DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oAdminister by subcutaneous injection. (2)oRecommended dosage is 210 mg administered once every weeks. (2). oAdminister by subcutaneous injection. (2). oRecommended dosage is 210 mg administered once every weeks. (2). 2.1 Recommended Dosage The recommended dosage of TEZSPIRE is 210 mg administered subcutaneously once every weeks.Missed Dose InformationIf dose is missed, administer the dose as soon as possible. Thereafter, the patient can continue (resume) dosing on the usual day of administration. If the next dose is already due, then administer as planned.. 2.2 Preparation and Administration Instructions TEZSPIRE is intended for administration by healthcare provider.Each vial and pre-filled syringe contains single dose of TEZSPIRE.oPrior to administration, remove TEZSPIRE from the refrigerator and allow it to reach room temperature. This generally takes 60 minutes. Do not expose to heat and do not shake. Do not use if the security seal on the carton has been broken. Do not put back in the refrigerator once TEZSPIRE has reached room temperature. After removal from the refrigerator, TEZSPIRE must be used within 30 days or discarded [see How Supplied/Storage and Handling (16)]. oVisually inspect TEZSPIRE for particulate matter and discoloration prior to administration. TEZSPIRE is clear to opalescent, colorless to light yellow solution. Do not use TEZSPIRE if liquid is cloudy, discolored, or if it contains large particles or foreign particulate matter. Do not use if the vial or pre-filled syringe has been dropped or damaged or if the expiration date has passed.oInject TEZSPIRE 210 mg (contents of one vial or one pre-filled syringe as described below) subcutaneously into the upper arm, thigh, or abdomen, except for the inches (5 cm) around the navel. TEZSPIRE should not be injected into areas where the skin is tender, bruised, erythematous, or hardened. It is recommended to rotate the injection site with each injection.Administration Instructions for Single-Dose Pre-filled SyringeRefer to Figure to identify the pre-filled syringe components for use in the administration steps. Do not remove the needle cover until Step of these instructions when you are ready to inject TEZSPIRE. Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard.Figure TEZSPIRE Pre-filled Syringe Components1.Grasp the syringe body to remove the pre-filled syringe from its tray. Do not grab the pre-filled syringe by the plunger.The pre-filled syringe may contain small air bubbles; this is normal. Do not expel the air bubbles prior to administration. 2.Do not remove the needle cover until ready to inject. Hold the syringe body and remove the needle cover by pulling straight off. Do not hold the plunger or plunger head while removing the needle cover. You may see drop of liquid at the end of the needle. This is normal. 3.Gently pinch the skin and administer subcutaneously at approximately 45 angle into the recommended injection site (i.e., upper arm, thigh, or abdomen). 4.Inject all of the medication by pushing in the plunger all the way until the plunger head is completely between the needle guard activation clips. This is necessary to activate the needle guard. 5.After injection, maintain pressure on the plunger head and remove the needle from the skin. Release pressure on the plunger head to allow the needle guard to cover the needle. Do not re-cap the pre-filled syringe. 6. Discard the used syringe into sharps container.. oPrior to administration, remove TEZSPIRE from the refrigerator and allow it to reach room temperature. This generally takes 60 minutes. Do not expose to heat and do not shake. Do not use if the security seal on the carton has been broken. Do not put back in the refrigerator once TEZSPIRE has reached room temperature. After removal from the refrigerator, TEZSPIRE must be used within 30 days or discarded [see How Supplied/Storage and Handling (16)]. oVisually inspect TEZSPIRE for particulate matter and discoloration prior to administration. TEZSPIRE is clear to opalescent, colorless to light yellow solution. Do not use TEZSPIRE if liquid is cloudy, discolored, or if it contains large particles or foreign particulate matter. Do not use if the vial or pre-filled syringe has been dropped or damaged or if the expiration date has passed.. oInject TEZSPIRE 210 mg (contents of one vial or one pre-filled syringe as described below) subcutaneously into the upper arm, thigh, or abdomen, except for the inches (5 cm) around the navel. TEZSPIRE should not be injected into areas where the skin is tender, bruised, erythematous, or hardened. It is recommended to rotate the injection site with each injection.. 1.Grasp the syringe body to remove the pre-filled syringe from its tray. Do not grab the pre-filled syringe by the plunger.The pre-filled syringe may contain small air bubbles; this is normal. Do not expel the air bubbles prior to administration.. 2.. 3.. 4.. 5.. 6. Discard the used syringe into sharps container.. Figure1. Number3picture. number4picture. number5picture. number6picture.