Reslizumab

1 INDICATIONS AND USAGE CINQAIR ® is indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype [see Clinical Studies ( 14 )] . Limitation of Use: CINQAIR is not indicated for treatment of other eosinophilic conditions. CINQAIR is not indicated for the relief of acute bronchospasm or status asthmaticus [see Warnings and Precautions ( 5.2 )] . CINQAIR is an interleukin-5 antagonist monoclonal antibody (IgG4 kappa) indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype ( 1 ). Limitations of Use : CINQAIR is not indicated for: treatment of other eosinophilic conditions ( 1 ) relief of acute bronchospasm or status asthmaticus ( 1 )

2 DOSAGE AND ADMINISTRATION CINQAIR is for intravenous infusion only. Do not administer as an intravenous push or bolus ( 2.1 ) CINQAIR should be administered by a healthcare professional prepared to manage anaphylaxis ( 2.2 ) Recommended dosage regimen is 3 mg/kg once every 4 weeks by intravenous infusion over 20-50 minutes ( 2.1 ) 2.1 Dosing CINQAIR is for intravenous infusion only. Do not administer as an intravenous push or bolus. The recommended dosage regimen is 3 mg/kg once every 4 weeks administered by intravenous infusion over 20-50 minutes [see Dosage and Administration ( 2.2 )] . Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. 2.2 Preparation and Administration Instructions CINQAIR is provided as a solution in a single-use vial for intravenous infusion only and should be prepared by a healthcare professional using aseptic technique as follows: Preparation of intravenous infusion Remove CINQAIR from the refrigerator. To minimize foaming, do not shake CINQAIR. Inspect visually for particulate matter and discoloration prior to administration. CINQAIR solution is clear to slightly hazy/opalescent, colorless to slightly yellow liquid. Since CINQAIR is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Do not administer if discolored or if other foreign particulate matter is present. Withdraw the proper volume of CINQAIR from the vial(s), based on the recommended weight-based dosage. Discard any unused portion. Dispense syringe contents slowly into an infusion bag containing 50 mL of 0.9% Sodium Chloride Injection, USP to minimize foaming of CINQAIR (CINQAIR 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 immediately after preparation. If not used immediately, store diluted solutions of CINQAIR in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature up to 25ºC (77ºF), protected from light, for up to 16 hours. The time between preparation of CINQAIR and administration should not exceed 16 hours. Administration instructions CINQAIR should be administered by a healthcare professional prepared to manage anaphylaxis [see Warnings and Precautions ( 5.1 )] . If refrigerated prior to administration, allow the diluted CINQAIR solution to reach room temperature. Use an infusion set with an in-line, low protein-binding filter (pore size of 0.2 micron). CINQAIR is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, and cellulose acetate in-line infusion filters. Infuse the diluted solution of CINQAIR intravenously, over a 20 to 50 minute period. Infusion time may vary depending on the total volume to be infused as based upon patient weight. Do not infuse CINQAIR concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of CINQAIR with other agents. Observe the patient over the infusion and for an appropriate period of time following infusion. Upon completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all CINQAIR has been administered.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Anaphylaxis [see Warnings and Precautions ( 5.1 )] Malignancy [see Warnings and Precautions ( 5.3 )] The most common adverse reaction (incidence greater than or equal to 2%) includes oropharyngeal pain. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Overall, 2195 subjects received at least 1 dose of CINQAIR. The data described below reflect exposure to CINQAIR in 1611 patients with asthma, including 1120 exposed for up to 16 weeks, 1006 exposed for 6 months, 759 exposed for 1 year, and 249 exposed for longer than 2 years. The above referenced safety exposure for CINQAIR is derived from placebo-controlled studies ranging from 15 to 52 weeks in duration (CINQAIR 0.3 mg/kg and 3 mg/kg [n=1131] and placebo [n=730]) and 480 new CINQAIR 3 mg/kg exposures (previously on placebo) from a single open-label extension study (n=1051). While a lower dose of CINQAIR 0.3 mg/kg (n=103) was included in a clinical trial, 3 mg/kg is the only recommended dose [see Dosage and Administration ( 2.1 )] . Of the 1611 patients, 1596 received the 3 mg/kg dose, 1028 of which were in the placebo-controlled studies. In the placebo-controlled asthma studies, the population studied was 12 to 76 years of age, 62% female, and 73% white. While subjects aged 12 to 17 years were included in these trials, CINQAIR is not approved for use in this age group [see Use in Specific Populations ( 8.4 )] . Serious adverse reactions that occurred in placebo-controlled studies in more than 1 subject and in a greater percentage of subjects treated with CINQAIR (n=1131) than placebo (n=730) included anaphylaxis (3 subjects vs. 0 subjects, respectively). The 3 subjects who experienced anaphylaxis were discontinued from the clinical studies [see Warnings and Precautions ( 5.1 )] . Malignancy also occurred more commonly in patients treated with CINQAIR than placebo (0.6% and 0.3%, respectively) [see Warnings and Precautions ( 5.3 )] . Adverse reactions that occurred at greater than or equal to 2% incidence and more commonly than in the placebo group included 1 event: oropharyngeal pain (2.6% vs. 2.2%). CPK elevations and muscle-related adverse reactions Elevated baseline creatine phosphokinase (CPK) was more frequent in patients randomized to CINQAIR (14%) versus placebo (9%). Transient CPK elevations in patients with normal baseline CPK values were observed more frequently with CINQAIR (20%) versus placebo (18%) during routine laboratory assessments. CPK elevations >10 x ULN, regardless of baseline CPK value, were 0.8% in the CINQAIR group compared to 0.4% in the placebo group. CPK elevations >10 x ULN were asymptomatic and did not lead to treatment discontinuation. Myalgia was reported in 1% (10/1028) of patients in the CINQAIR 3 mg/kg group compared to 0.5% (4/730) of patients in the placebo group. On the day of infusion, musculoskeletal adverse reactions were reported in 2.2% and 1.5% of patients treated with CINQAIR 3 mg/kg and placebo, respectively. These reactions included (but were not limited to) musculoskeletal chest pain, neck pain, muscle spasms, extremity pain, muscle fatigue, and musculoskeletal pain. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In placebo-controlled studies, a treatment-emergent anti-reslizumab antibody response developed in 53/983 (5.4%) of CINQAIR-treated patients (3 mg/kg). In the long-term, open-label study, treatment-emergent anti-reslizumab antibodies were detected in 49/1014 (4.8%) of CINQAIR-treated (3 mg/kg) asthma patients over 36 months. The antibody responses were of low titer and often transient. Neutralizing antibodies were not evaluated. There was no detectable impact of the antibodies on the clinical pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of CINQAIR [see Clinical Pharmacology ( 12.2 )] . Product-specific IgE antibodies were not detected in patients who reported anaphylactic reactions. The data reflect the percentage of patients whose test results were positive for antibodies to reslizumab in specific assays. The observed incidence of antibody response is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to reslizumab with the incidence of antibodies to other products may be misleading.

