In patients with rheumatoid arthritis, after a single dose of sarilumab, ANC decreased to a minimum value within 3-4 days and then recovered to baseline. Treatment with sarilumab led to a decrease in fibrinogen and serum amyloid A levels, as well as an increase in hemoglobin and serum albumin levels.

Clinical efficacy and safety

The efficacy and safety of Kevzara^® were evaluated in three randomized, double-blind, controlled, multicenter studies.

Placebo-controlled studies

The MOBILITY study involved 1197 patients with rheumatoid arthritis with an inadequate clinical response to methotrexate therapy. Patients received Kevzara^® at doses of 200 mg, 150 mg, or placebo every 2 weeks concurrently with methotrexate. The TARGET study involved 546 patients with rheumatoid arthritis with an inadequate clinical response to therapy with one or more TNFα antagonists or in case of their intolerance. Patients received Kevzara^® at doses of 200 mg or 150 mg or placebo in combination with conventional disease-modifying antirheumatic drugs [cDMARDs] every 2 weeks.

Clinical response

At week 24 of therapy in both studies, patients receiving Kevzara^® at a dose of 200 mg or 150 mg in combination with cDMARDs once every 2 weeks had higher ACR20, ACR50, and ACR70 response rates than patients receiving placebo. In the open-label extension phase of the study, these results were maintained for up to 3 years of therapy.

In the MOBILITY study, by week 52, a greater proportion of patients receiving Kevzara^® at a dose of 200 mg or 150 mg once every 2 weeks in combination with methotrexate achieved remission, defined as DAS28-CRP < 2.6 (Disease Activity Score in 28 joints - C-reactive protein), compared to the group of patients receiving placebo in combination with methotrexate.

In the MOBILITY and TARGET studies, a higher ACR20 response rate compared to the placebo group was observed as early as 2 weeks in the active treatment group; the results were maintained throughout the study.

The results of the MOBILITY study at 52 weeks of therapy were similar to the results of the TARGET study at 24 weeks.

Radiographic response

In the MOBILITY study, the efficacy of both doses of Kevzara^® in combination with methotrexate was superior to the efficacy of the placebo and methotrexate combination in terms of structural joint damage, assessed by the change from baseline in the modified Sharp/van der Heijde score at 24 and 52 weeks.

After 52 weeks of therapy with Kevzara^® at a dose of 200 mg and a dose of 150 mg in combination with methotrexate, a reduction in the progression of structural damage by 91% and 68%, respectively, was noted compared to the placebo and methotrexate combination.

Changes in functional status

In the MOBILITY and TARGET studies, by week 16 and week 12 of therapy, respectively, a more pronounced improvement in functional status according to HAQ-DI was demonstrated in the Kevzara^® groups compared to placebo, which persisted until week 52 in the MOBILITY study.

Study with an active drug as control

The MONARCH study was a 24-week randomized, double-blind, double-dummy study comparing monotherapy with Kevzara^® at a dose of 200 mg with monotherapy with adalimumab at a dose of 40 mg.

Kevzara^® at a dose of 200 mg was superior to adalimumab at a dose of 40 mg in terms of reducing disease activity and improving functional status.

Pharmacokinetics

The pharmacokinetics of sarilumab were studied in 2186 patients with rheumatoid arthritis, of which 751 patients received Kevzara^® at a dose of 150 mg and 891 patients at a dose of 200 mg subcutaneously once every 2 weeks for up to 52 weeks. The median maximum concentration was reached 2-4 days after drug administration.

Absorption

At steady state, the concentration of sarilumab between doses, measured by AUC, doubled when the dose was increased from 150 mg to 200 mg when administered once every 2 weeks. Steady state was reached after 12-16 weeks with 2-3-fold accumulation compared to the concentration after a single dose. When administered at a dose of 150 mg once every 2 weeks, the estimated mean values (± standard deviation) at steady state for AUC, C_min, and C_max of sarilumab were 210±115 mg×day/L, 6.95±7.6 mg/L, and 20.4±8.27 mg/L, respectively.

When administered at a dose of 200 mg once every 2 weeks, the estimated mean values (± standard deviation) at steady state for AUC, C_min, and C_max of sarilumab were 396±194 mg×day/L, 16.7±13.5 mg/L, and 35.4±13.9 mg/L, respectively.

Distribution

In patients with rheumatoid arthritis, the apparent V_d at steady state was 8.3 L.

In patients with rheumatoid arthritis, a more than dose-dependent increase in pharmacokinetic exposure was observed. At steady state, the concentration between drug administrations, measured by AUC, increased approximately 2-fold with a 1.33-fold dose increase from 150 to 200 mg when the drug was administered once every 2 weeks.

Metabolism

The metabolism of sarilumab has not been studied. It is assumed that Sarilumab, like other monoclonal antibodies, is broken down into small peptides and amino acids through catabolism in the same way as endogenous immunoglobulin (IgG).