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling:oHypersensitivity [seeWarnings and Precautions (5.1)]. oHypersensitivity [seeWarnings and Precautions (5.1)]. Most common adverse reactions (incidence >= 3%) are pharyngitis, arthralgia, and back pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of TEZSPIRE was based on the pooled safety population from PATHWAY and NAVIGATOR, which consists of 665 adult and pediatric patients 12 years of age and older with severe asthma who received at least one dose of TEZSPIRE 210 mg subcutaneously once every weeks. The two placebo-controlled clinical trials were of 52 weeks duration. In addition, similar safety profile was seen in trial that enrolled 150 adult patients with severe asthma who required treatment with daily oral corticosteroids [see Clinical Studies (14)].Adverse reactions that occurred at an incidence greater than or equal to 3% and more common than in the placebo group from the pooled safety population (PATHWAY and NAVIGATOR) are shown in Table 1.Table Adverse Reactions with TEZSPIRE with Incidence Greater than or Equal to 3% and More Common than Placebo in Patients with Severe Asthma in the Pooled Safety Population (PATHWAY and NAVIGATOR)Adverse ReactionTEZSPIREN=665%PlaceboN=669%PharyngitisPharyngitis (including Pharyngitis, Pharyngitis bacterial, Pharyngitis streptococcal and Viral pharyngitis) 43Arthralgia43Back pain43Specific Adverse ReactionInjection Site ReactionsIn the pooled safety population, injection site reactions (e.g., injection site erythema, injection site swelling, injection site pain) occurred at rate of 3.3% in patients treated with TEZSPIRE compared with 2.7% in patients treated with placebo.. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies described below with the incidence of antibodies in other studies or to other tezepelumab products may be misleading.In NAVIGATOR and an additional trial, anti-drug antibodies (ADA) were detected at any time in 29 (5%) out of 601 patients who received TEZSPIRE at the recommended dosing regimen during the 48 to 52-week study period. Of these 29 patients, 11 patients (2% of patients treated with TEZSPIRE) developed treatment-emergent antibodies and patient (<1% of patients treated with TEZSPIRE) developed neutralizing antibodies. ADA titers were generally low and often transient. No evidence of ADA impact on pharmacokinetics, pharmacodynamics, efficacy, or safety was observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Tezepelumab-ekko is thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody IgG2 that binds to human TSLP with dissociation constant of 15.8 pM and blocks its interaction with the heterodimeric TSLP receptor. TSLP is cytokine mainly derived from epithelial cells and occupies an upstream position in the asthma inflammatory cascade.Airway inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes, ILC2 cells) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in airway inflammation. Blocking TSLP with tezepelumab-ekko reduces biomarkers and cytokines associated with inflammation including blood eosinophils, airway submucosal eosinophils, IgE, FeNO, IL-5, and IL-13; however, the mechanism of tezepelumab-ekko action in asthma has not been definitively established. 12.2 Pharmacodynamics In NAVIGATOR, administration of TEZSPIRE 210 mg subcutaneously every weeks (n=528) reduced blood eosinophils counts, FeNO, IL-5 concentration and IL-13 concentration from baseline compared with placebo (n=531) with an onset of effect weeks after initiation of treatment and sustained reduction on treatment to 52 weeks. TEZSPIRE caused slow but progressive reduction in serum total IgE concentration throughout 52 weeks of treatment. Similar effects were seen in PATHWAY.. 12.3 Pharmacokinetics The pharmacokinetics of tezepelumab-ekko were dose-proportional following administration of single subcutaneous dose over dose range from 2.1 mg to 420 mg (0.01 to times the recommended dose). With an every weeks dosing regimen, tezepelumab-ekko achieves steady-state after 12 weeks and the accumulation ratio for Ctrough is 1.86-fold. AbsorptionFollowing subcutaneous administration, the maximum serum concentration was reached in approximately to 10 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 77%. There was no clinically relevant difference in bioavailability when administered to different injection sites (abdomen, thigh, or upper arm). DistributionBased on population pharmacokinetic analysis, central and peripheral volume of distribution of tezepelumab-ekko were 3.9 and 2.2 L, respectively, for 70 kg individual. EliminationAs human monoclonal antibody, tezepelumab-ekko is eliminated by intracellular catabolism and there is no evidence of target-mediated clearance within the studied dose range. Based on population pharmacokinetic analysis, the estimated clearance for tezepelumab-ekko was 0.17 L/d for 70 kg individual. The elimination half-life was approximately 26 days. MetabolismTezepelumab-ekko is human monoclonal antibody (IgG2) that is degraded by proteolytic enzymes widely distributed in the body and not metabolized by hepatic enzymes. Specific PopulationsAge, Sex, RaceBased on population pharmacokinetic analysis, age (12 to 80 years), sex and race (White, Black, Asian, Other) had no clinically meaningful effects on the pharmacokinetics of tezepelumab-ekko. Body WeightBased on population pharmacokinetic analysis, higher body weight was associated with lower exposure. However, the effect of body weight on exposure had no meaningful impact on efficacy or safety and does not require dose adjustment. Patients with Renal impairmentNo formal clinical studies have been conducted to investigate the effect of renal impairment on tezepelumab-ekko. The population pharmacokinetic analysis included 320 (23%) subjects with mild renal impairment and 38 (3%) subjects with moderate renal impairment. Tezepelumab-ekko clearance was similar in patients with mild renal impairment (estimated creatinine clearance 60 to 89 mL/min), moderate renal impairment (estimated creatinine clearance 30 to 59 mL/min) and those with normal renal function (estimated creatinine clearance >= 90 mL/min). Tezepelumab-ekko has not been studied in patients with severe renal impairment (estimated creatinine clearance 30 mL/min). Patients with Hepatic impairment No formal clinical studies have been conducted to investigate the effect of hepatic impairment on tezepelumab-ekko. Since tezepelumab-ekko is degraded by proteolytic enzymes widely distributed in the body and not metabolized by hepatic-specific enzymes, change in hepatic function is not expected to influence tezepelumab-ekko clearance. Drug Interaction StudiesNo formal drug interaction studies have been conducted with tezepelumab-ekko. Based on the population pharmacokinetic analysis, commonly co-administered asthma medications (leukotriene receptor antagonist, theophylline/aminophylline, oral and inhaled corticosteroid) had no clinically meaningful effect on tezepelumab-ekko clearance.