Kevzara Drug Information

Rheumatoid Arthritis (RA) KEVZARA ® is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

Polymyalgia Rheumatica (PMR) KEVZARA is indicated for treatment of adult patients with polymyalgia rheumatica who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.

Polyarticular Juvenile Idiopathic

Arthritis (pJIA) KEVZARA is indicated for treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients who weigh 63 kg or greater.

General Considerations Prior to Administration Not Recommended for Concomitant Use with Biological DMARDS The concurrent use of KEVZARA with biological DMARDs such as tumor necrosis factor (TNF) antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators has not been studied. Avoid using KEVZARA with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. Recommended Evaluations Prior to Treatment Complete blood count (CBC): Treatment initiation with KEVZARA is not recommended in patients with an absolute neutrophil count (ANC) below 2000 per mm 3, or platelet count below 150,000 per mm 3.

Monitor laboratory parameters. Liver function tests (LFT): Treatment initiation with KEVZARA is not recommended in patients with or who have alanine transaminase (ALT) or aspartate aminotransferase (AST) above 1.5 times the upper limit of normal (ULN). Monitor laboratory parameters.

Lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol and/or triglycerides): Assess lipid parameters at baseline. Monitor laboratory parameters. Active and latent tuberculosis infection evaluation: Prior to initiating KEVZARA, test patients for active and latent tuberculosis (TB).

KEVZARA should not be administered to patients with active TB. If positive for latent infection, consider treating for TB prior to KEVZARA use. Evaluate for infections: Avoid KEVZARA use in patients with active infections.

Recommended Dosage for Rheumatoid Arthritis

The recommended dosage of KEVZARA is 200 mg once every two weeks given as a subcutaneous injection. KEVZARA may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. Modify the dosage as recommended in Table 1 if the patient develops neutropenia, thrombocytopenia, or liver enzyme abnormalities.

Recommended Dosage for Polymyalgia Rheumatica

KEVZARA can be used as monotherapy following discontinuation of corticosteroids. Discontinue KEVZARA if the patient develops neutropenia (using ANC results obtained at the end of the dosing interval), thrombocytopenia, or liver enzyme abnormalities.

Dosage in this patient population can be achieved by administering the 200 mg/1.14 mL pre-filled syringe. The pre-filled pen is not intended for use in pediatric patients. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form.

In patients with pJIA, KEVZARA can be used alone or in combination with conventional DMARDs.

Preparation and Administration Instructions

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.

Rotate injection sites with each injection. Do not inject into skin that is tender, damaged, or has bruises or scars. Pre-filled Pen and Pre-filled Syringe 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. 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.

The ability of pediatric patients to self-inject with the pre-filled pen has not been tested.

Dosage Modifications for Cytopenias, Abnormal Liver Enzymes, or Infections Dosage Modifications for Patients with Rheumatoid Arthritis Laboratory Abnormalities: Modify dosage in case of neutropenia, thrombocytopenia, or liver enzyme elevations as shown in Table 1. For treatment initiation criteria, refer to the dosage recommendations for RA. Table 1: Dosage Modifications due to Neutropenia, Thrombocytopenia, or Elevated Liver Enzymes in Patients with Rheumatoid Arthritis Infections: If a patient with RA develops a serious infection or an opportunistic infection, hold treatment with KEVZARA until the infection is controlled.

Dosage Modifications for Patients with Polymyalgia Rheumatica Laboratory Abnormalities: Discontinue KEVZARA in patients with PMR who develop the following laboratory abnormalities: neutropenia (ANC below 1,000 per mm 3 at the end of the dosing interval) thrombocytopenia (platelet count below 100,000 per mm 3 ) AST or ALT elevations 3 times above the ULN Dosage modifications have not been studied in patients with PMR with these conditions. Dosage Modification for Patients with Polyarticular Juvenile Idiopathic Arthritis Dose reduction of KEVZARA has not been studied in the pJIA population. The decision to discontinue KEVZARA should be based upon the medical assessment of the individual patient.

If appropriate, the dose of concomitant methotrexate and/or other medications should be modified or discontinued.

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. Rheumatoid Arthritis 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).

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. 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. 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.

The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with KEVZARA was neutropenia. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis.

The overall rate of infections with KEVZARA + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported.

Gastrointestinal Perforation In the 52-week placebo-controlled population, one patient on KEVZARA therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess.

Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to KEVZARA in the development of GI perforations is not known. Hypersensitivity Reactions In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with KEVZARA mg than placebo (0%).

The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving KEVZARA. Laboratory Abnormalities Decreased neutrophil count In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm 3 occurred in 6% and 4% of patients in the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + DMARD group, respectively, compared to no patients in the placebo + DMARD groups.

Decrease in ANC was not associated with the occurrence of infections, including seriou s infections. In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies. Elevated liver enzymes Liver enzyme elevations in the pre-rescue placebo-controlled population (KEVZARA + DMARD or placebo + DMARD) are summarized in Table 2.