Simvastatin is a substrate of the CYP3A4 isoenzyme and the OATP1B1 transport protein. In 17 patients with rheumatoid arthritis one week after a single subcutaneous administration of sarilumab at a dose of 200 mg, the exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively.

Elimination

Sarilumab elimination occurs simultaneously via two pathways: linear and nonlinear. At high concentrations, elimination occurs predominantly via the linear, non-saturable proteolytic pathway, while at lower concentrations, nonlinear, saturable, target-mediated elimination predominates. These parallel pathways determine an initial T_1/2 of 8 to 10 days and a concentration-dependent terminal T_1/2 of 2 to 4 days.

After reaching steady state following the last dose of sarilumab 150 mg and 200 mg, the median time to undetectable concentrations is 30 and 49 days, respectively. Monoclonal antibodies are not eliminated by the kidneys and liver.

Pharmacokinetics in special patient groups

Population pharmacokinetic analysis in adult patients with rheumatoid arthritis (age from 18 to 88 years; 14% of patients over 65 years of age) showed that age, sex, and ethnicity do not have a significant effect on the pharmacokinetics of sarilumab. In patients weighing more than 100 kg, the use of sarilumab at both doses (150 mg and 200 mg) demonstrated efficacy; however, patients weighing more than 100 kg received greater therapeutic benefit when using the 200 mg dose.

No formal studies have been conducted on the effect of renal impairment on the pharmacokinetics of sarilumab. Mild to moderate renal impairment does not affect the pharmacokinetics of sarilumab. Dose adjustment is not required for patients with mild to moderate renal impairment. The use of sarilumab in patients with severe renal impairment has not been studied.

No formal studies have been conducted on the effect of hepatic impairment on the pharmacokinetics of sarilumab.

Indications

• In combination with methotrexate for the treatment of moderate to high activity rheumatoid arthritis in adult patients with an inadequate response to therapy with one or more disease-modifying antirheumatic drugs (DMARDs) or in case of their intolerance.

Kevzara^® can be used as monotherapy in case of intolerance to methotrexate or when methotrexate therapy is inappropriate.

ICD codes

Dosage Regimen

Treatment with Kevzara^® should be prescribed and conducted under the supervision of specialists with experience in the diagnosis and treatment of rheumatoid arthritis.

The recommended dose of Kevzara^® is 200 mg once every 2 weeks.

If neutropenia, thrombocytopenia, or increased liver enzyme activity develops, it is recommended to reduce the dose from 200 mg once every 2 weeks to 150 mg once every 2 weeks.

Dose adjustment

If serious infections develop, treatment with Kevzara^® should be discontinued until the infectious process is controlled.

It is not recommended to start treatment with Kevzara^® in patients with an absolute neutrophil count (ANC) of less than 2×10⁹/L.

It is not recommended to start treatment with Kevzara^® in patients with a platelet count below 150×10³/µL.

Recommendations for dose adjustment in case of neutropenia, thrombocytopenia, or increased liver enzyme activity are provided in the tables below.

Table 1. Low ANC value

Table 2. Decreased platelet count

Table 3. Increased liver enzyme activity

* Upper limit of normal.

Missed dose

If the administration of Kevzara^® is missed and 3 days or less have passed since the missed dose, the next dose should be administered as soon as possible. The next scheduled dose is then administered at the usual scheduled time.

If 4 days or more have passed since the missed dose, the next dose is administered at the next usual scheduled time. The dose should not be doubled.

Special patient groups

In patients with mild to moderate renal impairment, no dose adjustment of the drug is required. The use of Kevzara^® in patients with severe renal impairment has not been studied.

The safety and efficacy of Kevzara^® have not been studied in patients with impaired liver function, including patients with positive serological tests for hepatitis B virus (HBV) or hepatitis C virus (HCV).

In patients over 65 years of age, no dose adjustment is required.

Kevzara^® should not be used in children and adolescents under 18 years of age (safety and efficacy in rheumatoid arthritis have not been established).

Method of administration

Kevzara^® is administered subcutaneously.

The entire contents (1.14 ml) of the pre-filled syringe/pre-filled pen-injector should be administered subcutaneously.

Injection sites (abdomen, outer thigh, outer upper arm) should be rotated with each injection.

Do not inject into painful, damaged skin, or areas with bruising and scars.

The patient can self-administer the subcutaneous injection of Kevzara^®, or the injection can be performed by a caregiver. The patient or caregiver must be trained in the preparation and administration of Kevzara^® before starting use.

Instructions for use of pre-filled single-use pen-injectors

The figure shows the parts of the pre-filled pen-injector containing Kevzara^®.

The device is a pre-filled pen-injector (referred to in the instructions as the “pen-injector”) containing Kevzara^® in single doses of 150 mg and 200 mg. The drug is administered subcutaneously once every 2 weeks.

Before the first injection, ask your doctor to show you how to use the pen-injector correctly.

