Rilonacept interacts in the following cases:
No data are available on either the effects of live vaccination or the secondary transmission of infection by live vaccines in patients receiving rilonacept. Therefore, live vaccines should not be given concurrently with rilonacept, unless the benefits clearly outweigh the risks. Should vaccination with live vaccines be indicated after initiation of rilonacept treatment, the recommendation is to wait for at least 6 weeks after the last rilonacept injection and before the next one.
The concomitant administration of rilonacept with any TNF inhibitor is not recommended, 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 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, 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.
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 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 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. If a patient becomes neutropenic the ANC should be monitored closely and treatment discontinuation should be considered.
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. The risk for the foetus/mother is unknown. Women should use effective contraceptives during treatment with rilonacept 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 should be made taking into account the benefit of breast-feeding to the child and the benefit of rilonacept 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 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 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."
Adverse reactions with rilonacept 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, the incidence of patients reporting infections and considered by the investigator as related to treatment was greater with rilonacept (9%) than with placebo (0%). In Part B, randomised withdrawal, the incidence of infections were similar in the rilonacept (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. 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 in clinical studies. Nineteen of 55 patients (35%) who had received rilonacept 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 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.
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