In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of KEVZARA or reduction in dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active Rheumatoid Arthritis Phase 3 placebo-controlled safety population through the pre-rescue period Lipid Abnormalities Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of KEVZARA + DMARDs in the placebo-controlled population.

Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below: Mean LDL increased by 12 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 16 mg/dL in the KEVZARA 200 mg every two weeks + DMARD group. Mean HDL increased by 3 mg/dL in both the KEVZARA 150 mg every two weeks + DMARD and KEVZARA 200 mg every two weeks + DMARD groups.

In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies. In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on KEVZARA + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3.

Table 3: Common Adverse Reactions Adverse reactions occurring in 2% or more in the 150 mg KEVZARA + DMARD or 200 mg KEVZARA + DMARD groups and greater than observed in Placebo + DMARD in Adults with Moderately to Severely Active Rheumatoid Arthritis Pre-rescue, placebo-controlled population Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with KEVZARA in controlled studies was oral herpes. The total patient years duration in the KEVZARA PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study. Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group.

In both cases of neutropenia, the participants had a neutrophil count less than 500 per mm 3 without any infections and resolved following permanent discontinuation of study drug. The most common adverse reactions that resulted in permanent discontinuation of therapy with KEVZARA were neutropenia in 3 patients (5.1%) and infection in 3 separate patients (5.1%), including COVID-19 (n=1), intervertebral discitis (n=1), and pneumonia (n=1). Overall Infections In Study 3, the proportion of patients with infections was lower in the KEVZARA group (37.3%) compared to the placebo group (50.0%).

Two patients (3.2%) in the KEVZARA group and 1 patient (1.7%) in the placebo group had an event of herpes zoster. Serious infections In Study 3, the proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). Injection Site Reactions In Study 3, three patients (5.1%) in the KEVZARA group experienced injection site reactions of pruritus which were mild in severity.

No patient in the placebo group experienced injection site reactions. Laboratory Abnormalities Decreased neutrophil count In Study 3, decreases in neutrophil counts less than 1,000 per mm 3 occurred in 12% of the KEVZARA treated group and no patient in the placebo treated group. Decreases in neutrophil counts less than 500 per mm 3 occurred in 3.4% of patients in KEVZARA treated group compared to no patient in the placebo treated group.

These platelet count decreases were transient and not associated with bleeding events. Elevated liver enzymes In Study 3, no KEVZARA treated patients had an ALT or AST greater than 3 times the upper limit of normal (ULN). In the placebo treated group, 2 patients had ALT elevations greater than 3 times the ULN.

No significant differences in mean HDL between KEVZARA group and placebo group were observed. At Week 52, mean increase from baseline for LDL and triglycerides levels were observed in the KEVZARA group though both remained within the normal range. Polyarticular Juvenile Idiopathic Arthritis (pJIA) The safety of KEVZARA was studied in patients 2 to 17 years of age with pJIA who have had an inadequate response to current therapy (Study 4).

The overall median duration of study treatment for the recommended dose was 672 days. The cumulative exposure to treatment for patients who received the recommended dose at any time during the study was 184.1 patient-years. The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.

The most common adverse drug reaction that resulted in permanent discontinuation of therapy with KEVZARA was neutropenia (5.4%). No new adverse reactions and safety concerns were identified in the pJIA population compared to the RA population. Infections In Study 4, the rate of infections was 146.6 events per 100 patient-years.

The most common infections observed were nasopharyngitis (36.6%) and upper respiratory tract infections (URTI) (14.0%). The majority of these events were mild and none of the ISRs required patient withdrawal from treatment or dose interruption. The frequency of decreased neutrophil count was higher until Week 12.

Decrease in ANC was not associated with an occurrence of infections, including serious infections. Decrease monocyte count In Study 4, decrease in monocyte counts occurred in 4 (4.3%) patients and were mild in severity and non-serious. All patients recovered.

Three (3.2%) patients overall had elevation in triglycerides, and all were mild in severity and non-serious. No significant changes in mean LDL, HDL or total cholesterol were observed during the entire 156-week treatment period.

Use with Other Drugs

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.

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 co-administering 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.

Live Vaccines

Avoid concurrent use of live vaccines during treatment with KEVZARA.

Pregnancy Risk Summary The limited human data with KEVZARA in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ). From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers (see Clinical Considerations and Data ).

In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD) (see Data ). The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is respectively. KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations Fetal/Neonatal Adverse Reactions Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to KEVZARA in utero. Data Animal Data In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165.

Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth.

Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta. Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with KEVZARA.

Parturition is associated with significant increases of IL-6 in the cervix and myometrium. For mice deficient in IL-6 (ll6 -/- null mice), parturition was delayed relative to wild-type (ll6 +/+ ) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery.

Pediatric Use KEVZARA is approved for active polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients who weigh 63 kg or greater. Use of KEVZARA in this patient population is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with pJIA 2 years of age and older. KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form.

The safety and effectiveness of KEVZARA have not been established in pediatric patients with pJIA below the age of 2 years.

KEVZARA is contraindicated in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.