KEVZARA has an established safety profile as a combination therapy
KEVZARA combination therapy has more than 10 years of RA safety data with no new safety signals1,2
Common adverse reactions in pre-rescue, placebo-controlled trials1*
|
Preferred Term |
Placebo + DMARD(s) N=579 |
KEVZARA 150 mg + DMARD(s) N=579 |
KEVZARA 200 mg + DMARD(s) N=582 |
|
Neutropenia |
0.2% |
7% |
10% |
|
ALT increased |
2% |
5% |
5% |
|
Injection type 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 AE occurring at an incidence of less than 2% in patients with RA treated with KEVZARA in controlled studies was oral herpes1
- Decrease in ANC was not associated with higher incidence of infections, including serious infections1
- In the long-term safety population, the overall rates of serious infections, GI perforations, neutrophil counts, platelet counts, and lipid parameters were consistent with what was observed in the placebo-controlled trials1
*Adverse reactions occurring in ≥2% of patients administered KEVZARA 200 mg or KEVZARA 150 mg + DMARD(s) and greater than observed in patients on placebo + DMARD(s).1
Long-term combination therapy safety data
Studied in 2887 MTX-IR and TNF-IR patients with over 10,000 patient-years of exposure2,3
Mean duration of treatment in the safety population (N=2887) was 3.5 years (max 10.1 years), representing 10,007.6 cumulative PY of exposure.2
- 62 patients (2.1%) were treated for >480 weeks (9.2 years)
Incidence rate of AEs was generally stable over time, with no indication of increased incidence rate in serious AEs and serious infections.1,4
Long-term combination therapy
MOBILITY (MTX-IR), TARGET (TNF-IR), long-term safety populations5
|
Placebo-Controlled Population |
Long-Term Safety Population |
|||
|
|
Placebo + MTX/ |
KEVZARA |
KEVZARA |
KEVZARA |
|
Cumulative total TEAE observation period, |
382.3 |
440.7 |
441.4 |
10,322.0 |
|
Any TEAE |
57.2% (260.0) |
70.5% (338.1) |
73.8% (385.8) |
87.2% (197.5) |
|
Serious TEAE |
4.7% (12.8) |
6.4% (15.2) |
8.9% (18.4) |
26.8% (12.9) |
|
TEAE leading to discontinuation |
4.7% (8.6) |
10.9% (20.4) |
12.6% (20.6) |
26.7% (8.5) |
|
TEAE leading to death |
0.5% (1.3) |
0.3% (0.5) |
0.2% (0.2) |
1.6% (0.6) |
|
Overall infections |
28.9% (75.6) |
34.4% (81.0) |
35.2% (84.5) |
57.5% (50.5) |
|
Serious infections |
1.8% (3.9) |
1.8% (3.6) |
2.9% (5.2) |
9.3% (3.3) |
|
Upper respiratory tract infection |
4.8% (10.2) |
6.4% (12.3) |
7.1% (12.5) |
14.5% (7.4) |
|
Urinary tract infection |
4.2% (7.8) |
4.4% (7.0) |
5.7% (10.9) |
11.9% (5.4) |
|
Neutropenia |
0.5% (0.8) |
9.8% (22.9) |
14.2% (31.0) |
19.1% (12.1) |
|
ALT increased |
2.6% (4.4) |
6.7% (11.6) |
6.8% (10.9) |
11.3% (4.4) |
|
Thromboembolic events |
0 |
0.6% (1.1) |
0.2% (0.2) |
1.4% (0.5) |
|
Deep vein thrombosis |
0 |
0.2% (0.2) |
0 |
0.8% (0.2) |
|
Pulmonary embolism |
0 |
0.3% (0.5) |
0 |
0.6% (0.2) |
|
Injection site erythema§ |
0.9% (1.6) |
5.5% (29.5) |
5.3% (23.8) |
7.4% (11.1) |
|
Injection site pruritus§ |
0.2% (0.5) |
2.6% (9.3) |
2.4% (9.3) |
3.7% (3.9) |
|
Hypertriglyceridemia |
0.8% (1.3) |
2.9% (4.5) |
1.8% (3.2) |
4.2% (1.8) |
|
Leukopenia |
0 |
1.7% (4.1) |
3.5% (7.9) |
5.1% (2.6) |
In the long-term safety population, the rate of exposure-adjusted DVT was 0.2 per 100 PY; rate of PE was 0.2 per 100 PY.5,6
In the long-term safety population, the rate of thromboembolic events (MedDRA high-level group term “embolism and thrombosis”) was 0.8 per 100 PY (as reported and evaluated post hoc; not a prespecified AESI).6
Safety observations in the open-label extension population were consistent with those in the placebo-controlled trials.1,4
†nE/100 PY is the exposure-adjusted event rate. Incidence rate per 100 PY at risk of first event.7
‡TEAE period from day of first treatment dose to 60 days after the last treatment dose.5
§Injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 18 (0.6%) out of 2887 patients receiving KEVZARA (any dose).7