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of TEZSPIRE was evaluated in two randomized, double-blind, parallel group, placebo-controlled clinical trials (PATHWAY [NCT02054130] and NAVIGATOR [NCT03347279]) of 52 weeks duration. The two trials enrolled total of 1609 patients 12 years of age and older with severe asthma. PATHWAY was 52-week dose-ranging exacerbation trial that enrolled 550 adult patients with severe asthma who received treatment with tezepelumab-ekko 70 mg subcutaneously every weeks, TEZSPIRE 210 mg subcutaneously every weeks, tezepelumab-ekko 280 mg subcutaneously every weeks, or placebo subcutaneously. Patients were required to have history of or more asthma exacerbations requiring oral or injectable corticosteroid treatment or asthma exacerbation resulting in hospitalization in the past 12 months. NAVIGATOR was 52-week exacerbation trial that enrolled 1061 patients (adult and pediatric patients 12 years of age and older) with severe asthma who received treatment with TEZSPIRE 210 mg subcutaneously every weeks or placebo subcutaneously every weeks. Patients were required to have history of or more asthma exacerbations requiring oral or injectable corticosteroid treatment or resulting in hospitalization in the past 12 months. In both PATHWAY and NAVIGATOR, patients were required to have an Asthma Control Questionnaire (ACQ-6) score of 1.5 or more at screening and reduced lung function at baseline [pre-bronchodilator forced expiratory volume in second (FEV1) below 80% predicted in adults, and below 90% predicted in adolescents]. Patients were required to have been on regular treatment with medium or high-dose inhaled corticosteroids (ICS) and at least one additional asthma controller, with or without oral corticosteroids (OCS). Patients continued background asthma therapy throughout the duration of the trials. In both trials, patients were enrolled without requiring minimum baseline level of blood eosinophils or FeNO.The demographics and baseline characteristics of PATHWAY and NAVIGATOR are provided in Table below.Table Demographics and Baseline Characteristics of Patients in PATHWAY and NAVIGATORPATHWAYN=550NAVIGATORN=1059Mean age (year) (SD) 52 (12)50 (16)Female (%)6664White (%)9262Black or African American (%)36Asian (%)328Hispanic or Latino (%)115Never smoked (%)8180High-dose ICS use (%)4975OCS use (%)99Mean number of exacerbations in previous year (SD)2.4 (1.2)2.8 (1.4)Mean duration of asthma (years) (SD)17 (12)22 (16)Mean baseline predicted FEV1 (SD)60 (13)63 (18)Mean post-bronchodilator FEV1 reversibility (%) (SD)23 (20)15 (15)Mean baseline blood EOS count (cells/uL) (SD)371 (353)340 (403)Positive serum specific IgE to any perennial allergen (%)in the FEIA panel 4664Mean FeNO (ppb) (SD) 35 (39)44 (41) EOS, Eosinophils; FEIA, Fluorescent enzyme immunoassay; FeNO, Fractional exhaled nitric oxide; FEV1, Forced expiratory volume in one second; ICS, Inhaled corticosteroid, IgE, Immunoglobulin E; OCS, Oral corticosteroid; ppb, Parts per billion; SD, Standard deviation.The results summarized below are for the recommended TEZSPIRE 210 mg subcutaneously every weeks dosing regimen.ExacerbationsThe primary endpoint for PATHWAY and NAVIGATOR was the rate of clinically significant asthma exacerbations measured over 52 weeks. Clinically significant asthma exacerbations were defined as worsening of asthma requiring the use of or increase in oral or injectable corticosteroids for at least days, or single depo-injection of corticosteroids, and/or emergency department visits requiring use of oral or injectable corticosteroids and/or hospitalization.In both PATHWAY and NAVIGATOR, patients receiving TEZSPIRE had significant reductions in the annualized rate of asthma exacerbations compared to placebo. There were also fewer exacerbations requiring emergency room visits and/or hospitalization in patients treated with TEZSPIRE compared with placebo (Table 3).Table Rate of Clinically Significant Exacerbations Over 52 Weeks in PATHWAY and NAVIGATORTrialTreatmentExacerbations per yearRateRate Ratio (95% CI)Annualized Asthma Exacerbation RatePATHWAY TEZSPIRE (N=137)0.200.29 (0.16, 0.51)Placebo (N=138)0.72NAVIGATOR TEZSPIRE (N=528)0.930.44 (0.37, 0.53)Placebo (N=531)2.10Exacerbations requiring emergency room visit/hospitalizationPATHWAYTEZSPIRE (N=137)0.030.15 (0.04, 0.58)Placebo (N=138)0.18NAVIGATORTEZSPIRE (N=528)0.060.21 (0.12, 0.37)Placebo (N=531)0.28Exacerbations requiring hospitalizationPATHWAYTEZSPIRE (N=137)0.020.14 (0.03, 0.71)Placebo (N=138)0.14NAVIGATORTEZSPIRE (N=528)0.030.15 (0.07, 0.22)Placebo (N=531)0.19In NAVIGATOR, patients receiving TEZSPIRE experienced fewer exacerbations than those receiving placebo regardless of baseline levels of blood eosinophils or FeNO (Figure 2). Similar results were seen in PATHWAY.Figure Annualized Asthma Exacerbation Rate Ratio Over 52 Weeks Across Different Baseline Biomarkers in NAVIGATORThe time to first exacerbation was longer for the patients receiving TEZSPIRE compared with placebo in NAVIGATOR (Figure 3). Similar findings were seen in PATHWAY.Figure Kaplan-Meier