Reslizumab (Cinqair) is a humanized monoclonal antibody that targets interleukin 5, inhibiting its action. The drug reduces eosinophil-meditated inflammation of the airways, It is indicated for add-on maintenance treatment of adult patients with severe asthma with an eosinophilic phenotype. During two, randomized, double-blind, placebo-controlled clinical trials, patients who received reslizumab (n = 477) had significant reductions in the rate of all asthma exacerbations compared to placebo (n = 476) (study 1 rate ratio 0.5, 95% CI 0.37 to 0.67; study 2 rate ratio 0.41, 95% CI 0.28 to 0.59). Reslizumab was also associated with reductions in exacerbations requiring systemic corticosteroid use and exacerbations requiring emergency care or hospitalization. Improvements in FEV1 were observed at 4 weeks following the first dose of reslizumab and were maintained throughout the 52-week treatment periods. The FDA approved reslizumab in March 2016.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-For intravenous (IV) infusion administration only. Do not administer via IV push or bolus or by any other route.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Infusion Preparation:
-Remove the appropriate number of vials from refrigeration. To minimize foaming, do not shake reslizumab.
-The solution is a clear to slightly hazy/opalescent, colorless to slightly yellow liquid. Proteinaceous particles may be present that appear as translucent to white, amorphous particulates. Do not use if the solution is discolored or if other foreign particulate matter is present.
-Withdraw the necessary volume of reslizumab based on the weight-based dosage needed. Discard any remaining unused portion in open vials. The vials are for single-use only.
-Must be further diluted prior to administration.
-Inject contents slowly into an infusion bag of 50 mL of 0.9% Sodium Chloride Injection to minimize foaming. Reslizumab is compatible with polyvinylchloride (PVC) or polyolefin infusion bags.
-Gently invert the bag to mix the solution. Do NOT shake. Do not mix or dilute with other drugs.
-Administer the infusion immediately after preparation.
-Storage following dilution: If not used immediately, the prepared infusion may be stored in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F) or at room temperature up to 25 degrees C (77 degrees F), protected from light, for up to 16 hours. The time between preparation of reslizumab and administration should not exceed 16 hours.
Intravenous Infusion Administration:
-Give only in a healthcare setting by professionals prepared to manage anaphylaxis.
-If the infusion was refrigerated prior to use, allow the refrigerated infusion solution to reach room temperature before administration. Do not use a warming device to bring the infusion to room temperature.
-Use an infusion set with an in-line, low protein-binding filter (pore size of 0.2 micron). Reslizumab is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, and cellulose acetate in-line infusion filters.
-Infuse intravenously over 20 to 50 minutes. Infusion time may vary depending on the total volume to be infused.
-Do not infuse reslizumab in the same intravenous line with other agents. No compatibility studies have been conducted to evaluate co-administration with other agents.
-Observe the patient during the infusion and for an appropriate amount of time following the infusion for adverse reactions. Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis, and treat appropriately.
-Flush the intravenous administration set with 0.9% Sodium Chloride Injection to ensure complete administration.
During placebo-controlled trials with reslizumab, anaphylaxis was observed in 3 asthma patients (0.3%) during or within 20 minutes after completion of the reslizumab infusions compared to 0% in the placebo group. These events were reported as early as the second dose of reslizumab. Manifestations included dyspnea, decreased oxygen saturation, hypotension, dizziness, wheezing, vomiting, and skin and mucosal involvement, including rash and urticaria. Reslizumab is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients. Due to the potential risk of serious hypersensitivity reactions or anaphylaxis, administer reslizumab in a healthcare setting by healthcare professionals prepared to manage anaphylaxis. Observe the patient for a clinically appropriate amount of time after administration. If signs or symptoms of anaphylaxis develop, discontinue reslizumab permanently and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur.
During clinical trials of reslizumab, oropharyngeal pain (e.g., pharyngitis) occurred in 2.6% of patients who received reslizumab (n = 1611) vs. 2.2% of patients who received placebo (n = 730). Other less common side effects reported during published clinical trials in adult and pediatric patients for the treatment of severe asthma or other conditions include headache, upper respiratory tract infection, cough, nasal congestion, naso-pharyngitis, sinusitis, and fatigue. The incidence of infection in published studies is similar or less than placebo.