AESI=adverse event of special interest; ALT=alanine aminotransferase; ANC=absolute neutrophil count; AST=aspartate aminotransferase; DMARDs=disease-modifying antirheumatic drugs; DVT=deep vein thrombosis; GI=gastrointestinal; IR=incidence rate; MTX=methotrexate; MTX-IR=methotrexate inadequate response; PE=pulmonary embolism; PY=patient years; Q2W=once every 2 weeks; TEAE=treatment-emergent adverse event; TNF-IR=tumor necrosis factor inhibitor inadequate response or intolerant.
IMPORTANT SAFETY INFORMATION
|
WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Reported infections include:
Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection. |
CONTRAINDICATION
Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.
WARNINGS AND PRECAUTIONS
- 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. Among opportunistic infections, TB, candidiasis, and pneumocystis were reported with KEVZARA. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis.
- Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
- Patients with latent TB should be treated with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection.
- 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 that may predispose them to infection, been exposed to TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
- Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
- Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
- Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
- 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 have been reported in clinical studies.
- Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. 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.
- 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.
- Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. Prior to initiating treatment, it is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines.
ADVERSE REACTIONS
- For Rheumatoid Arthritis: The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.
- For Polymyalgia Rheumatica: Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. The proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia, leukopenia, constipation, rash pruritic, myalgia, fatigue, and injection site pruritus.
- For Polyarticular Juvenile Idiopathic Arthritis: 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 most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.
DRUG INTERACTIONS
- Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
- 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.
USE IN SPECIFIC POPULATIONS
- KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
- Use caution when treating the elderly.
Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Please see full Prescribing Information, including Boxed WARNING.
INDICATIONS
KEVZARA® (sarilumab) is indicated for treatment of:
- adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
- adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
- patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA).
IMPORTANT SAFETY INFORMATION
|
WARNING: RISK OF SERIOUS INFECTIONS Patients treated with KEVZARA are at increased risk for developing serious infections that may lead to hospitalization or death. Opportunistic infections have also been reported in patients receiving KEVZARA. Most patients who developed infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of KEVZARA in patients with an active infection. Reported infections include:
Closely monitor patients for signs and symptoms of infection during treatment with KEVZARA. If a serious infection develops, interrupt KEVZARA until the infection is controlled. Consider the risks and benefits of treatment with KEVZARA prior to initiating therapy in patients with chronic or recurrent infection. |
CONTRAINDICATION
Do not use KEVZARA in patients with known hypersensitivity to sarilumab or any of the inactive ingredients.
WARNINGS AND PRECAUTIONS
- 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. Among opportunistic infections, TB, candidiasis, and pneumocystis were reported with KEVZARA. The most frequently observed serious infections with KEVZARA in RA patients included pneumonia and cellulitis.
- Hold treatment with KEVZARA if a patient develops a serious infection or an opportunistic infection.