Cumulative Incidence Curves for Time to First Exacerbation in NAVIGATOR Lung FunctionChange from baseline in FEV1 was assessed as secondary endpoint in PATHWAY and NAVIGATOR. Compared with placebo, TEZSPIRE provided clinically meaningful improvements in the mean change from baseline in FEV1 in both trials (Table 4).Table Mean Change from Baseline in Pre-Bronchodilator FEV1 at End of Trial in PATHWAY and NAVIGATORWeek 52 in PATHWAY, Week 52 in NAVIGATOR TrialTreatmentLS Mean Change from Baseline (L)Difference from Placebo(95% CI)PATHWAYTEZSPIRE (N=133)Number of patients contributing to the full analysis (FA) with at least change from baseline value 0.080.13 (0.03, 0.23)Placebo (N=138) -0.06NAVIGATORTEZSPIRE (N=527) 0.230.13 (0.08, 0.18)Placebo (N=531) 0.10In NAVIGATOR, improvement in FEV1 was seen as early as weeks after initiation of treatment and was sustained through week 52 (Figure 4).Figure Mean Change (95% CI) from Baseline in Pre-Bronchodilator FEV1 (L) in NAVIGATORPatient Reported OutcomesChanges from baseline in Asthma Control Questionnaire (ACQ-6) and Standardized Asthma Quality of Life Questionnaire for ages 12 and older [AQLQ(S)+12] were also assessed as secondary endpoints in PATHWAY and NAVIGATOR. In both trials, more patients treated with TEZSPIRE compared to placebo had clinically meaningful improvement in ACQ-6 and AQLQ(S)+12. Clinically meaningful improvement (responder rate) for both measures was defined as improvement in score of 0.5 or more at end of trial. In NAVIGATOR, the ACQ-6 responder rate for TEZSPIRE was 86% compared with 77% for placebo (OR=1.99; 95% CI 1.43, 2.76) and the AQLQ(S)+12 responder rate for TEZSPIRE was 78% compared with 72% for placebo (OR=1.36; 95% CI 1.02, 1.82). Similar findings were seen in PATHWAY. Additional Trial In randomized, double-blind, parallel group, placebo-controlled clinical trial, the effect of TEZSPIRE (210 mg subcutaneously every weeks) on reducing the use of maintenance OCS was evaluated. The trial enrolled 150 adult patients with severe asthma who required treatment with daily OCS (7.5 mg to 30 mg per day) in addition to regular use of high-dose ICS and long-acting beta-agonist with or without additional controller(s). The primary endpoint was categorized percent reduction from baseline of the final OCS dose at Week 48 (>=90% reduction, >=75% to <90% reduction, >=50% to <75% reduction, >0% to <50 reduction, and no change or no decrease in OCS), while maintaining asthma control. TEZSPIRE did not demonstrate statistically significant reduction in maintenance OCS dose compared with placebo (cumulative OR=1.28; 95% CI 0.69, 2.35).. EOS, Eosinophils; FEIA, Fluorescent enzyme immunoassay; FeNO, Fractional exhaled nitric oxide; FEV1, Forced expiratory volume in one second; ICS, Inhaled corticosteroid, IgE, Immunoglobulin E; OCS, Oral corticosteroid; ppb, Parts per billion; SD, Standard deviation.. figure2. figure3. figure4.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of tezepelumab-ekko were dose-proportional following administration of single subcutaneous dose over dose range from 2.1 mg to 420 mg (0.01 to times the recommended dose). With an every weeks dosing regimen, tezepelumab-ekko achieves steady-state after 12 weeks and the accumulation ratio for Ctrough is 1.86-fold. AbsorptionFollowing subcutaneous administration, the maximum serum concentration was reached in approximately to 10 days. Based on population pharmacokinetic analysis, the estimated absolute bioavailability was approximately 77%. There was no clinically relevant difference in bioavailability when administered to different injection sites (abdomen, thigh, or upper arm). DistributionBased on population pharmacokinetic analysis, central and peripheral volume of distribution of tezepelumab-ekko were 3.9 and 2.2 L, respectively, for 70 kg individual. EliminationAs human monoclonal antibody, tezepelumab-ekko is eliminated by intracellular catabolism and there is no evidence of target-mediated clearance within the studied dose range. Based on population pharmacokinetic analysis, the estimated clearance for tezepelumab-ekko was 0.17 L/d for 70 kg individual. The elimination half-life was approximately 26 days. MetabolismTezepelumab-ekko is human monoclonal antibody (IgG2) that is degraded by proteolytic enzymes widely distributed in the body and not metabolized by hepatic enzymes. Specific PopulationsAge, Sex, RaceBased on population pharmacokinetic analysis, age (12 to 80 years), sex and race (White, Black, Asian, Other) had no clinically meaningful effects on the pharmacokinetics of tezepelumab-ekko. Body WeightBased on population pharmacokinetic analysis, higher body weight was associated with lower exposure. However, the effect of body weight on exposure had no meaningful impact on efficacy or safety and does not require dose adjustment. Patients with Renal impairmentNo formal clinical studies have been conducted to investigate the effect of renal impairment on tezepelumab-ekko. The population pharmacokinetic analysis included 320 (23%) subjects with mild renal impairment and 38 (3%) subjects with moderate renal impairment. Tezepelumab-ekko clearance was similar in patients with mild renal impairment (estimated creatinine clearance 60 to 89 mL/min), moderate renal impairment (estimated creatinine clearance 30 to 59 mL/min) and those with normal renal function (estimated creatinine clearance >= 90 mL/min). Tezepelumab-ekko has not been studied in patients with severe renal impairment (estimated creatinine clearance 30 mL/min). Patients with Hepatic impairment No formal clinical studies have been conducted to investigate the effect of hepatic impairment on tezepelumab-ekko. Since tezepelumab-ekko is degraded by proteolytic enzymes widely distributed in the body and not metabolized by hepatic-specific enzymes, change in hepatic function is not expected to influence tezepelumab-ekko clearance. Drug Interaction StudiesNo formal drug interaction studies have been conducted with tezepelumab-ekko. Based on the population pharmacokinetic analysis, commonly co-administered asthma medications (leukotriene receptor antagonist, theophylline/aminophylline, oral and inhaled corticosteroid) had no clinically meaningful effect on tezepelumab-ekko clearance.