What to do

• Before using the pen, carefully read all instructions;
• Make sure that you are using exactly the medicinal product prescribed by your doctor and in the dose recommended for you;
• Store unused pens in the original cardboard pack in the refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F);
• During travel, store this cardboard pack in a cooler bag with ice;
• Before use, leave the pen at room temperature for at least 60 minutes to allow it to warm up;
• Use the pen within 14 days after removing it from the refrigerator or cooler bag;
• Store the pen out of sight and reach of children.

What not to do

× Do not use the pen if it is damaged, its cap is lost or not attached;

× Do not remove the cap until you are ready to inject;

× Do not press the yellow needle cap or touch it with your fingers;

× Do not attempt to put the cap back on the pen;

× Do not reuse the pen;

× Do not freeze or heat the pen;

× Do not store the pen at temperatures above 25°C (77°F) after removing it from the refrigerator;

× Do not expose the pen to direct sunlight;

× Do not inject through clothing.

If you have any additional questions, consult your doctor or call the company phone number provided in the instructions.

Step A. Prepare for the injection.

1. On a clean, flat work surface, lay out everything you will need.

• Alcohol, cotton or gauze swab, puncture-resistant container;
• Take one pen from the packaging, holding it by the middle of the body. Leave the other pens in the cardboard pack in the refrigerator.

2. Look at the label.

• Check that you have the exact medicinal product prescribed by your doctor and in the dose recommended for you;
• Check the expiration date (Use by), it is indicated on the side of the pen.

Do not use the pen after this date.

3. Look at the inspection window.

• Make sure the liquid in the pen is clear, from colorless to yellowish;
• If you notice air bubbles, this is normal;

× Do not inject the drug if the liquid is cloudy, a different color, or contains particles;

× Do not use the pen if the inspection window is uniformly yellow.

4. Place the pen on a flat surface and leave it for at least 60 minutes to allow it to warm up to room temperature (<25°C (77°F)).

• Using the pen at room temperature may make the injection more comfortable;

× Do not use the pen if it has been outside the refrigerator for more than 14 days;

× Do not heat the pen; let it warm up on its own;

× The pen must not be exposed to direct sunlight.

5. Choose the injection site.

• You can inject into the outer thigh or the front of the abdomen, except for an area 5 cm in diameter directly around the navel. If someone else is injecting the drug, the injection can also be given in the outer upper arm;
• Change the injection site each time you administer the drug;

× Do not inject into areas with sensitive, damaged skin or areas with bruises or scars.

6. Prepare the injection site.

• Wash your hands;
• Wipe the skin at the injection site with an alcohol swab;

× Do not touch the injection site again before administering the drug.

Step B. Perform the injection (perform Step B only after completing Step A “Prepare for the injection”).

1. Turn or pull the orange cap.

× Do not remove the needle cap until you are ready to perform the injection;

× Do not press the yellow needle cap or touch it with your fingers;

× Do not put the orange cap back on.

2. Press the yellow needle cap vertically against the skin at approximately a 90° angle .

• Make sure you can see the inspection window.

3. Press the pen against the skin and hold it.

• When the drug delivery begins, you will hear a click.

4. Continue holding the pen, pressing it firmly against the skin.

• The inspection window will begin to turn yellow;
• The injection continues for up to 15 seconds.

5. You will hear a second click. Before removing the pen, check that the inspection window has turned completely yellow.

• If you did not hear the second click, continue to watch the inspection window; it should become completely yellow;
• If the inspection window has not turned completely yellow, do not inject a second dose without consulting your doctor.

6. Remove the pen from the skin.

• If you notice blood, press the site with a cotton ball or gauze;

× Do not rub the skin after the injection.

7. Place the used pen and cap into a puncture-resistant container immediately after the injection.

• Always store this container out of sight and reach of children;

× Do not put the cap back on;

× Do not dispose of the used pen with household waste;

× Do not use the used puncture-resistant container for other purposes;

× Do not dispose of the used puncture-resistant container with household waste, unless permitted by local regulations. Ask your doctor how to dispose of this container.

Instructions for using prefilled disposable syringes

The figure shows the parts of a prefilled syringe containing the drug Kevzara^®.

The device is a prefilled syringe (referred to in the instructions as the “syringe”), containing Kevzara^® in single doses of 150 mg and 200 mg. The drug is administered subcutaneously once every 2 weeks.

Before the first injection, you should ask your doctor to show you how to use the syringe correctly.

What to do

• Before using the syringe, carefully read all instructions;
• Make sure that you are using exactly the medicinal product prescribed by your doctor and in the dose recommended for you;
• Store unused syringes in the original cardboard pack in the refrigerator at a temperature between 2°C (35.6°F) and 8°C (46.4°F);
• During travel, store this cardboard pack in a cooler bag with ice;
• Before use, leave the syringe for at least 30 minutes to allow it to warm up to room temperature;
• Use the syringe within 14 days after removing it from the refrigerator or cooler bag;
• Store the syringe out of sight and reach of children.