- Patients with latent TB should be treated with standard antimycobacterial therapy before initiating KEVZARA. Consider anti-TB therapy prior to initiation of KEVZARA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection.
- 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 that may predispose them to infection, been exposed to TB, or lived in or traveled to areas of endemic TB or endemic mycoses.
- Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with KEVZARA.
- Laboratory Abnormalities. Treatment with KEVZARA was associated with decreases in absolute neutrophil counts (including neutropenia), and platelet counts; and increases in transaminase levels and lipid parameters (LDL, HDL cholesterol, and/or triglycerides). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with KEVZARA. Assess neutrophil count, platelet count, and ALT/AST levels prior to initiation with KEVZARA. Monitor these parameters 4 to 8 weeks after start of therapy and every 3 months thereafter. Assess lipid parameters 4 to 8 weeks after start of therapy, then at 6 month intervals.
- Gastrointestinal Perforation. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. Promptly evaluate patients presenting with new onset abdominal symptoms.
- 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 have been reported in clinical studies.
- Hypersensitivity Reactions. Hypersensitivity reactions have been reported in association with KEVZARA. 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.
- 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.
- Live Vaccines. Avoid concurrent use of live vaccines during treatment with KEVZARA due to potentially increased risk of infections. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving KEVZARA. Prior to initiating treatment, it is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines.
ADVERSE REACTIONS
- For Rheumatoid Arthritis: The most common serious adverse reactions were infections. The most frequently observed serious infections included pneumonia and cellulitis. The most common adverse reactions (occurred in at least 3% of patients treated with KEVZARA + DMARDs) are neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections.
- For Polymyalgia Rheumatica: Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. The proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%). The common adverse reactions occurring in ≥5% of patients treated with KEVZARA were neutropenia, leukopenia, constipation, rash pruritic, myalgia, fatigue, and injection site pruritus.
- For Polyarticular Juvenile Idiopathic Arthritis: 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 most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.
DRUG INTERACTIONS
- Exercise caution when KEVZARA is co-administered with CYP substrates with a narrow therapeutic index (e.g. warfarin or theophylline), or with CYP3A4 substrates (e.g. oral contraceptives or statins) as there may be a reduction in exposure which may reduce the activity of the CYP3A4 substrate.
- 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.
USE IN SPECIFIC POPULATIONS
- KEVZARA should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Because monoclonal antibodies could be excreted in small amounts in human milk, the benefits of breastfeeding and the potential adverse effects on the breastfed child should be considered along with the mother’s clinical need for KEVZARA.
- Use caution when treating the elderly.
Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Please see full Prescribing Information, including Boxed WARNING.
INDICATIONS
KEVZARA® (sarilumab) is indicated for treatment of:
- adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
- adult patients with polymyalgia rheumatica (PMR) who have had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.
- patients who weigh 63 kg or greater with active polyarticular juvenile idiopathic arthritis (pJIA).
References: 1. Kevzara [prescribing information]. Bridgewater, NJ: Sanofi/Regeneron Pharmaceuticals, Inc. 2. Data on file. Bridgewater, NJ: Sanofi/Regeneron. Integrated Summary of Safety: Appendix 1.3. June 2019. 3. Data on file. Bridgewater, NJ: Sanofi/Regeneron. Integrated Summary. October 2019. 4. Data on file. Bridgewater, NJ: Sanofi/Regeneron. EXTEND Clinical Study Report. January 2016. 5. Data on file. Bridgewater, NJ: Sanofi/Regeneron. Summary of treatment emergent adverse events-sarilumab combination population (pool 1 and pool 2). April 2023. 6. Burmester GR, Strand V, Kivitz AJ, et al. Long-term safety and efficacy of sarilumab with or without background csDMARDs in rheumatoid arthritis. Rheumatology (Oxford). 2023;62(10):3268-3279. 7. Data on file. Bridgewater, NJ: Sanofi/Regeneron. ISR statement-data source. June 2021.