During clinical trials of reslizumab, myalgia occurred in 1% of patients who received reslizumab at a dose of 3 mg/kg (n = 1028) vs. 0.5% of patients who received placebo (n = 730). Musculoskeletal reactions were reported in 2.2% of patients on the day of infusion. These reactions included musculoskeletal chest pain, neck pain, muscle cramps or spasms, extremity pain, muscle fatigue, and musculoskeletal pain. Transient creatine phosphokinase (CPK) elevations in patients with normal baseline CPK values were observed more frequently with reslizumab (20%) vs. placebo (18%). CPK elevations of 10-times the upper limit of normal (ULN) or more occurred in 0.8% of patients given active drug vs. 0.4% of patients given placebo, regardless of baseline CPK values. CPK elevations of 10-times the ULN or more were asymptomatic and did not lead to drug discontinuation.
New primary malignancy occurred more frequently in patients who received reslizumab than placebo during clinical studies (0.6% vs. 0.3%, respectively). Six of 1028 patients who received reslizumab had at least 1 malignant neoplasm reported compared to 2 of 730 patients who received placebo. Most malignancies were diagnosed within 6 months or less after exposure to reslizumab. The neoplasms were diverse in nature, and without a clustering of any specific tissue type.
Anti-reslizumab antibody formation occurred in 4.8% to 5.4% of patients treated with reslizumab during placebo-controlled and open-label clinical trials. Neutralizing antibodies and product-specific IgE antibodies were not evaluated. The clinical relevance of the presence of anti-reslizumab antibodies is unknown; there were no detectable impacts of the antibodies on the clinical pharmacokinetics, pharmacodynamics, efficacy, or safety of reslizumab.
Reslizumab is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients. During placebo-controlled trials with reslizumab, anaphylaxis was observed during or within 20 minutes after completion of the reslizumab infusions. These events were reported as early as the second dose of reslizumab. Due to the potential risk of serious hypersensitivity reactions or anaphylaxis the administration of reslizumab requires a specialized care setting and requires an experienced clinician prepared to manage anaphylaxis. Observe the patient during the infusion and for a clinically appropriate amount of time after administration. If signs or symptoms of anaphylaxis develop, discontinue reslizumab permanently and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should symptoms occur.
Reslizumab should not be used to treat acute asthma symptoms such as acute bronchospasm or status asthmaticus. If deterioration of asthma occurs during therapy with reslizumab, appropriate evaluation of the patient and the treatment strategy is warranted.
Use reslizumab cautiously in patients with a history of systemic neoplastic disease and in patients with a high risk of malignancy. In clinical trials, 0.6% of patients treated with reslizumab, compared to 0.3% of placebo-treated patients, developed a new primary malignancy. The malignancies were diverse and no clustering of any specific tissue type was observed. Most malignancies were diagnosed within 6 months or less after reslizumab exposure.
Treat patients with pre-existing helminth infection prior to initiating therapy with reslizumab. It a patient becomes infected while receiving reslizumab therapy and does not respond to anti-helminth treatment, discontinue reslizumab until the infection resolves. Reslizumab reduces the production and survival of eosinophils, which may be involved in the immunological response to some helminth infections. Although it is unknown whether reslizumab will influence the body's response against parasitic infections, caution is warranted. Patients with known parasitic infections were excluded from clinical trials.
Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with reslizumab. Corticosteroid withdrawal and dosage reduction, if appropriate, should be gradual and performed under healthcare supervision. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Pregnancy exposure data is insufficient to inform on drug-associated risk with reslizumab. Monoclonal antibodies, such as reslizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential fetal effects are likely to be greater during the second and third trimesters. Reslizumab has a long half-life of 24 days; this time should be taken into account when considering exposure during pregnancy. In two development studies conducted in mice and rabbits, there was no evidence of fetal harm with IV reslizumab administration during organogenesis at drug exposures approximately 6 times the maximum recommended human dose (MRHD, 3 mg/kg IV) in rabbits and approximately 17 times the MHRD in mice. In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Asthma control should be closely monitored during pregnancy and treatment adjusted to maintain optimal control.
