2.1 Recommended Dosage

KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs.

The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection.

Reduce dose to 150 mg once every two weeks for management of neutropenia, thrombocytopenia and elevated liver enzymes [see Dosage and Administration (2.4), Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

2.2 General Considerations for Administration

• KEVZARA initiation is not recommended in patients with an absolute neutrophil count (ANC) less than 2000 per mm3, platelet count less than 150,000 per mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN) [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)].
• Prior to initiating KEVZARA, test patients for latent tuberculosis (TB). If positive, consider treating for TB prior to KEVZARA use [see Warnings and Precautions (5.1)].
• Avoid using KEVZARA with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of KEVZARA with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators has not been studied.
• Avoid KEVZARA use in patients with active infections [see Warnings and Precautions (5.1)].

2.3 Important Administration Instructions

• KEVZARA is intended for use under the guidance of a healthcare professional. A patient may self-inject KEVZARA or the patient's caregiver may administer KEVZARA. Provide proper training to patients and/or caregivers on the preparation and administration of KEVZARA prior to use according to the Instructions for Use (IFU).
• Allow the pre-filled syringe to sit at room temperature for 30 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way.
• If using a pre-filled pen, allow the pre-filled pen to sit at room temperature for 60 minutes prior to subcutaneous injection. Do not warm KEVZARA in any other way.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. KEVZARA solution should be clear and colorless to pale yellow. Do not use if the solution is cloudy, discolored or contains particles, or if any part of the pre-filled syringe or pre-filled pen appears to be damaged.
• Instruct patients to inject the full amount in the syringe or pen (1.14 mL), which provides 200 mg or 150 mg of KEVZARA, according to the directions provided in the IFU.
• Rotate injection sites with each injection. Do not inject into skin that is tender, damaged, or has bruises or scars.

2.4 Dosage Modifications for Laboratory Abnormalities or Serious Infection

If a patient develops a serious infection, hold treatment with KEVZARA until the infection is controlled.

Modify dosage in case of neutropenia, thrombocytopenia or liver enzyme elevations (see Table 1). For treatment initiation criteria, see Dosage and Administration (2.2).

5.1 Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including KEVZARA for rheumatoid arthritis (RA). The most frequently observed serious infections with KEVZARA included pneumonia and cellulitis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with KEVZARA. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids, which in addition to RA may predispose them to infections. While not reported in KEVZARA clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA.

Avoid use of KEVZARA in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating KEVZARA in patients who have:

• chronic or recurrent infection;
• a history of serious or opportunistic infections;
• underlying conditions, in addition to RA, that may predispose them to infection;
• been exposed to tuberculosis; or
• lived in or traveled to areas of endemic tuberculosis or endemic mycoses.

Closely monitor patients for the development of signs and symptoms of infection during treatment with KEVZARA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see Dosage and Administration (2.4), Adverse Reactions (6.1)].

Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.

Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with KEVZARA; initiate appropriate antimicrobial therapy, and closely monitor the patient.

5.2 Laboratory Abnormalities

5.3 Gastrointestinal Perforation

Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms [see Adverse Reactions (6.1)].

5.4 Immunosuppression

Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with KEVZARA on the development of malignancies is not known but malignancies were reported in clinical studies [see Adverse Reactions (6.1)].

5.5 Hypersensitivity Reactions

Hypersensitivity reactions have been reported in association with KEVZARA [see Adverse Reactions (6.1)]. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of KEVZARA immediately. Do not administer KEVZARA to patients with known hypersensitivity to sarilumab [see Contraindications (4) and Adverse Reactions (6.1)].

5.6 Active Hepatic Disease and Hepatic Impairment

Treatment with KEVZARA is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with KEVZARA was associated with transaminase elevations [see Adverse Reactions (6.1), Use in Specific Populations (8.6)].

5.7 Live Vaccines

Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections; clinical safety of live vaccines during KEVZARA treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. The interval between live vaccinations and initiation of KEVZARA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents [see Drug Interactions (7.3)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

All patients in the safety data described below had moderately to severely active rheumatoid arthritis.

The safety of KEVZARA in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received KEVZARA for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks.

The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to KEVZARA. In this population, 582 patients, 579 patients, and 579 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs.

The 52-week placebo-controlled population includes patients from one Phase 2 study of 12 week duration and two Phase 3 efficacy studies (one of 24 week duration and the other of 52 week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received KEVZARA 200 mg, KEVZARA 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs.

Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used.

The most common serious adverse reactions were infections [see Warnings and Precautions (5.1)].

