Source: European Medicines Agency (EU) Revision Year: 2012 Publisher: Regeneron UK Limited, 40 Bank Street, E14 5DS, London, United Kingdom
Hypersensitivity to rilonacept or to any of the excipients.
Active, severe infections (see section 4.4).
Interleukin-1 (IL-1) blockade may interfere with immune response to infections. Serious, life-threatening infections have been reported uncommonly in patients taking Rilonacept Regeneron.
In an open-label extension study, one patient developed bacterial meningitis and died. Rilonacept Regeneron should be discontinued if a patient develops a serious infection. Treatment should not be initiated in patients with an active or chronic infection (see section 4.3) and physicians should exercise caution when administering Rilonacept Regeneron to patients with a history of recurring infections or with underlying conditions that may predispose them to infections.
Because Rilonacept Regeneron dampens an inflammatory response, vigilance in excluding underlying infection in unwell patients is required.
Tumour necrosis factor (TNF) inhibitors have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is unknown whether the use of IL-1 inhibitors like rilonacept increases the risk of reactivation of TB or of opportunistic infections. Before starting treatment with Rilonacept Regeneron, all patients should be evaluated for both active and inactive (latent) tuberculosis.
The combination of Rilonacept Regeneron with TNF inhibitors has not been evaluated in clinical studies. An increased incidence of serious infections has been associated with administration of another IL-1 inhibitor, in combination with a TNF inhibitor.
Rilonacept Regeneron should not be used with TNF inhibitors because of increased risk of serious infections (see section 4.5).
The concomitant use of Rilonacept Regeneron with other IL-1 inhibitors is not recommended (see section 4.5).
Although hypersensitivity reactions related to treatment with Rilonacept Regeneron were not seen in the initial clinical program, if a hypersensitivity reaction occurs, administration should be stopped immediately and permanently, and appropriate therapy initiated.
The risk for severe hypersensitivity reactions, which is not uncommon for injectable proteins, cannot be excluded (see section 4.3).
Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in 35% of patients (19 out of 55) treated for at least 6 weeks in the clinical study. There was no correlation of antibody activity with either clinical efficacy or safety.
Neutropenia (absolute neutrophil count [ANC] <1.5 × 109/l) has been observed commonly with another medicinal product that inhibits IL-1 used in a patient population (rheumatoid arthritis) other than CAPS. Neutropenia was observed commonly in patients with rheumatoid arthritis (not an approved use) who were administered Rilonacept Regeneron subcutaneously in clinical studies. None of these patients had serious infections associated with the neutropenia. Although neutropenia was observed uncommonly in CAPS patients, the numbers studied are small. Treatment with Rilonacept Regeneron should not be initiated in patients with neutropenia. It is recommended that neutrophil counts be assessed prior to initiating treatment, after 1 to 2 months, and periodically thereafter while receiving Rilonacept Regeneron. If a patient becomes neutropenic the ANC should be monitored closely and treatment discontinuation should be considered.
The impact of treatment with Rilonacept Regeneron on the development of malignancies is not known. However, treatment with immunosuppressants, including Rilonacept Regeneron, may result in an increase in the risk of malignancies.
Live vaccines should not be given concurrently with Rilonacept Regeneron (see section 4.5). Prior to initiation of Rilonacept Regeneron therapy, adult and paediatric patients should receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine.
Patients should be monitored for changes in their lipid profiles and provided with medical treatment if warranted (see section 4.8).
All cases in the clinical trials had a confirmed mutation in the NLRP3 gene. The efficacy was not evaluated in patients without a confirmed NLRP3 gene mutation.
No interaction studies have been performed.
The concomitant administration of Rilonacept Regeneron with any TNF inhibitor is not recommended (see section 4.4), because an increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors.
The concomitant administration of Rilonacept Regeneron with other IL-1 inhibitors has not been studied and is therefore not recommended.
The formation of CYP450 enzymes is suppressed by increased levels of cytokines during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin). Upon initiation of Rilonacept Regeneron, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or plasma levels should be performed and the individual dose of the medicinal product may need to be adjusted as needed.
No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving Rilonacept Regeneron. Therefore, live vaccines should not be given concurrently with Rilonacept Regeneron, unless the benefits clearly outweigh the risks. Should vaccination with live vaccines be indicated after initiation of Rilonacept Regeneron treatment, the recommendation is to wait for at least 6 weeks after the last Rilonacept Regeneron injection and before the next one (see section 4.4).