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no available data on TEZSPIRE use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Placental transfer of monoclonal antibodies such as tezepelumab-ekko is greater during the third trimester of pregnancy; therefore, potential effects on fetus are likely to be greater during the third trimester of pregnancy. In an enhanced pre- and post-natal development (ePPND) study conducted in cynomolgus monkeys, placental transport of tezepelumab-ekko was observed but there was no evidence of fetal harm following intravenous administration of tezepelumab-ekko throughout pregnancy at doses that produced maternal exposures up to 168 times the exposure at the maximum recommended human dose (MRHD) of 210 mg administered subcutaneously [see Data]. The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.DataAnimal DataIn the ePPND study, pregnant cynomolgus monkeys received tezepelumab-ekko from GD20 to GD22 (dependent on pregnancy determination), at the beginning of organogenesis, and once every days until the end of gestation at doses that produced exposures up to 168 times that achieved with the MRHD (on an AUC basis with maternal intravenous doses up to 300 mg/kg/week). There were no tezepelumab-ekko related adverse effects on maternal health, pregnancy outcome, embryo-fetal development, or neonatal growth and development up to 6.5 months of age. Tezepelumab-ekko crossed the placenta in cynomolgus monkeys and tezepelumab-ekko serum concentrations were 0.5- to 6.7-fold higher in infants relative to maternal animals.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONTEZSPIRE(TM) (TEZ-SPY-ER)(tezepelumab-ekko)injection, for subcutaneous useWhat is TEZSPIRETEZSPIRE is prescription medicine used with other asthma medicines for the maintenance treatment of severe asthma in people 12 years of age and older whose asthma is not controlled with their current asthma medicine. TEZSPIRE helps prevent severe asthma attacks (exacerbations) and can improve your breathing.TEZSPIRE is not used to treat sudden breathing problems. Tell your healthcare provider if your asthma does not get better or if it gets worse after you start treatment with TEZSPIRE.It is not known if TEZSPIRE is safe and effective in children under 12 years of age.Do not receive TEZSPIRE if you:oare allergic to tezepelumab or any of the ingredients in TEZSPIRE. See the end of this Patient Information leaflet for complete list of ingredients in TEZSPIRE.Before you receive TEZSPIRE, tell your healthcare provider about all of your medical conditions, including if you:ohave ever had severe allergic reaction (hypersensitivity). ohave parasitic (helminth) infection.ohave recently received or are scheduled to receive any live attenuated vaccinations. People who receive TEZSPIRE should not receive live attenuated vaccines.oare pregnant, think you may be pregnant, or plan to become pregnant. It is not known if TEZSPIRE may harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if TEZSPIRE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive TEZSPIRE.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not change or stop your corticosteroid medicines or other asthma medicines unless your healthcare provider tells you to. How will receive TEZSPIREoYour healthcare provider will give you TEZSPIRE in healthcare setting.oTEZSPIRE is injected under your skin (subcutaneously) time every weeks.oIf you miss an appointment, ask your healthcare provider when to schedule your next treatment.What are the possible side effects of TEZSPIRETEZSPIRE may cause serious side effects, including:osevere allergic reactions. Call your healthcare provider or get emergency medical care if you getany of the following symptoms of allergic reaction:rashhivesbreathing problemsred, itchy, swollen, or inflamed eyesThe most common side effects of TEZSPIRE include:osore throat (pharyngitis)ojoint pain (arthralgia)oback painThese are not all of the possible side effects of TEZSPIRE. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of TEZSPIREMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about TEZSPIRE that is written for health professionals.What are the ingredients in TEZSPIREActive ingredient: tezepelumab-ekkoInactive ingredients: glacial acetic acid, L-proline, polysorbate 80, sodium hydroxide, and water for injectionManufactured by:AstraZeneca AB, Sodertalje, Sweden SE-15185US License No. 2059At: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799Marketed by: Amgen Inc. and AstraZeneca AB(C)AstraZeneca and Amgen 2021TEZSPIRE is trademark of Amgen Inc.For more information, go to https://www.TEZSPIRE.com or call 1-800-236-9933. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 12/2021. oare allergic to tezepelumab or any of the ingredients in TEZSPIRE. See the end of this Patient Information leaflet for complete list of ingredients in TEZSPIRE.. ohave ever had severe allergic reaction (hypersensitivity). ohave parasitic (helminth) infection.. ohave recently received or are scheduled to receive any live attenuated vaccinations. People who receive TEZSPIRE should not receive live attenuated vaccines.. oare pregnant, think you may be pregnant, or plan to become pregnant. It is not known if TEZSPIRE may harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if TEZSPIRE passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you receive TEZSPIRE.. oYour healthcare provider will give you TEZSPIRE in healthcare setting.. oTEZSPIRE is injected under your skin (subcutaneously) time every weeks.. oIf you miss an appointment, ask your healthcare provider when to schedule your next treatment.. osevere allergic reactions. Call your healthcare provider or get emergency medical care if you getany of the following symptoms of allergic reaction:. rash. hives. breathing problems. red, itchy, swollen, or inflamed eyes. osore throat (pharyngitis). ojoint pain (arthralgia). oback pain.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryThere are no available data on TEZSPIRE use in pregnant women to evaluate for any drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Placental transfer of monoclonal antibodies such as tezepelumab-ekko is greater during the third trimester of pregnancy; therefore, potential effects on fetus are likely to be greater during the third trimester of pregnancy. In an enhanced pre- and post-natal development (ePPND) study conducted in cynomolgus monkeys, placental transport of tezepelumab-ekko was observed but there was no evidence of fetal harm following intravenous administration of tezepelumab-ekko throughout pregnancy at doses that produced maternal exposures up to 168 times the exposure at the maximum recommended human dose (MRHD) of 210 mg administered subcutaneously [see Data]. The estimated background risk of major birth defects and miscarriages for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryo/fetal risk: In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.DataAnimal DataIn the ePPND study, pregnant cynomolgus monkeys received tezepelumab-ekko from GD20 to GD22 (dependent on pregnancy determination), at the beginning of organogenesis, and once every days until the end of gestation at doses that produced exposures up to 168 times that achieved with the MRHD (on an AUC basis with maternal intravenous doses up to 300 mg/kg/week). There were no tezepelumab-ekko related adverse effects on maternal health, pregnancy outcome, embryo-fetal development, or neonatal growth and development up to 6.5 months of age. Tezepelumab-ekko crossed the placenta in cynomolgus monkeys and tezepelumab-ekko serum concentrations were 0.5- to 6.7-fold higher in infants relative to maternal animals.. 8.2 Lactation Risk SummaryThere is no information regarding the presence of tezepelumab-ekko in human milk, its effects on the breastfed infant, or its effects on milk production. However, tezepelumab-ekko is human monoclonal antibody immunoglobulin G2 (IgG2), and immunoglobulin (IgG) is present in human milk in small amounts. Tezepelumab-ekko was present in the milk of cynomolgus monkeys postpartum following dosing during pregnancy [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TEZSPIRE and any potential adverse effects on the breastfed infant from TEZSPIRE or from the underlying maternal condition. DataAnimal DataIn prenatal and postnatal development study in cynomolgus monkeys, tezepelumab-ekko concentrations in milk were up to 0.5% of the maternal serum concentrations after intravenous administration of tezepelumab-ekko up to 300 mg/kg/week (168 times the exposures based on AUC achieved at MRHD). The concentration of tezepelumab-ekko in animal milk does not necessarily predict the concentration of drug in human milk.. 8.4 Pediatric Use The safety and effectiveness of TEZSPIRE for the add-on maintenance treatment of severe asthma have been established in pediatric patients aged 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14)] Use of TEZSPIRE for this indication is supported by evidence from total of 82 pediatric patients aged 12 to 17 years enrolled in NAVIGATOR and received treatment with TEZSPIRE 210 mg subcutaneously every weeks (n=41) or placebo (n=41). Compared with placebo, improvements in annualized asthma exacerbation (rate ratio 0.70; 95% CI 0.34, 1.46) and FEV1 (LS mean change versus placebo 0.17 L; 95% CI -0.01, 0.35) were observed in pediatric patients treated with TEZSPIRE. The safety profile and pharmacodynamic responses in pediatric patients were generally similar to the overall study population. The safety and effectiveness in patients younger than 12 years of age have not been established.. 8.5 Geriatric Use Of the 665 patients with asthma treated with TEZSPIRE in clinical trials (PATHWAY and NAVIGATOR) for severe asthma, 119 patients (18%) were 65 years or older. No overall differences in safety or effectiveness of TEZSPIRE have been observed between patients 65 years of age and older and younger patients [see Adverse Reactions (6.1) and Clinical Studies (14)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity Reactions: Hypersensitivity reactions (e.g., rash, allergic conjunctivitis) can occur after administration of TEZSPIRE. Initiate appropriate treatment as clinically indicated in the event of hypersensitivity reaction. (5.1)oRisk Associated with Abrupt Reduction in Corticosteroid Dosage: Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with TEZSPIRE. Decrease corticosteroids gradually, if appropriate. (5.3)oParasitic (Helminth) Infection: Treat patients with pre-existing helminth infections before therapy with TEZSPIRE. If patients become infected while receiving TEZSPIRE and do not respond to anti-helminth treatment, discontinue TEZSPIRE until the parasitic infection resolves. (5.4)oVaccination: Avoid use of live attenuated vaccines. (5.5). oHypersensitivity Reactions: Hypersensitivity reactions (e.g., rash, allergic conjunctivitis) can occur after administration of TEZSPIRE. Initiate appropriate treatment as clinically indicated in the event of hypersensitivity reaction. (5.1). oRisk Associated with Abrupt Reduction in Corticosteroid Dosage: Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with TEZSPIRE. Decrease corticosteroids gradually, if appropriate. (5.3). oParasitic (Helminth) Infection: Treat patients with pre-existing helminth infections before therapy with TEZSPIRE. If patients become infected while receiving TEZSPIRE and do not respond to anti-helminth treatment, discontinue TEZSPIRE until the parasitic infection resolves. (5.4). oVaccination: Avoid use of live attenuated vaccines. (5.5). 