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 including sarilumab for RA. 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 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 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 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 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 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 common adverse reactions were nasopharyngitis (36.6%), neutropenia (31.2%), upper respiratory tract infection (14.0%), injection site erythema (9.7%), pharyngitis (9.7%) and alanine aminotransferase increased (9.7%).
The most common adverse reaction that resulted in permanent discontinuation of therapy with sarilumab was neutropenia (5.4%).
Adverse reactions listed in the table have been reported in a clinical study. 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 3. Adverse reactions in pJIA patients who received at least one administration of the recommended dose of sarilumab:
| MedDRA System Organ Class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | Very Common | Upper respiratory tract infection* Nasopharyngitis‡ |
| Blood and lymphatic system disorders | Very common | Neutropenia† |
| Hepatobiliary disorders | Common | Alanine aminotransferase increased |
| General disorders and administration site conditions | Very Common | Injection site reaction†† |
* Includes upper respiratory tract infection and viral upper respiratory tract infection
‡ Includes nasopharyngitis and pharyngitis
† Includes neutropenia and neutrophil count decreased
†† Including injection site erythema, injection site pruritus, injection site swelling, injection site bruising, injection site inflammation, injection site reaction, injection site urticaria, injection site warmth
In the pJIA study, 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 nasopharyngitis and URTI events were mild.
In the pJIA study, 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.
In the pJIA study, decreases in neutrophil counts below 1 × 109/L 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.
In the pJIA study, decrease in monocyte counts occurred in 4 (4.3%) patients and were mild in severity and non-serious.
In the pJIA study, one (1.1%) patient had ALT greater than 3 times the upper limit of normal (ULN). Nine (9.7%) patients overall had ALT increase and majority were mild in severity and all were non-serious.
In the pJIA study, triglyceride levels of ≥150 mg/dL (1 x 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.
In the pJIA population, 3 (4.3%) patients treated with the recommended dose exhibited an antidrug antibody (ADA) response. Neutralizing antibodies were detected in one pJIA patient with ADA response. Because of the low occurrence of anti-drug antibodies, the effect of antibodies on the safety, and/or effectiveness of sarilumab is unknown.
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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