12.3 Pharmacokinetics The pharmacokinetics (PK) of reslizumab were characterized in healthy adults (n=130), in patients with asthma (n=438), and in other patient populations (n=236). The PK characteristics of reslizumab were similar across these populations. Inter-individual variability in peak and overall exposure was approximately 20-30%. Peak serum concentrations were typically observed at the end of the infusion. Serum reslizumab concentrations generally declined from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1.5 to 1.9-fold. Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies. Distribution Reslizumab has a volume of distribution of approximately 5 liters, suggesting minimal distribution to the extravascular tissues. Metabolism Similar to other monoclonal antibodies, reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, it is not expected to go through a target-mediated clearance. Elimination Reslizumab clearance was approximately 7 mL/hour. Reslizumab has a half-life of about 24 days. Specific Populations Age, Race, and Gender Population PK analyses demonstrated that there was no significant effect of age, race, or gender on the PK of reslizumab. Hepatic Impairment No clinical studies were conducted to assess the effect of hepatic impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal liver function tests (total bilirubin less than or equal to the ULN and aspartate aminotransferase [AST] less than or equal to the ULN) and 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 ULN and total bilirubin less than or equal to the ULN). Renal Impairment No clinical studies have been conducted to assess the effect of renal impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal renal function (estimated glomerular filtration rate [eGFR] greater than or equal to 90 mL/min/1.73 m 2 ), mild renal impairment (eGFR 60-89 mL/min/1.73 m 2 ), and moderate renal impairment (eGFR 30-59 mL/min/1.73 m 2 ). Drug Interactions In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity. No formal clinical drug interaction studies have been conducted with reslizumab. Population PK analyses indicate that concomitant use of either leukotriene antagonists or corticosteroids does not affect the PK of reslizumab.