The most frequent adverse reactions (occurring in at least 3% of patients treated with KEVZARA in combination with DMARDs) observed with KEVZARA in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.

In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with KEVZARA 200 mg, KEVZARA 150 mg, and placebo, respectively.

The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia.

The use of KEVZARA as monotherapy was assessed in 132 patients, of which 67 received KEVZARA 200 mg and 65 patients received KEVZARA 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to sarilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In the pre-rescue population, 4.0% of patients treated with KEVZARA 200 mg + DMARD, 5.7% of patients treated with KEVZARA 150 mg + DMARD and 1.9% of patients treated with placebo + DMARD, exhibited an anti-drug antibody (ADA) response. Neutralizing antibodies (NAb) were detected in 1.0% of patients on KEVZARA 200 mg + DMARD, 1.6% of patients on KEVZARA 150 mg + DMARD, and 0.2% of patients on placebo + DMARD.

In patients treated with KEVZARA monotherapy, 9.2% of patients exhibited an ADA response with 6.9% of patients also exhibiting NAbs. Prior to administration of KEVZARA, 2.3% of patients exhibited an ADA response.

No correlation was observed between ADA development and either loss of efficacy or adverse reactions.

7.1 Use with Other Drugs for Treatment of Rheumatoid Arthritis

Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on sarilumab clearance. KEVZARA has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists [see Dosage and Administration (2.2)].

7.2 Interactions with CYP450 Substrates

Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as KEVZARA might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations.

The modulation of IL-6 effect on CYP enzymes by KEVZARA may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of KEVZARA, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed.

Exercise caution when coadministering KEVZARA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of KEVZARA on CYP450 enzyme activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)].

7.3 Live Vaccines

Avoid concurrent use of live vaccines during treatment with KEVZARA [see Warnings and Precautions (5.7)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and efficacy of KEVZARA in pediatric patients have not been established.

8.5 Geriatric Use

Of the total number of patients in clinical studies of KEVZARA [see Clinical Studies (14)], 15% were 65 years of age and over, while 1.6% were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infection among KEVZARA and placebo-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

8.6 Hepatic Impairment

The safety and efficacy of KEVZARA have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology [see Warnings and Precautions (5.6)].

8.7 Renal Impairment

No dose adjustment is required in patients with mild to moderate renal impairment. KEVZARA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.

12.2 Pharmacodynamics

Following single-dose subcutaneous administration of sarilumab 200-mg and 150-mg in patients with RA, rapid reduction of CRP levels was observed. Levels were reduced to normal within 2 weeks after treatment initiation. Following single-dose sarilumab administration, in patients with RA, absolute neutrophil counts decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline [see Warnings and Precautions (5.2)]. Treatment with sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in hemoglobin and serum albumin.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to establish the carcinogenicity potential of sarilumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as sarilumab, is presently unknown.

Fertility and reproductive performance were unaffected in male and female mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses of 10, 25, and 100 mg/kg twice per week.

Design of Clinical Studies in Adults with Moderately to Severely Active RA

The efficacy and safety of KEVZARA were assessed in two randomized, double-blind, placebo-controlled multicenter studies (Study 1 and Study 2) in patients older than 18 years with moderately to severely active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline.

Study 1 evaluated 1197 patients with moderately to severely active rheumatoid arthritis who had inadequate clinical response to methotrexate (MTX). Patients received subcutaneous KEVZARA 200 mg, KEVZARA 150 mg, or placebo every two weeks with concomitant MTX. After Week 16 in Study 1, patients with an inadequate response could have been rescued with KEVZARA 200 mg every two weeks.

Study 2 evaluated 546 patients with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. Patients received subcutaneous KEVZARA 200 mg, KEVZARA 150 mg, or placebo every two weeks with concomitant conventional DMARDs (MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine). After Week 12 in Study 2, patients with an inadequate response could have been rescued with KEVZARA 200 mg every two weeks.

In Studies 1 and 2, the primary endpoint was the proportion of patients who achieved an ACR20 response at Week 24. Other key endpoints evaluated included change from baseline in HAQ-DI at Week 16 in Study 1 and at Week 12 in Study 2, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52 in Study 1.

Clinical Response

The percentages of KEVZARA every two weeks + MTX/DMARD-treated patients achieving ACR20, ACR50 and ACR70 responses in Studies 1 and 2 are shown Table 4. In both studies, patients treated with either 200 mg or 150 mg of KEVZARA every two weeks + MTX/DMARD had higher ACR20, ACR50, and ACR70 response rates versus placebo + MTX/DMARD-treated patients at Week 24.