5.1 Hypersensitivity Reactions Hypersensitivity reactions (e.g., rash and allergic conjunctivitis) can occur following administration of TEZSPIRE [see Contraindications (4) and Adverse Reactions (6)]. These reactions can occur within hours of administration, but in some instances have delayed onset (i.e., days). In the event of hypersensitivity reaction, consider the benefits and risks for the individual patient to determine whether to continue or discontinue treatment with TEZSPIRE.. 5.2 Acute Asthma Symptoms or Deteriorating Disease TEZSPIRE should not be used to treat acute asthma symptoms or acute exacerbations. Do not use TEZSPIRE to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with TEZSPIRE.. 5.3 Risk Associated with Abrupt Reduction of Corticosteroid Dosage Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with TEZSPIRE. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the direct supervision of physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.. 5.4 Parasitic (Helminth) Infection Thymic stromal lymphopoietin (TSLP) may be involved in the immunological response to some helminth infections. Patients with known helminth infections were excluded from participation in clinical trials. It is unknown if TEZSPIRE will influence patients response against helminth infections. Treat patients with pre-existing helminth infections before initiating therapy with TEZSPIRE. If patients become infected while receiving treatment with TEZSPIRE and do not respond to anti-helminth treatment, discontinue treatment with TEZSPIRE until infection resolves.. 5.5 Live Attenuated Vaccines The concomitant use of TEZSPIRE and live attenuated vaccines has not been evaluated. The use of live attenuated vaccines should be avoided in patients receiving TEZSPIRE.

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USETEZSPIRE(R) (TEZ-SPY-ER)(tezepelumab-ekko)injection, for subcutaneous useSingle-dose Pre-filled penThis Instructions for Use contains information on how to inject TEZSPIRE.Before using your TEZSPIRE pre-filled pen, your healthcare provider should show you or your caregiver how to use it the right way.Read this Instructions for Use before you start using your TEZSPIRE pre-filled pen and each time you get refill. There may be new information. This information should not replace talking to your healthcare provider about your medical condition and your treatment.If you or your caregiver have any questions, talk to your healthcare provider.Important information you need to know before injecting TEZSPIREStore TEZSPIRE in refrigerator between 36F to 46F (2C to 8C) in its original carton until you are ready to use it.TEZSPIRE may be kept at room temperature between 68F to 77F (20C to 25C) for maximum of 30 days.Store TEZSPIRE in the original carton to protect it from light.When TEZSPIRE has reached room temperature, do not put it back in the refrigerator.Throw away (dispose of) TEZSPIRE that has been stored at room temperature for more than 30 days.Do not use your TEZSPIRE pre-filled pen if:oit has been frozenoit has been dropped or damagedothe security seal on the carton has been brokenothe expiration date (EXP) has passedDo not:ofreeze your pre-filled pen or expose it to heatoshake your pre-filled penoshare, or use your pre-filled pen more than time.If any of the above happens, throw away the pre-filled pen in puncture-resistant (sharps) container and use new TEZSPIRE pre-filled pen.Each TEZSPIRE pre-filled pen contains dose of TEZSPIRE that can only be used time.TEZSPIRE is given only as an injection under the skin (subcutaneous).Keep the TEZSPIRE pre-filled pen and all medicines out of the sight and reach of children.Your TEZSPIRE pre-filled penDo not remove the cap until Step of these instructions when you are ready to inject TEZSPIRE.Preparing to inject TEZSPIREStep - Gather supplies o1 TEZSPIRE pre-filled pen from the refrigeratoro1 alcohol wipeo1 cotton ball or gauzeo1 small bandage (optional)o1 puncture-resistant (sharps) disposal container. See Step 10 for instructions on how to throw away (dispose of) the used TEZSPIRE pre-filled pen safely.Step - Prepare to use your TEZSPIRE pre-filled penLet TEZSPIRE come to room temperature between 68F to 77F (20C to 25C) for about 60 minutes before giving the injection.Keep the pre-filled pen in its original carton to protect it from light.Do not warm the pre-filled pen in any other way. For example, do not warm it in microwave or hot water, in direct sunlight, or near other heat sources.Do not put TEZSPIRE back in the refrigerator after it has reached room temperature. Throw away (dispose of) TEZSPIRE that has been stored at room temperature for more than 30 days.Do not remove the cap until Step 6.Step - Remove and check the pre-filled penGrab the middle of the pre-filled pen body to remove the pre-filled pen from its tray.Check the pre-filled pen for damage. Do not use the pre-filled pen if the pre-filled pen is damaged.Check the expiration date on the pre-filled pen. Do not use the pre-filled pen if the expiration date has passed.Look at