Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Sanofi-aventis groupe, 54, rue La Boétie, 75008 Paris, France
Hypersensitivity to the active substance or any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Patients should be closely monitored for the development of signs and symptoms of infection during treatment with Kevzara (see sections 4.2 and 4.8). As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Kevzara should not be administered in patients with an active infection, including localised infections.
Consider the risks and benefits of treatment prior to initiating Kevzara in patients who have:
Treatment with Kevzara should be withheld if a patient develops a serious infection or an opportunistic infection.
A patient who develops an infection during treatment with Kevzara should also undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
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 RA. The most frequently observed serious infections with Kevzara included pneumonia and cellulitis (see section 4.8). Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with Kevzara. In isolated cases, disseminated rather than localised infections were observed in patients often taking concomitant immunosuppressants such as MTX or corticosteroids, which in addition to RA may predispose them to infections.
Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating treatment with Kevzara. Patients with latent or active tuberculosis should be treated with standard antimycobacterial therapy before initiating Kevzara. Consider anti-tuberculosis therapy prior to initiation of Kevzara in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. When considering anti-tuberculosis therapy, consultation with a physician with expertise in tuberculosis may be appropriate.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with Kevzara. No cases of Hepatitis B reactivation were reported in the clinical studies; however patients who were at risk for reactivation were excluded.
Treatment with Kevzara was associated with a higher incidence of decrease in ANC. Decrease in ANC was not associated with higher incidence of infections, including serious infections.
Treatment with Kevzara was associated with a reduction in platelet counts in clinical studies. Reduction in platelets was not associated with bleeding events (see section 4.8).
Treatment with Kevzara was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies (see section 4.8). Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic medicinal products (e.g., MTX) were used in combination with Kevzara.
Initiating treatment with Kevzara is not recommended in patients with elevated transaminases, ALT or AST greater than 1.5 x ULN. In patients who develop elevated ALT greater than 5 x ULN, treatment with Kevzara should be discontinued (see section 4.2).
ALT and AST levels should be monitored 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. For recommended dose modifications based on transaminase elevations see section 4.2.
Lipid levels may be reduced in patients with chronic inflammation. Treatment with Kevzara was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol, and/or triglycerides (see section 4.8).
Lipid parameters should be assessed approximately 4 to 8 weeks following initiation of treatment with Kevzara, then at approximately 6 month intervals.
Patients should be managed according to clinical guidelines for the management of hyperlipidaemia.
Events of gastrointestinal perforation have been reported in clinical studies, primarily as complications of diverticulitis. Use Kevzara with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with new onset abdominal symptoms such as persistent pain with fever should be evaluated promptly (see section 4.8).
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 section 4.8).
Hypersensitivity reactions have been reported in association with Kevzara (see section 4.8). Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Patients should be advised to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, administration of Kevzara should be stopped immediately. Kevzara should not be administered to patients with known hypersensitivity to sarilumab (see section 4.3).
Treatment with Kevzara is not recommended in patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Avoid concurrent use of live vaccines as well as live attenuated vaccines during treatment with Kevzara as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Kevzara. Prior to initiating Kevzara, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. The interval between live vaccinations and initiation of Kevzara therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents (see section 4.5).
RA patients have an increased risk for cardiovascular disorders and risk factors (e.g. hypertension, hyperlipidaemia) should be managed as part of usual standard of care.
Sarilumab exposure was not affected when coadministered with MTX based on the population pharmacokinetic analyses and across study comparisons. MTX exposure is not expected to be changed by sarilumab coadministration; however, no clinical data was collected. Kevzara has not been investigated in combination with Janus kinase (JAK) inhibitors or biological DMARDs such as Tumor Necrosis Factor (TNF) antagonists.
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 (CYP1A2, CYP2C9, CYP2C19, and CYP3A4) and therefore have the potential to alter the pharmacokinetics of concomitantly administered medicinal products that are substrates of these enzymes. Elevated levels of interleukin-6 (IL-6) 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 signalling by IL-6Rα antagonists such as sarilumab might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered medicinal products concentrations.