What not to do

× Do not use the syringe if it is damaged, or if the needle cap is missing or not attached;

× Do not remove the needle cap until you are ready to inject;

× Do not touch the needle;

× Do not attempt to put the cap back on the syringe;

× Do not reuse the syringe;

× Do not freeze or heat the syringe;

× Do not store the syringe at temperatures above 25°C (77°F) after removing it from the refrigerator;

× Do not expose the syringe to direct sunlight;

× Do not inject through clothing.

If you have any additional questions, consult your doctor or call the company phone number provided in the instructions.

Step A. Prepare for the injection.

1. On a clean, flat work surface, lay out everything you will need.

• Alcohol, cotton or gauze swab, puncture-resistant container;
• Take one syringe from the packaging, holding it by the middle of the body;
• Leave the other syringes in the cardboard pack in the refrigerator.

2. Look at the label.

• Check that you have the exact medicinal product prescribed by your doctor and in the dose recommended for you;
• Check the expiration date (Use by);

× Do not use the prefilled syringe after this date.

3. Look at the medicinal product.

• Make sure the liquid in the syringe is clear, from colorless to yellowish;
• If you notice air bubbles, this is normal;

× Do not inject the drug if the liquid is cloudy, a different color, or contains particles.

4. Place the syringe on a flat surface and leave it for at least 30 minutes to allow it to warm up to room temperature (<25°C (77°F)).

• Using the syringe at room temperature may make the injection more comfortable;

× Do not use the syringe if it has been outside the refrigerator for more than 14 days;

× Do not heat the syringe; let it warm up on its own;

× The syringe must not be exposed to direct sunlight.

5. Choose the injection site.

• You can inject into the outer thigh or the front of the abdomen, except for an area 5 cm in diameter directly around the navel. If someone else is injecting the drug, the injection can also be given in the outer upper arm;
• Change the injection site each time you administer the drug;

× Do not inject into areas with sensitive, damaged skin or areas with bruises or scars.

6. Prepare the injection site.

• Wash your hands;
• Wipe the skin at the injection site with an alcohol swab;

× Do not touch the injection site again before administering the drug.

Step B. Perform the injection (perform Step B only after completing Step A “Prepare for the injection”).

1. Remove the needle cap.

• Hold the syringe by the middle of the body with the needle pointing away from you;

× Do not touch the plunger with your hands;

× Do not attempt to remove air bubbles from the syringe;

× Do not remove the needle cap until you are ready to perform the injection;

× Do not put the cap back on the needle.

2. Pinch the skin.

• Using your thumb and index finger, gently pinch the skin into a fold at the injection site.

3. Insert the needle into the skin fold at a 45° angle.

4. Press the plunger.

• Slowly press the plunger until the syringe is empty.

5. Before removing the needle, make sure the syringe is empty.

• Remove the needle at the same angle at which it was inserted for the injection;
• If you notice blood, press the site with a cotton ball or gauze;

× Do not rub the skin after the injection.

6. Place the used syringe and cap into a puncture-resistant container immediately after the injection.

• Always store this container out of sight and reach of children;

× Do not put the cap back on the needle;

× Do not dispose of the used syringe with household waste;

× Do not use the used puncture-resistant container for other purposes;

× Do not dispose of the used puncture-resistant container with household waste, unless permitted by local regulations. Ask your doctor how to dispose of this container.

Preparation and handling of the drug

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If the solution is cloudy, discolored, or contains visible particles, it should not be used.

After removing the prefilled pen or prefilled syringe from the refrigerator, they should be allowed to warm to room temperature (<25°C (77°F)) before administration of Kevzara^®.

After removal from the refrigerator, Kevzara^® should be used within 14 days and must not be stored at temperatures above 25°C (77°F).

Prefilled pens or prefilled syringes should be stored in the original packaging to protect from direct sunlight.

Any unused medicinal product or waste material should be disposed of in accordance with local regulatory requirements.

Adverse Reactions

The most common adverse reactions observed in clinical trials were neutropenia, increased ALT, injection site erythema, upper respiratory tract infections, urinary tract infections.

The most common serious adverse reactions were infections.

The safety of Kevzara^® in combination with DMARDs was evaluated based on data from 7 clinical trials, 2 of which were placebo-controlled, involving 2887 patients (long-term safety population). Of these, 2170 patients received Kevzara^® for at least 24 weeks, 1546 patients for at least 48 weeks, 1020 patients for at least 96 weeks, and 624 patients for at least 144 weeks.

The frequency of adverse reactions listed below is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000). Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations Common – upper respiratory tract infections, urinary tract infections, nasopharyngitis, oral herpes.

Blood and lymphatic system disorders Very common – neutropenia; Common – thrombocytopenia.

Hepatobiliary disorders Increased hepatic transaminases.

Metabolism and nutrition disorders Common – hypertriglyceridemia, hypercholesterolemia.

General disorders and administration site conditions Common – erythema and pruritus at the injection site.