the liquid through the viewing window. The liquid should be clear and colorless to light yellow.Do not inject TEZSPIRE if the liquid is cloudy, discolored, or contains large particles.You may see small air bubbles in the liquid. This is normal. You do not need to do anything about it.Injecting TEZSPIREStep - Choose an injection siteIf you are giving yourself the injection, the recommended injection site is the front of your thigh or the lower part of your stomach (abdomen). Do not inject yourself in the arm.A caregiver may inject you in the upper arm, thigh, or abdomen.For each injection, choose different site that is at least inch (3 cm) away from where you last injected.Do not inject:ointo the 2-inch (5 cm) area around your belly buttonowhere the skin is tender, bruised, scaly or hardointo scars or damaged skinothrough clothing Step - Wash your hands and clean the injection siteWash your hands well with soap and water.Clean the injection site with an alcohol wipe in circular motion. Let it air dry.Do not touch the cleaned area before injecting.Do not fan or blow on the cleaned area.Step - Pull off the capDo not remove the cap until you are ready to inject.Hold the pre-filled pen body with hand, and carefully pull the cap straight off with your other hand.Put the cap to the side and throw it away later.The orange needle guard is now exposed. The orange needle guard is there to prevent you from touching the needle.Do not touch the needle or push on the orange needle guard with your finger.Do not put the cap back on the pre-filled pen. You could cause the injection to happen too soon or damage the needle.Step - Inject TEZSPIREFollow your healthcare providers instruction on how to inject. You can either gently pinch the skin at the injection site or give the injection without pinching the skin.Inject TEZSPIRE by following the steps in figures a, b, and d.When injecting, you will hear the first click that tells you the injection has started. Press and hold the pre-filled pen for 15 seconds until you hear the second click.Do not change the position of the pre-filled pen after the injection has started.Position the pre-filled pen.oPlace the orange needle guard flat against your skin (90-degree angle).oMake sure you can see the viewing window.Step - Check the viewing windowCheck the viewing window to make sure all the medicine has been injected.If the orange plunger rod does not fill the viewing window, you may not have received the full dose.If this happens or if you have any other concerns, contact your healthcare provider.Step - Check the injection siteThere may be small amount of blood or liquid where you injected. This is normal.Gently hold pressure over your skin with cotton ball or gauze until the bleeding stops.Do not rub the injection site. If needed, cover the injection site with small bandage.Disposing of TEZSPIREStep 10 Dispose of the used pre-filled pen safelyEach pre-filled pen contains single dose of TEZSPIRE and cannot be used again. Do not put the cap back on the pre-filled pen.Put your used pre-filled pen and cap in sharps disposal container right away after use. Put other used supplies in your household trash.Do not throw away the pre-filled pen in your household trash.Throw away (Disposal) guidelinesIf you do not have FDA-cleared sharps disposal container, you may use household container that is: omade of heavy-duty plastic,ocan be closed with tight-fitting puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the container.When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the area that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this.Do not recycle your used sharps disposal container.Manufactured by:AstraZeneca AB, Sodertalje, Sweden SE-15185US License No. 2059At: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799Marketed by: Amgen Inc. and AstraZeneca AB(C)AstraZeneca and Amgen 2023TEZSPIRE is trademark of Amgen Inc. and AstraZeneca.For more information, go to https://www.TEZSPIRE.com or call 1-800-236-9933. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 02/2023. oit has been frozen. oit has been dropped or damaged. othe security seal on the carton has been broken. othe expiration date (EXP) has passed. ofreeze your pre-filled pen or expose it to heat. oshake your pre-filled pen. oshare, or use your pre-filled pen more than time. o1 TEZSPIRE pre-filled pen from the refrigeratoro1 alcohol wipeo1 cotton ball or gauzeo1 small bandage (optional)o1 puncture-resistant (sharps) disposal container. See Step 10 for instructions on how to throw away (dispose of) the used TEZSPIRE pre-filled pen safely.. o1 TEZSPIRE pre-filled pen from the refrigerator. o1 alcohol wipe. o1 cotton ball or gauze. o1 small bandage (optional). o1 puncture-resistant (sharps) disposal container. See Step 10 for instructions on how to throw away (dispose of) the used TEZSPIRE pre-filled pen safely.. ointo the 2-inch (5 cm) area around your belly button. owhere the skin is tender, bruised, scaly or hard. ointo scars or damaged skin. othrough clothing. oPlace the orange needle guard flat against your skin (90-degree angle).. oMake sure you can see the viewing window.. omade of heavy-duty plastic,ocan be closed with tight-fitting puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the container.. omade of heavy-duty plastic,. ocan be closed with tight-fitting puncture-resistant lid, without sharps being able to come out,. oupright and stable during use,. oleak-resistant, and. oproperly labeled to warn of hazardous waste inside the container.. This Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 02/2023. Tezspire-prefille-pen. Step1. Step2. step3. step4injectionsite. step5. step6. step7. step7-b-c-d. step8with text. step8. step9. step10.