Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Sanofi Winthrop Industrie, 82 avenue Raspail, 94250 Gentilly, 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 must be closely monitored for the development of signs and symptoms of infection during treatment with sarilumab (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.
Sarilumab must not be administered in patients with an active infection, including localised infections. The risks and benefits should be considered prior to initiating treatment in patients who have:
Treatment with sarilumab must be withheld if a patient develops a serious infection or an opportunistic infection. Once the infection is controlled, treatment with sarilumab may be re-initiated at the discretion of the healthcare professional.
A patient who develops an infection during treatment 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. The most frequently observed serious infections with sarilumab in RA patients included pneumonia and cellulitis (see section 4.8). Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with sarilumab in RA. In some patients with RA with concomitant tuberculosis, disseminated rather than localised infections were observed, most of whom were taking concomitant immunosuppressants such as MTX or corticosteroids, which may increase the risk of infection.
Patients must be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating treatment with sarilumab. Patients with latent or active tuberculosis must be treated with standard antimycobacterial therapy before initiating treatment. Anti-tuberculosis therapy must be considered prior to initiation of treatment in patients with a past medical 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. Healthcare professionals are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised. 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 sarilumab (see section 4.8). No cases of Hepatitis B reactivation were reported in the clinical studies; however patients who were at risk for reactivation were excluded.
Treatment with sarilumab was associated with a higher incidence of decrease in ANC (see section 4.8). Decrease in ANC was not associated with higher incidence of infections, including serious infections.
Treatment with sarilumab 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 sarilumab 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 sarilumab.
Initiating treatment with sarilumab 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 sarilumab must be discontinued (see section 4.2).
ALT and AST levels must 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 sarilumab 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 sarilumab, then at approximately 6 month intervals. Patients should be managed according to clinical guidelines for the management of hyperlipidaemia.
Cases of gastrointestinal perforation and diverticulitis have been reported in association with sarilumab. Gastrointestinal perforation has been reported in patients with and without diverticulitis. Patients presenting with symptoms potentially indicative of diverticulitis, such as abdominal pain, gastrointestinal haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation. Sarilumab should be used with caution in patients with previous history of intestinal ulceration or diverticulitis (see section 4.8).
Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with sarilumab 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 sarilumab (see section 4.8). Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Patients must 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 Sarilumab must be stopped immediately (see section 4.3).
Treatment with sarilumab is not recommended in patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Concurrent use of live vaccines as well as live attenuated vaccines should be avoided during treatment with sarilumab 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 sarilumab. Prior to initiating treatment, 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 therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
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.
This medicinal product contains 2.28 mg of polysorbate 20 in each 1.14 ml of solution for injection which is equivalent to 2 mg/ml. Polysorbates may cause allergic reactions.
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. Sarilumab has not been investigated in combination with Janus kinase (JAK) inhibitors or biological DMARDs such as tumour 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 or PMR and hence increase drug levels compared to subjects without RA or PMR. 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 sarilumab in patients being treated with CYP substrate medicinal products, therapeutic monitoring of effect (e.g., warfarin) or concentration of the medicinal product (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 sarilumab treatment while on therapy with CYP3A4 substrates (e.g., oral contraceptives or statins), as sarilumab 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 (see section 4.5).
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).
Sarilumab 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 must be made whether to discontinue breast-feeding 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 and use machines.
The most frequent adverse reactions in RA (n=661) and PMR (n=59) patients are neutropenia (14.3%), upper respiratory infections (6.8%), increased ALT (6.3%), urinary tract infections (5.3%), and injection site erythema (5.0%). The most common serious adverse reactions are infections (3.1%) (see section 4.4).
Adverse reactions listed in the table have been reported in controlled clinical studies. 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 2. Adverse reactions in patients with RA and PMR:
| MedDRA System Organ Class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Common | Upper respiratory tract infection Urinary tract infection Oral herpes Cellulitis Pneumonia |
| Uncommon | Nasopharyngitis Diverticulitis | |
| Blood and lymphatic system disorders | Very common | Neutropenia* |
| Common | Leukopenia* Thrombocytopenia | |
| Metabolism and nutrition disorders | Common | Hypertriglyceridemia Hypercholesterolemia |
| Gastrointestinal disorders | Rare | Gastrointestinal perforation |
| Hepatobiliary disorders | Common | Transaminases increased |
| General disorders and administration site conditions | Common | Injection site erythema Injection site pruritus* |
* In the SAPHYR study, the reported ADRs in PMR patients are neutropenia, leukopenia and 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 sarilumab + 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 sarilumab + DMARDs, and placebo + DMARDs groups, respectively.
In the sarilumab +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 sarilumab monotherapy population were consistent with rates in the sarilumab + DMARDs population.
Gastrointestinal perforation was reported in patients with and without diverticulitis. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medicinal products (NSAIDs), corticosteroids, or MTX. The contribution of these concomitant medicinal products relative to sarilumab in the development of gastrointestinal perforations is not known (see section 4.4).