Description of selected adverse reactions

Infections

In the patient population participating in placebo-controlled studies, the incidence of infections was 84.5, 81.0, and 75.1 events per 100 patient-years for the combinations of Kevzara^® 200 mg and DMARDs, Kevzara^® 150 mg and DMARDs, and placebo and DMARDs, respectively. The most common infections (5% to 7% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. The incidence of serious infections was 4.3, 3.0, and 3.1 events per 100 patient-years for the combinations of Kevzara^® 200 mg and DMARDs, Kevzara^® 150 mg and DMARDs, and placebo and DMARDs, respectively.

In the long-term safety assessment in the patient population receiving Kevzara^® in combination with DMARDs, the incidence of infections and serious infections was 57.3 and 3.4 events per 100 patient-years, respectively. The most common serious infections were pneumonia and cellulitis. Cases of opportunistic infections have been reported.

The overall incidence of infections and serious infections in the patient population receiving Kevzara^® as monotherapy was comparable to the incidence in the patient population receiving therapy with Kevzara^® in combination with DMARDs.

Gastrointestinal perforation

In the patient population participating in placebo-controlled studies, one patient receiving Kevzara^® developed a gastrointestinal perforation (0.11 events per 100 patient-years). In the long-term safety assessment in the patient population receiving Kevzara^® in combination with DMARDs, the incidence of gastrointestinal perforations was 0.14 events per 100 patient-years.

Reports of gastrointestinal perforation were mainly recorded as complications of diverticulitis, including lower GI perforation and abscess. Most patients who developed gastrointestinal perforation were receiving concomitant therapy with NSAIDs, corticosteroids, or methotrexate. It is not known how these drugs additionally influence the development of gastrointestinal perforation when used concomitantly with Kevzara^®. In the patient population receiving Kevzara^® as monotherapy, no gastrointestinal perforations were reported.

Hypersensitivity reactions

In the patient population participating in placebo-controlled studies, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among patients receiving Kevzara^® (0.9% in the group receiving the drug at a dose of 200 mg, 0.5% in the group receiving the drug at a dose of 150 mg) than in the placebo group (0.2%).

In the long-term safety assessment, the incidence of discontinuation of Kevzara^® due to hypersensitivity reactions in the patient population receiving Kevzara^® in combination with DMARDs and in the patient population receiving Kevzara^® as monotherapy was comparable to the incidence in the patient population from placebo-controlled studies. In placebo-controlled studies, serious adverse hypersensitivity reactions occurred in 0.2% of patients who received Kevzara^® 200 mg every 2 weeks in combination with DMARDs, and no cases were noted in the group of patients receiving Kevzara^® 150 mg every 2 weeks in combination with DMARDs.

Injection site reactions

In the patient population participating in placebo-controlled studies, injection site reactions were reported in 9.5%, 8%, and 1.4% of patients receiving Kevzara^® at doses of 200 mg, 150 mg, and placebo, respectively. In most patients, injection site reactions (including erythema and pruritus) were mild in severity. Due to injection site reactions, Kevzara^® was prematurely discontinued in two patients (0.2%).

Laboratory abnormalities

To allow a direct comparison of the frequency of laboratory abnormalities between the placebo and active treatment groups, data obtained during the 0-12 week period were used, as they were obtained before patients could be switched from placebo to Kevzara^®.

Neutrophil count. Decreased neutrophil count <1×10⁹/L was observed in 6.4% and 3.6% of patients in the groups taking Kevzara^® 200 mg in combination with DMARDs and Kevzara^® 150 mg in combination with DMARDs, respectively; this adverse reaction was not observed in the placebo group in combination with DMARDs. Decreased neutrophil count <0.5×10⁹/L was observed in 0.8% and 0.6% of patients in the groups taking Kevzara^® 200 mg in combination with DMARDs and Kevzara^® 150 mg in combination with DMARDs, respectively. In patients with decreased ANC, a change in treatment regimen, such as interruption of Kevzara^® therapy or dose reduction, led to an increase or normalization of ANC. Decreased ANC was not associated with a higher incidence of infections, including serious infections.

In the assessment of long-term safety in the patient population receiving Kevzara^® in combination with DMARDs, and in the patient population receiving Kevzara^® monotherapy, observations regarding the neutrophil count were comparable to the observations obtained for the patient population from placebo-controlled studies.

Platelet count. A decrease in platelet count <100×10³/µL was observed in 1.2% and 0.6% of patients in the groups receiving Kevzara^® 200 mg in combination with DMARDs and Kevzara^® 150 mg in combination with DMARDs, respectively; this adverse reaction was not observed in the group of patients receiving placebo in combination with DMARDs.

In the assessment of long-term safety in the patient population receiving Kevzara^® in combination with DMARDs, and in the patient population receiving Kevzara^® monotherapy, observations regarding the platelet count were comparable to the observations obtained for the patient population from placebo-controlled studies.

No bleeding associated with a decrease in platelet count was reported.