The modulation of IL-6 effect on CYP enzymes by sarilumab 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, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) should be performed and the individual dose of the medicinal product should be adjusted as needed.
Caution should be exercised in patients who start Kevzara treatment while on therapy with CYP3A4 substrates (e.g., oral contraceptives or statins), as Kevzara may reverse the inhibitory effect of IL-6 and restore CYP3A4 activity, leading to decreased exposure and activity of CYP3A4 substrate. (see section 5.2).Interaction of sarilumab with substrates of other CYPs (CYP2C9, CYP 2C19, CYP2D6) has not been studied.
Women of childbearing potential should use effective contraception during and up to 3 months after treatment.
There are no or limited amount of data from the use of sarilumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
Kevzara should not be used during pregnancy unless the clinical condition of the woman requires treatment with sarilumab.
It is unknown whether sarilumab is excreted in human milk or absorbed systemically after ingestion. The excretion of sarilumab in milk has not been studied in animals (see section 5.3). Because IgG1 are excreted in human milk, a decision should be made whether to discontinue breastfeeding or to discontinue sarilumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
No data are available on the effect of sarilumab on human fertility. Animal studies showed no impairment of male or female fertility (see section 5.3).
Kevzara has no or negligible influence on the ability to drive or operate machinery.
The most frequent adverse reactions observed with Kevzara in clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. The most common serious adverse reactions were infections (see section 4.4).
The safety of Kevzara in combination with DMARDs was evaluated based on data from seven clinical 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 frequency of adverse reactions listed below is defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. ADRs in controlled clinical studies:
Common: Upper respiratory tract infection, Urinary tract infection, Nasopharyngitis, Oral herpes
Very Common: Neutropenia
Common: Thrombocytopenia
Common: Hypercholesterolemia, Hypertriglyceridemia
Common: Transaminases increased
Common: Injection site erythema, Injection site pruritus
In the placebo-controlled population, the rates of infections were 84.5, 81.0, and 75.1 events per 100 patient-years, in the 200 mg and 150 mg Kevzara + DMARDs and placebo + DMARDs groups respectively. The most commonly reported infections (5% to 7% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. The rates of serious infections were 4.3, 3.0, and 3.1 events per 100 patient-years, in the 200 mg, 150 mg Kevzara + DMARDs, and placebo + DMARDs groups, respectively.
In the Kevzara + DMARDs long-term safety population, the rates of infections and serious infection were 57.3 and 3.4 events per 100-patient years, respectively.
The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported (see section 4.4).
The overall rates of infections and serious infections in the Kevzara monotherapy population were consistent with rates in the Kevzara + DMARDs population.
In the placebo-controlled population, one patient on Kevzara therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). In the Kevzara + DMARDs long-term safety population, the rate of GI perforations was 0.14 events per 100 patient-years.
Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The contribution of these concomitant medications relative to Kevzara in the development of gastrointestinal perforations is not known (see section 4.4).
There were no reports of gastrointestinal perforation in the Kevzara monotherapy population.
In the placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with Kevzara (0.9% in 200 mg group, 0.5% in 150 mg group) than placebo (0.2%). The rates of discontinuations due to hypersensitivity in the Kevzara + DMARDs long-term safety population and the Kevzara monotherapy population were consistent with the placebo-controlled population. In the placebo-controlled population, 0.2% of the patients treated with Kevzara 200 mg q2w + DMARD reported serious adverse events of hypersensitivity reactions, and none from Kevzara 150 mg q2w + DMARD group.
In the placebo-controlled population, injection site reactions were reported in 9.5%, 8%, and 1.4% of patients receiving Kevzara 200 mg, 150 mg, and placebo respectively. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients. Two patients on Kevzara (0.2%) discontinued treatment due to injection site reactions.
