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.

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). 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.

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. Overall Infections In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg KEVZARA + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group.

The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with KEVZARA 200 mg + DMARD, 0.6% (4 patients) treated with KEVZARA 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster . 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. Serious Infections In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group.

In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg KEVZARA + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. In the long-term safety population, the overall rate of serious infections 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 (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving KEVZARA 200 mg, 6% receiving KEVZARA 150 mg, and 1% receiving placebo. 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.

Decreases in neutrophil counts less than 500 per mm 3 occurred in 0.7% of patients in both the 200 mg KEVZARA + DMARD and 150 mg KEVZARA + 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 . Decreased platelet count In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm 3 occurred in 1% and 0.7% of patients on 200 mg and 150 mg KEVZARA + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events.

In the long-term safety population, the observations on platelet 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 Placebo + DMARD N=579 KEVZARA 150 mg + DMARD N=579 KEVZARA 200 mg + DMARD N=582 ULN = Upper Limit of Normal AST Greater than ULN to 3 times ULN or less 15% 27% 30% Greater than 3 times ULN to 5 times ULN 0% 1% 1% Greater than 5 times ULN 0% 0.7% 0.2% ALT Greater than ULN to 3 times ULN or less 25% 38% 43% Greater than 3 times ULN to 5 times ULN 1% 4% 3% Greater than 5 times ULN 0% 1% 0.7% 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 triglycerides increased by 20 mg/dL in the KEVZARA 150 mg every two weeks + DMARD group and 27 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.

Malignancies In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving KEVZARA + DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years). 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 Adverse Reactions Placebo + DMARD (N=579) KEVZARA 150 mg + DMARD (N=579) KEVZARA 200 mg + DMARD (N=582) Neutropenia 0.2% 7% 10% Alanine aminotransferase increased 2% 5% 5% Injection site erythema 0.9% 5% 4% Injection site pruritus 0.2% 2% 2% Upper respiratory tract infection 2% 4% 3% Urinary tract infection 2% 3% 3% Hypertriglyceridemia 0.5% 3% 1% Leukopenia 0% 0.9% 2% 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. Polymyalgia Rheumatica Safety has been studied in one Phase 3 study (Study 3) in 117 PMR patients of whom 59 received subcutaneous KEVZARA 200 mg . Of these, 45 patients received KEVZARA for at least 24 weeks, 44 patients for at least 40 weeks, and 10 patients for at least 52 weeks. The total patient years duration in the KEVZARA PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study.

The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia (15.3%), leukopenia (6.8%), constipation (6.8%), rash pruritic (5.1%), myalgia (6.8%), fatigue (5.1%), and injection site pruritus (5.1%). 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. Decreased platelet count In Study 3, decreases in platelet counts between 75,000 to 100,000 per mm 3 occurred in two patients (3.4%) in the KEVZARA 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. Lipid Abnormalities In Study 3, cholesterol levels ≥299.27 mg/dL were observed in 8/58 (13.8%) patients in the KEVZARA group compared to 4/58 (6.9%) patients in the placebo group. Triglycerides ≥407.4 mg/dL were observed in 3/58 (5.2%) patients in the KEVZARA group compared to 1/58 (1.7%) in the placebo group. 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) . A total of 93 patients received at least one administration of the recommended dose: 79 (84.9%) patients received the recommended dose for 52 weeks, 53 (57%) patients received it for 96 weeks and 30 (32.2%) patients received it for 156 weeks. 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%). Injection Site Reactions In Study 4, injection site reactions (ISRs) occurred in 13 (14.0%) patients and the most commonly reported ISR was injection site erythema (9.7%). The majority of these events were mild and none of the ISRs required patient withdrawal from treatment or dose interruption. Laboratory Abnormalities Decrease neutrophil count In Study 4, decreases in neutrophil counts less than 1000 per mm 3 occurred in 10/52 (19.2%) patients weighing in ≥30 kg and 20/41 (48.8%) patients weighing 10 to <30 kg.

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. Elevated liver enzymes In Study 4, nine (9.7%) patients had ALT increases, including one (1.1%) patient who had ALT >3 times upper limit of normal (ULN) and up to ≤5 times ULN, and two (2.2%) patients who had ALT increases >5 times ULN and up to ≤10 times ULN that resulted in permanent discontinuation.

All patients recovered. Lipid Abnormalities In Study 4, triglyceride levels of ≥150 mg/dL (1 × ULN) were observed in one (1.1%) patient. 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 2% to 4% and 15% to 20%, 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. From the 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 Data ). Data Animal Data In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received sarilumab at intravenous doses of 0, 5, 15, or 50 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.

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. 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.

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