There is no information regarding the presence of reslizumab in human milk, the effects on the breast-fed infant, or the effects on milk production. Reslizumab is a humanized monoclonal antibody (IgG1 kappa), and human immunoglobulin G (IgG) is present in human milk in small amounts. The FDA-approved product label recommends considering the developmental and health benefits of breast-feeding, the mother's need for reslizumab therapy, and potential adverse effects of the drug or inadequately treated asthma on the breast-fed infant. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
The safety and efficacy of reslizumab have not been established in children and adolescents under 18 years of age. During two, 52-week exacerbation studies in pediatric patients aged 12 to 17 years, the asthma exacerbation rate was higher in those treated with reslizumab (n = 14, rate 2.86, 95% CI 1.02 to 8.09) than with placebo (n = 11, rate 2.09, 95% CI 0.82 to 5.36). Patients who had at least 1 asthma exacerbation requiring systemic corticosteroid treatment in the year proceeding study entry were included in the study. Infants have not been studied.
For asthma maintenance add-on therapy in severe asthma (eosinophilic phenotype):
Adults: 3 mg/kg IV infusion once every 4 weeks. Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis.
Maximum Dosage Limits:
3 mg/kg IV infusion once every 4 weeks.
3 mg/kg IV infusion once every 4 weeks.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
There are no drug interactions associated with Reslizumab products.
Reslizumab is an interleukin-5 antagonist (IgG4, kappa). IL-5 is the major cytokine involved in the growth, differentiation, recruitment, activation, and survival of eosinophils. Eosinophils are one of multiple cell types involved in the inflammatory pathogenesis of asthma. Reslizumab binds to and inhibits the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil surface. Reductions in eosinophil production and survival are produced by the inhibition of IL-5 signaling.
Reslizumab is administered intravenously by infusion. Minimal distribution into extravascular tissues is expected due to a volume of distribution of approximately 5 liters. Reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. It is not expected to go through a target-mediated clearance due to soluble target binding. Reslizumab clearance is approximately 7 mL/hour. The half-life of reslizumab is approximately 24 days.
During clinical studies with reslizumab dose of 3 mg/kg, a 92% reduction in eosinophil counts was observed following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. Early eosinophil reduction (days 2 to 3 post-treatment) was observed in 35 of 245 patients. Eosinophils returned to baseline approximately 120 days after the last dose. Systemic exposure appears to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, CYP2B6, or CYPA4 activity.
Peak and overall exposure to reslizumab after intravenous infusion are similar across patient populations of healthy adults and those with asthma using weight-based dosing. Peak serum concentrations of reslizumab are typically observed at the end of the infusion. Concentrations decline in a biphasic manner. During pharmacokinetic analyses, serum concentrations accumulated 1.5 to 1.9-fold following multiple doses. Greater reductions in eosinophil serum concentrations are produced with higher drug concentrations.
Population pharmacokinetic analysis demonstrated that there was no significant difference in the pharmacokinetics of reslizumab between patients with normal liver function tests, (total bilirubin and AST less than or equal to the upper limit of normal or ULN) and those patients with mildly increased liver function tests (total bilirubin above the ULN and less than or equal to 1.5-times the ULN or AST greater than the ULN and total bilirubin less than or equal to the ULN).
Population pharmacokinetic analysis demonstrated that there was no significant differences in the pharmacokinetics of reslizumab between patients with normal renal function (estimated GFR of 90 mL/minute or more), mild renal impairment (estimated GFR of 60 to 89 mL/minute), and moderate renal impairment (estimated GFR of 30 to 59 mL/minute).
Population pharmacokinetic analysis demonstrated that there was no significant effect of age on the pharmacokinetics of reslizumab.
Population pharmacokinetic analysis demonstrated that there was no significant effect of gender on the pharmacokinetics of reslizumab.
Population pharmacokinetic analysis demonstrated that there was no significant effect of race on the pharmacokinetics of reslizumab.