To allow for a direct comparison of frequency of laboratory abnormalities between placebo and active treatment, data from weeks 0-12 were used as this was prior to patients being permitted to switch from placebo to Kevzara.
Decreases in neutrophil counts below 1 × 109 /L occurred in 6.4% and 3.6% of patients in the 200 mg and 150 mg Kevzara + DMARDs group, respectively, compared to no patients in the placebo + DMARDs group. Decreases in neutrophil counts below 0.5 × 109 /L occurred in 0.8% and 0.6% of patients in the 200 mg and 150 mg Kevzara + DMARDs groups, respectively. In patients experiencing a decrease in absolute neutrophil count (ANC), modification of treatment regimen such as interruption of Kevzara or reduction in dose resulted in an increase or normalization of ANC (see section 4.2). Decrease in ANC was not associated with higher incidence of infections, including serious infections.
In the Kevzara + DMARDs long-term safety population and the Kevzara monotherapy population, the observations on neutrophil counts were consistent with those seen in the placebo-controlled population (see section 4.4).
Decreases in platelet counts below 100 × 103/µL occurred in 1.2% and 0.6% of patients on 200 mg and 150 mg Kevzara + DMARDs, respectively, compared to no patients on placebo + DMARDs.
In the Kevzara + DMARDs long-term safety population and the Kevzara monotherapy population, the observations on platelet counts were consistent with those seen in the placebo-controlled population.
There were no bleeding events associated with decreases in platelet count.
Liver enzyme abnormalities are summarised 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 (see section 4.2). These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency (see section 4.4).
Table 2. Incidence of liver enzyme abnormalities in controlled clinical studies:
| Placebo + DMARDs N=661 | Kevzara 150 mg + DMARDs N=660 | Kevzara 200 mg + DMARDs N=661 | Kevzara Monotherapy Any Dose N=467 | |
|---|---|---|---|---|
| AST | ||||
| >3 x ULN – 5 x ULN | 0% | 1.2% | 1.1% | 1.1% |
| >5 x ULN | 0% | 0.6% | 0.2% | 0% |
| ALT | ||||
| >3 x ULN – 5 x ULN | 0.6% | 3.2% | 2.4% | 1.9% |
| >5 x ULN | 0% | 1.1% | 0.8% | 0.2% |
Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of Kevzara + DMARDs in the placebo-controlled population. At Week 4 the mean LDL increased by 14 mg/dL; mean triglycerides increased by 23 mg/dL; and mean HDL increased by 3 mg/dL. After Week 4 no additional increases were observed. There were no meaningful differences between doses.
In the Kevzara + DMARDs long-term safety population and the Kevzara monotherapy population, the observations in lipid parameters were consistent with those seen in the placebo-controlled population.
As with all therapeutic proteins, there is a potential for immunogenicity with Kevzara.
In the placebo-controlled population, 4.0%, 5.6%, and 2.0% of patients treated with Kevzara 200 mg + DMARDs, Kevzara 150 mg + DMARDs and placebo + DMARDs respectively, exhibited a positive response in the anti-drug antibody (ADA) assay. Positive responses in the neutralizing antibody (NAb) assay were detected in 1.0%, 1.6%, and 0.2% of patients on Kevzara 200 mg, Kevzara 150 mg, and placebo respectively.
In the Kevzara monotherapy population, observations were consistent with the Kevzara + DMARDs population.
Anti Drug Antibody (ADA) formation may affect pharmacokinetics of Kevzara. No correlation was observed between ADA development and either loss of efficacy or adverse events.
The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used and testing conditions. For these reasons, comparison of the incidence of antibodies to Kevzara with the incidence of antibodies to other products may be misleading.
In the placebo-controlled population, malignancies occurred at the same rate in patients receiving either Kevzara + DMARDs or placebo + DMARDs (1.0 events per 100 patient-years).
In the Kevzara + DMARDs long-term safety population and the Kevzara monotherapy population, the rates of malignancies were consistent with the rate observed in the placebo-controlled population (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