Liver enzymes. Changes in liver enzyme parameters are presented in Table 4. In patients with elevated liver transaminase activity, modification of the treatment regimen, i.e., interruption of Kevzara^® therapy or dose reduction, led to a decrease or normalization of liver transaminase activity. These changes were not accompanied by a clinically significant increase in direct bilirubin concentration, nor by clinical manifestations of hepatitis or liver failure.

Table 4. Frequency of elevated liver transaminase activity in controlled clinical studies

Lipids. In the patient population participating in placebo-controlled studies, lipid profile parameters (LDL, HDL, and triglycerides) were first assessed 4 weeks after the start of treatment with the combination of Kevzara^® and DMARDs. At week 4 of therapy, the mean LDL value increased by 14 mg/dL, the mean triglyceride value by 23 mg/dL, and the mean HDL value by 3 mg/dL. After week 4 of therapy, no further increase in these parameters was observed. No significant differences between doses were noted.

In the assessment of long-term safety in the patient population receiving Kevzara^® in combination with DMARDs, and in the patient population receiving Kevzara^® monotherapy, the data on lipid profile parameters were comparable to the observations obtained for the patient population from placebo-controlled studies.

Immunogenicity

Like all therapeutic protein drugs, Kevzara^® has the potential for immunogenicity. In the patient population participating in placebo-controlled studies, a positive response for antibodies to sarilumab was detected in 4%, 5.6%, and 2% of patients receiving Kevzara^® 200 mg in combination with DMARDs, Kevzara^® 150 mg in combination with DMARDs, and the combination of placebo and DMARDs, respectively. A positive response for neutralizing antibodies was detected in 1%, 1.6%, and 0.2% of patients receiving Kevzara^® 200 mg, 150 mg, and placebo, respectively.

Data in the patient population receiving Kevzara^® monotherapy were comparable to the results of the patient population receiving Kevzara^® in combination with DMARDs.

Formation of antibodies to sarilumab may affect its pharmacokinetics. No correlation was observed between the formation of antibodies to sarilumab and loss of therapeutic efficacy or development of adverse reactions.

The detection of an immune response is highly dependent on the sensitivity and specificity of the methods used, the timing and method of sample collection, concomitant therapy, and the underlying disease. For these reasons, comparing the incidence of antibodies to sarilumab with the incidence of antibodies to other drugs may be unreliable.

Malignancies

In the patient population participating in placebo-controlled studies, the incidence of malignancies in patients receiving either Kevzara^® in combination with DMARDs or the combination of placebo and DMARDs was the same (1.0 case per 100 patient-years).

In the assessment of long-term safety in the patient population receiving Kevzara^® in combination with DMARDs, and in the patient population receiving Kevzara^® monotherapy, observations regarding the incidence of malignancies were comparable to the observations obtained in the patient population from placebo-controlled studies.

Contraindications

• Hypersensitivity to the active substance or any excipient of the drug;
• Active serious infectious diseases;
• Age under 18 years due to unestablished efficacy and safety in children with rheumatoid arthritis.

Use with caution

• In patients with chronic or recurrent infection; history of serious or opportunistic infections; with concomitant conditions predisposing to infections; after contact with tuberculosis patients; those who have lived in or visited regions endemic for tuberculosis or mycoses (the benefit-risk ratio should be assessed before initiation of use);
• In patients with HIV infection;
• In patients with an increased risk of gastrointestinal perforation;
• In elderly patients (due to a higher frequency of infections in this category of patients);

Age-related restrictions for the use of the drug are provided in the “Dosage Regimen” section.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of sarilumab in pregnant women are limited or absent. It is known that monoclonal antibodies cross the placental barrier, with a greater amount of antibodies crossing the placental barrier in the third trimester.

Animal studies do not provide direct or indirect evidence of adverse effects of sarilumab in terms of reproductive toxicity. Kevzara^® should not be used during pregnancy, except in cases where the potential benefit to the mother outweighs the potential risk to the fetus.

Women of childbearing potential should use effective methods of contraception during therapy with Kevzara^® and for 3 months after its completion.

Breastfeeding period

It is unknown whether Sarilumab is excreted in human milk or undergoes systemic absorption in the newborn after breastfeeding. Information regarding the effect of sarilumab on the breastfed infant or on milk production is lacking. Since IgG1 may be excreted in small amounts in breast milk, a decision should be made whether to discontinue breastfeeding or to discontinue sarilumab, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of sarilumab on human fertility. Animal studies showed no adverse effects on female and male fertility.

Use in Hepatic Impairment

Treatment with Kevzara^® is not recommended for patients with active liver disease or impaired liver function.

Use in Renal Impairment

No dose adjustment of the drug is required in patients with mild to moderate renal impairment.

The use of Kevzara^® in patients with severe renal impairment has not been studied.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years.

Geriatric Use

The drug should be prescribed with caution to elderly patients (due to a higher frequency of infections in this category of patients).

Special Precautions

Serious infections

Patients should be carefully monitored for the development of signs and symptoms of infections during treatment with Kevzara^®. Since the frequency of infections is higher among elderly patients, treatment of this category of patients should be conducted with caution.

