Sarilumab interacts in the following cases:
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.
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 should be used with caution in patients with previous history of intestinal ulceration or diverticulitis.
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.
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.
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.
Women of childbearing potential should use effective contraception during and up to 3 months after treatment.
No data are available on the effect of sarilumab on human fertility. Animal studies showed no impairment of male or female fertility.
Sarilumab 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%).
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 1. 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.
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.
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. 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.
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 2. 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. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.
Table 2. 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.
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. 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.
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.
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