In the placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with sarilumab (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 sarilumab + DMARDs long-term safety population and the sarilumab monotherapy population were consistent with the placebo-controlled population. In the placebo-controlled population, 0.2% of the patients treated with sarilumab 200 mg every two weeks (q2w) + DMARD reported serious adverse reactions of hypersensitivity reactions, and none from sarilumab 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 sarilumab 200 mg, 150 mg, and placebo respectively. These injection site reactions (including erythema and pruritus) were mild to moderate in severity for the majority of patients (99.5%, 100%, and 100%, for sarilumab 200 mg, 150 mg, and placebo respectively). Two patients on sarilumab (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 sarilumab.
Decreases in neutrophil counts below 1 × 109/L occurred in 6.4% and 3.6% of patients in the 200 mg and 150 mg sarilumab + 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 sarilumab+ DMARDs groups, respectively. In patients experiencing a decrease in absolute neutrophil count (ANC), modification of treatment regimen such as interruption of sarilumab or reduction in dose resulted in an increase or normalisation of ANC (see section 4.2). Decrease in ANC was not associated with higher incidence of infections, including serious infections.
In the sarilumab + DMARDs long-term safety population and the sarilumab 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 sarilumab + DMARDs, respectively, compared to no patients on placebo + DMARDs.
In the sarilumab + DMARDs long-term safety population and the sarilumab 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 3. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of treatment or reduction in dose, resulted in decrease or normalisation 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 3. Incidence of liver enzyme abnormalities in controlled clinical studies:
| Placebo + DMARD N=661 | Sarilumab 150 mg + DMARD N=660 | Sarilumab 200 mg + DMARD N=661 | Sarilumab 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 sarilumab+ 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 sarilumab + DMARDs long-term safety population and the sarilumab monotherapy population, the observations in lipid parameters were consistent with those seen in the placebo-controlled population.
In the placebo-controlled population, malignancies occurred at the same rate in patients receiving either sarilumab + DMARDs or placebo + DMARDs (1.0 events per 100 patient-years).
In the sarilumab + DMARDs long-term safety population and the sarilumab monotherapy population, the rates of malignancies were consistent with the rate observed in the placebo-controlled population (see section 4.4).
As with all therapeutic proteins, there is a potential for immunogenicity with sarilumab.
In the placebo-controlled population, 4.0%, 5.6%, and 2.0% of patients treated with sarilumab 200 mg + DMARDs, sarilumab 150 mg + DMARDs and placebo + DMARDs respectively, exhibited a positive response in the antidrug antibody (ADA) assay. Positive responses in the neutralising antibody (NAb) assay were detected in 1.0%, 1.6%, and 0.2% of patients on sarilumab 200 mg, sarilumab 150 mg, and placebo respectively.
In the sarilumab monotherapy population, observations were consistent with the sarilumab + DMARDs population.
Antidrug antibodies (ADA) formation may affect pharmacokinetics of sarilumab. No correlation was observed between ADA development and either loss of efficacy or adverse reactions.
The safety of sarilumab was studied in one Phase 3 study (SAPHYR) in 117 PMR patients of whom 59 received subcutaneous sarilumab 200 mg (see section 5.1). The total patient years duration in the sarilumab PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study. Safety data are available for up to 1 year.
In the SAPHYR study, the proportion of patients with infections was lower in the sarilumab 200 mg with 14-week prednisone taper group (37.3%) compared to the placebo with 52-week prednisone taper group (50.0%). Serious infections were reported in 3 (5.1%) patients in the sarilumab 200 mg with 14- week prednisone taper group (all of which were cases of bacterial infections) and 3 (5.2%) patients in the placebo with 52-week prednisone taper group (all of which were cases of COVID-19 infection). Laboratory abnormalities
In the SAPHYR study, decreases in neutrophil counts below 1 × 109/L occurred in 7 (12%) patients in the sarilumab group of which 2 (3.4%) were serious (decreases in neutrophil counts below 0.5 × 109/L).
In the SAPHYR study, no sarilumab treated patients had an ALT or AST greater than 3 times the upper limit of normal (ULN). In the placebo group, 2 patients had ALT elevations greater than 3x ULN.
As with all therapeutic proteins, there is a potential for immunogenicity with sarilumab.
In the PMR population, 1 (1.8%) patient treated with sarilumab 200 mg exhibited a persistent anti-drug antibody (ADA) response and none of the patients in the placebo group exhibited an ADA response. Positive response in the neutralising antibody assay was detected in the PMR patient with ADA response on sarilumab 200 mg. Because of the low occurrence of ADA, the effect of these antibodies on the safety, and/or efficacy of sarilumab is unknown.
The safety and efficacy of sarilumab pre-filled syringe and pre-filled pen in children less than 18 years of age have not been established. No data are available.
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.
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