There are no adequate data from use of rilonacept in pregnant women. Reproductive toxicity studies have been conducted in animals and have shown no effects on fertility or foetal morphology; however a study in pregnant monkeys showed reduced levels of oestrogen (see section 5.3). The risk for the foetus/mother is unknown. Women should use effective contraceptives during treatment with Rilonacept Regeneron and for up to 6 weeks after the last dose. Women who are pregnant or who desire to become pregnant should therefore only be treated after a thorough benefit-risk evaluation.
It is unknown whether rilonacept is excreted in human or animal breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Rilonacept Regeneron should be made taking into account the benefit of breast-feeding to the child and the benefit of Rilonacept Regeneron therapy to the woman.
The ability to drive and operate machines may be impaired by some symptoms associated with CAPS. Patients who experience vertigo during Rilonacept Regeneron treatment should wait for this to resolve completely before driving or operating machines.
The majority of the related adverse events in the clinical trials were classified as injection site reactions, experienced by approximately 50% of the patients in the Phase 3 study. Reported ISRs were generally mild to moderate in severity. No patients withdrew from the study due to ISRs.
ADRs to Rilonacept Regeneron reported during the Phase ⅔ program in a total of 109 patients, some treated for longer than 2 years, are listed below using the following categories of frequency: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100).
Due to the small patient population, an ADR reported in 2 or more patients is classified as "common."
Table 2. Adverse reactions with Rilonacept Regeneron in CAPS patients:
Very common: Injection site reactions, including erythema, bruising, pruritus, swelling, inflammation, pain, dermatitis, oedema, urticaria, vesicles
Common: Fatigue
Very common: Upper respiratory tract infection; sinusitis
Common: Bronchitis; gastroenteritis; viral infections; skin, eye and ear infections; pneumonia
Uncommon: Bacterial meningitis
Common: Eosinophil count increased
Very common: Headache
Common: Dizziness
Common: Hypertension, flushing
Common: Vertigo
Iritis uncommon
Common: Anxiety, insomnia
Common: Hypersensitivity
During Part A of the pivotal study (see section 5.1), the incidence of patients reporting infections and considered by the investigator as related to treatment was greater with Rilonacept Regeneron (9%) than with placebo (0%). In Part B, randomised withdrawal, the incidence of infections were similar in the Rilonacept Regeneron (0%) and the placebo patients (4%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months.
In placebo-controlled studies across a variety of patient populations encompassing 336 patients treated with rilonacept and 165 treated with placebo, the incidence of infections was 6.8% and 3% (0.44 per patient-exposure year and 0.19 per patient-exposure year), respectively, for rilonacept and placebo.
One patient in an open-label study of CAPS died after developing sinusitis and bacterial (Streptococcus pneumoniae) meningitis.
In a study in patients with adult Still’s disease, one patient developed an infection in his elbow with Mycobacterium intracellulare after an intraarticular glucocorticoid injection and subsequent local exposure to a suspected source of mycobacteria. In a study in patients with polymyalgia rheumatica, one patient developed bronchitis and sinusitis, which resulted in hospitalization.
During the initial placebo-controlled portion of the pivotal trial, mean values increased for haemoglobin and decreased for neutrophils and platelets in the patients treated with Rilonacept Regeneron. These changes were not deemed as clinically significant and were potentially due to a decrease in the chronic inflammatory state present in CAPS with an attendant decrease in acute-phase response.
In patients with CAPS, the most common and consistently reported adverse event associated with treatment was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritus, and bruising. Most ISRs lasted for one to two days. In studies of patients with CAPS, no ISRs were assessed as severe, and no patient discontinued study participation due to an ISR.
Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with Rilonacept Regeneron in clinical studies. Nineteen of 55 patients (35%) who had received Rilonacept Regeneron for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19 patients, 7 tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and 5 patients tested positive for neutralising antibodies on at least one occasion. There was no correlation of antibody activity and either clinical efficacy or safety.
The data reflect the percentage of patients whose test results were positive for antibodies to rilonacept in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody positivity in an assay may be influenced by several factors including assay sensitivity and specificity, sample handling, concomitant medicinal products, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading.
Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with Rilonacept Regeneron experienced mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides of 19 mg/dl, 2 mg/dl, 10 mg/dl, and 57 mg/dl respectively after 6 weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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