Kevzara^® should not be used in patients with active infectious diseases, including localized infections. The benefit-risk ratio should be assessed before initiating Kevzara^® in patients

• With chronic or recurrent infection;
• With a history of serious or opportunistic infections;
• With HIV infection;
• With concomitant conditions predisposing to infections;
• After contact with tuberculosis patients;
• Who have lived in or visited regions endemic for tuberculosis or mycoses.

Treatment with Kevzara^® should be interrupted if a patient develops a serious or opportunistic infection.

A patient who develops an infection during treatment with Kevzara^® should undergo a complete diagnostic examination appropriate for immunocompromised individuals; then, adequate antimicrobial therapy should be initiated followed by careful monitoring.

Serious infections, sometimes fatal, caused by bacterial, mycobacterial, invasive fungal, viral, and other opportunistic pathogens have been reported in patients receiving immunosuppressive drugs for the treatment of rheumatoid arthritis, including Kevzara^®. The most frequently observed serious infections with Kevzara^® use were pneumonia and cellulitis. Among opportunistic infections reported with Kevzara^® use were tuberculosis, candidiasis, and pneumocystosis. Isolated cases of disseminated, rather than localized, infections were observed in patients often receiving concomitant therapy with immunosuppressive drugs such as methotrexate or corticosteroids, which, in combination with rheumatoid arthritis, may predispose to the development of infection.

Tuberculosis

Before starting treatment with Kevzara^®, patients should be assessed for risk factors for tuberculosis and screened for latent infection. Patients with latent or active tuberculosis should receive standard anti-tuberculosis therapy before initiating treatment with Kevzara^®. In patients with a history of latent or active tuberculosis for whom the necessary course of therapy cannot be confirmed, and in patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection, the possibility of anti-tuberculosis therapy prior to initiating Kevzara^® treatment should be considered. Consultation with a phthisiatrician is advisable when deciding on anti-tuberculosis therapy.

Patients should be carefully monitored for the development of signs and symptoms of tuberculosis, including patients whose pre-therapy screening for latent tuberculosis was negative.

Viral infection reactivation

Reactivation of viral infections has been reported with the use of immunosuppressive biological drugs. Cases of herpes zoster were observed in clinical studies of Kevzara^®. Cases of hepatitis B virus reactivation were not recorded in clinical studies; however, patients at risk of infection reactivation were excluded from the studies.

Laboratory parameters

Neutrophil count. A higher frequency of decreased ANC was observed during treatment with Kevzara^®. The decrease in ANC was not accompanied by a higher frequency of infections, including serious infections. It is not recommended to initiate treatment with Kevzara^® in patients with ANC <2×10⁹/L. In patients with a decrease in ANC <0.5×10⁹/L, treatment with Kevzara^® should be discontinued. Neutrophil count should be monitored 4-8 weeks after initiation of Kevzara^® therapy and thereafter as clinically indicated. Recommendations for dose modification based on ANC values are provided in the “Dosage Regimen” section. When modifying the dose of Kevzara^®, the values obtained at the end of the dosing interval should be used.

Platelet count. A decrease in platelet count was observed in clinical studies during treatment with Kevzara^®. The decrease in platelet count was not accompanied by the development of bleeding. It is not recommended to initiate treatment with Kevzara^® in patients with a platelet count <150×10³/µL. If the platelet count decreases to <50×10³/µL, therapy with Kevzara^® should be discontinued. Platelet count should be monitored 4-8 weeks after initiation of therapy and thereafter as clinically indicated. Recommendations for drug dose modification based on platelet count are provided in the “Dosage Regimen” section.

Liver enzymes. A higher frequency of elevated liver enzyme activity was observed during treatment with Kevzara^®, which in clinical studies was transient and did not lead to any clinically apparent symptoms of liver damage. An increase in the frequency and severity of elevated liver enzyme activity was observed with the use of Kevzara^® in combination with potentially hepatotoxic drugs (e.g., methotrexate). It is not recommended to initiate treatment with Kevzara^® in patients with elevated liver transaminases ALT or AST >1.5×ULN. If ALT activity increases to >5×ULN, therapy with Kevzara^® should be discontinued. ALT and AST activity should be monitored 4-8 weeks after initiation of therapy and every 3 months thereafter. If clinically necessary, other liver function parameters such as bilirubin should be considered. Recommendations for dose modification based on elevated liver transaminases are provided in the “Dosage Regimen” section.

Changes in lipid metabolism parameters. In patients with chronic inflammatory diseases, blood lipid concentrations may be decreased. Treatment with Kevzara^® was accompanied by an increase in concentrations of lipids such as LDL cholesterol, HDL cholesterol, and/or triglycerides. Lipid metabolism parameters should be monitored approximately 4-8 weeks after initiation of Kevzara^® therapy, then approximately every 6 months. Treatment of patients should be managed according to clinical guidelines for the management of patients with hyperlipidemia.