In Studies 1 and 2, a greater proportion of patients treated with KEVZARA 200 mg or 150 mg every two weeks plus MTX/DMARD achieved a low level of disease activity as measured by a Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) <2.6 compared with placebo + MTX/DMARD at the end of the studies (Table 4). In Study 1, the proportion of patients achieving DAS28-CRP <2.6 who had at least 3 or more active joints at the end of Week 24 was 33.1%, 37.8% and 20%, in the KEVZARA 200 mg + MTX/DMARD arm, KEVZARA 150 mg + MTX/DMARD arm, and placebo arm respectively.

The percent ACR20 response by visit in Study 1 is shown in Figure 1. A similar response curve was observed in Study 2.

Figure 1: Percent of ACR20 Response by Visit for Study 1 (Adults with Moderately to Severely Active RA)

The results of the components of the ACR response criteria at Week 12 for Studies 1 and 2 are shown in Table 5.

Radiographic Response

In Study 1, structural joint damage was assessed radiographically and expressed as the van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks and scored independently by at least two well-trained readers who were blinded to treatment group and visit number.

Both doses of KEVZARA + MTX were superior to placebo + MTX in the change from baseline in mTSS over 52 weeks (see Table 6). Less progression of both erosion and joint space narrowing scores over 52 weeks was reported in the KEVZARA + MTX treatment groups compared to the placebo + MTX group.

Treatment with KEVZARA + MTX was associated with significantly less radiographic progression of structural damage as compared with placebo + MTX. At Week 52, 55.6% of patients receiving KEVZARA 200 mg + MTX and 47.8% of patients receiving KEVZARA 150 mg + MTX had no progression of structural damage (as defined by a change in the Total Sharp Score of zero or less) compared with 38.7% of patients receiving placebo.

Physical Function Response

In Studies 1 and 2, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients receiving KEVZARA 200 mg every two weeks + MTX/DMARD and KEVZARA 150 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline in physical function compared to placebo + MTX/DMARD at Week 16 and Week 12 in Studies 1 and 2, respectively (Table 7).

Other Health Related Outcomes

General health status was assessed by the Short Form health survey (SF-36) in Studies 1 and 2. Patients receiving KEVZARA 200 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline compared to placebo + MTX/DMARD in the physical component summary (PCS) at Week 24, but there was no evidence of a difference between the treatment groups in the mental component summary (MCS) at Week 24. Patients receiving KEVZARA 200 mg + MTX/DMARD reported greater improvement relative to placebo in the domains of Physical Functioning, Role Physical, Bodily Pain, General Health Perception, Vitality, Social Functioning and Mental Health, but not in the Role Emotional domain.

Storage and Stability

Refrigerate at 36°F to 46°F (2°C to 8°C) in original carton to protect from light. Do not freeze. Do not shake.

If needed, patients/caregivers may store KEVZARA at room temperature up to 77°F (25°C) up to 14 days in the outer carton. Do not store above 77°F (25°C). After removal from the refrigerator, use KEVZARA within 14 days or discard.

Infections

Inform patients that KEVZARA may lower their resistance to infections. Instruct patients to contact their physician immediately when symptoms suggesting infection appear, to ensure rapid evaluation and appropriate treatment [see Warning and Precautions (5.1)].

Gastrointestinal Perforation

Inform patients that some patients, particularly those also taking NSAIDS, and/or steroids, have had tears (perforations) of the stomach or intestines. Inform patients that gastrointestinal perforations have been reported in KEVZARA-treated patients in clinical studies, primarily as a complication of diverticulitis. Instruct patients to contact their physician immediately when symptoms of severe, persistent abdominal pain appear to ensure rapid evaluation and appropriate treatment.

Hypersensitivity and Serious Allergic Reaction

Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with KEVZARA have developed serious allergic reactions. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KEVZARA during pregnancy. Encourage participation in the registry [see Use in Specific Populations (8.1)].

Instruction on Injection Technique

Instruct patients and caregivers to read the Instructions for Use before the patient starts using KEVZARA, and each time the patient gets a refill as there may be new information they need to know.

Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled syringe or pre-filled pen correctly (see Instructions for Use).

The pre-filled syringe or pre-filled pen should be left at room temperature for 30 minutes or 60 minutes respectively (see the Instructions for Use) prior to use. The syringe or pen should be used within 14 days after being taken out of the refrigerator. A puncture-resistant container should be used to dispose the used pre-filled syringes or pre-filled pens and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper pre-filled syringe or pre-filled pen disposal, and caution against reuse of these items.