Gastrointestinal perforation

Gastrointestinal perforation has been reported as an adverse event in clinical studies, which is primarily a complication of diverticulitis. Kevzara^® should be used with caution in patients with a history of gastrointestinal ulcers or diverticulitis. The appearance of new abdominal symptoms in patients, such as persistent pain and fever, should be promptly addressed.

Malignancies

Treatment with immunosuppressive drugs may lead to an increased risk of malignancies. The effect of Kevzara^® therapy on the development of malignancies is unknown, but cases of malignancies have been reported in clinical studies.

Hypersensitivity reactions

The development of hypersensitivity reactions associated with the use of Kevzara^® has been reported. The most common hypersensitivity reactions were injection site rash, skin rash, and urticaria. The patient should be informed to seek immediate medical attention if any hypersensitivity reactions occur. If anaphylactic reactions or hypersensitivity reactions occur, administration of Kevzara^® should be discontinued immediately. Kevzara^® is not prescribed to patients with known hypersensitivity to sarilumab.

Impaired liver function

Treatment with Kevzara^® is not recommended for patients with active liver disease or impaired liver function.

Vaccination

Concomitant use of live and live attenuated vaccines during treatment with Kevzara^® should be avoided, as the clinical safety of this interaction has not been established. There are no data on the secondary transmission of infection from persons vaccinated with live vaccines to patients receiving Kevzara^®. Before starting treatment with Kevzara^®, it is recommended that all patients be vaccinated in accordance with current vaccination guidelines. The interval between vaccination with live vaccines and the start of treatment with Kevzara^® should be in accordance with current vaccination guidelines regarding the concomitant use of immunosuppressive drugs.

Cardiovascular risk

Patients with rheumatoid arthritis have an increased risk of cardiovascular disease. Risk factors (e.g., hypertension, hyperlipidemia) should be managed as part of standard therapy.

Incompatibility

Due to the lack of compatibility studies, Kevzara^® must not be mixed with other medicinal products.

Pediatric use

Kevzara^® should not be used in children and adolescents under 18 years of age (safety and efficacy have not been established currently).

Effect on ability to drive and use machines

Kevzara^® has no or negligible influence on the ability to drive and use machines.

Overdose

There are limited data on overdose with Kevzara^®.

Treatment: There is no specific treatment for Kevzara^® overdose. In case of overdose, the patient’s condition should be carefully monitored, and symptomatic and supportive therapy should be provided.

Drug Interactions

Use with other drugs for the treatment of rheumatoid arthritis

Concomitant use with methotrexate did not affect the exposure of sarilumab. No effect of sarilumab on the exposure of methotrexate is expected with their concomitant use; clinical data are not available.

The concomitant use of Kevzara^® with Janus kinase inhibitors (JAK inhibitors) or other biological DMARDs, such as TNF antagonists, interleukin-1 receptor antagonists (IL-1R), anti-CD20 monoclonal antibodies, selective co-stimulatory modulators, has not been studied. Concomitant use of Kevzara^® with biological DMARDs should be avoided.

Interaction with drugs that are substrates of cytochrome P450

Various in vitro studies and a limited number of in vivo studies in humans have shown that cytokines and cytokine modulators can affect the expression and activity of specific cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C19, CYP3A4) and thus have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates for these isoenzymes.

An increase in IL-6 concentration may reduce cytochrome P450 activity in patients with rheumatoid arthritis, and consequently increase the concentration of drugs that are cytochrome P450 substrates in these patients compared to patients without rheumatoid arthritis.

Blockade of the IL-6 signaling pathway by IL-6Rα antagonists, such as sarilumab, may eliminate the inhibitory effect of IL-6 and restore cytochrome P450 activity, leading to a change in drug concentrations.

The change in the effect of IL-6 on cytochrome P450 isoenzymes under the influence of sarilumab may be clinically significant for cytochrome P450 substrates with a narrow therapeutic concentration range, for which the dose is adjusted individually.

After initiation or discontinuation of Kevzara^®, patients receiving treatment with drugs that are cytochrome P450 substrates should be monitored for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for theophylline) and the drug dose should be adjusted as necessary.

Caution should be exercised when initiating therapy with Kevzara^® in patients taking drugs that are substrates of cytochrome P450 isoenzyme 3A4 (CYP3A4) (e.g., oral contraceptives or statins), as sarilumab may eliminate the inhibitory effect of IL-6 and restore CYP3A4 isoenzyme activity, leading to a decrease in the exposure and activity of CYP3A4 substrates.

The interaction of sarilumab with substrates of other CYP isoenzymes (CYP2C9, CYP2C19, CYP2D6) has not been studied.

Storage Conditions

The drug should be stored in the original packaging to protect it from light, in a place inaccessible to children at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

The shelf life is 2 years. The drug should not be used after the expiration date.

After removal from the refrigerator, the drug should be stored at a temperature not exceeding 25°C (77°F) and used within 14 days.

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.