Tezepelumab-Ekko

1 INDICATIONS AND USAGE TEZSPIRE is a thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody (IgG2λ), indicated: • for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. ( 1.1 ) Limitations of Use: Not for relief of acute bronchospasm or status asthmaticus. ( 1.1 ) • for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP). ( 1.2 ) 1.1 Asthma TEZSPIRE is indicated for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with severe asthma. Limitations of Use: TEZSPIRE is not indicated for the relief of acute bronchospasm or status asthmaticus. 1.2 Chronic Rhinosinusitis with Nasal Polyps TEZSPIRE is indicated for the add-on maintenance treatment of adult and pediatric patients aged 12 years and older with inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP).

2 DOSAGE AND ADMINISTRATION Recommended dosage is 210 mg administered once every 4 weeks. ( 2.1 ) • Administer by subcutaneous injection. ( 2.1 ) • See full prescribing information for preparation and administration instructions. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of TEZSPIRE is 210 mg administered subcutaneously once every 4 weeks. Missed Dose Information If a 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 vial and pre‑filled syringe are intended for administration by a healthcare provider. TEZSPIRE pre-filled pen can be administered by patients/caregivers or healthcare providers. Patients/caregivers may administer TEZSPIRE pre-filled pen after proper training in subcutaneous injection technique and after the healthcare provider determines it is appropriate. Each vial, pre-filled syringe and pre‑filled pen contain a single dose of TEZSPIRE. • Prior 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. • Visually inspect TEZSPIRE for particulate matter and discoloration prior to administration. TEZSPIRE is a 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, pre-filled syringe or pre‑filled pen has been dropped or damaged or if the expiration date has passed. • Inject TEZSPIRE 210 mg (contents of one vial, one pre-filled syringe or one pre-filled pen as described below) subcutaneously into the thigh or abdomen, except for the 2 inches (5 cm) around the navel. If a healthcare provider or caregiver administers the injection, the upper arm can also be used. A patient should not self-inject in the upper arm. 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 Syringe Refer to Figure 1 to identify the pre-filled syringe components for use in the administration steps. Do not remove the needle cover until Step 2 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 1 TEZSPIRE Pre-filled Syringe Components 1. Grasp the syringe body to remove the pre-filled syringe from its carton. 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 a 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 a sharps container. Administration Instructions for Single-Dose Pre-filled Pen These administration instructions are intended for healthcare providers use only. Patients and caregivers should refer to the TEZSPIRE pre-filled pen ‘Instructions for Use’ for more detailed instructions on the preparation and administration of TEZSPIRE pre-filled pen [See Instructions for Use] . Patients/caregivers may inject after proper training in subcutaneous injection technique according to the ‘Instructions for Use’, and after the healthcare provider determines it is appropriate. Refer to Figure 2 to identify the pre-filled pen components for use in the administration steps. Do not remove the cap until you are ready to inject TEZSPIRE. Figure 2 TEZSPIRE Pre-filled Pen Components 1. Grab the middle of the pre-filled pen body to remove the pre-filled pen from its carton. The pre-filled pen may contain small air bubbles; this is normal. Do not expel the air bubbles prior to administration. 2. Do not remove the cap until ready to inject. Hold the pre-filled pen body with 1 hand and carefully pull the cap straight off with your other hand. Do not touch the needle or push 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. 3. Gently pinch the skin at the injection site or give the injection without pinching the skin. Inject TEZSPIRE by following the steps into the recommended injection site (i.e., upper arm, thigh, or abdomen). 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. 4. Position the pre-filled pen. Place the orange needle guard flat against the skin (90‑degree angle). Make sure you can see the viewing window. 5. Press down firmly until you cannot see the orange needle guard. You will hear the first ‘click’, this tells you the injection has started. The orange plunger will move down in the viewing window during the injection. 6. Hold down firmly for about 15 seconds. You will hear a second ‘click’, this tells you the injection has finished. The orange plunger will fill the viewing window. 7. After you have completed the injection, lift the pre-filled pen straight up. The orange needle guard will slide down and lock into place over the needle. 8. Discard the used pre-filled pen into a sharps container. 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6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥ 3%) are: • Asthma: pharyngitis, arthralgia, and back pain. ( 6.1 ) • Chronic rhinosinusitis with nasal polyps: nasopharyngitis, upper respiratory tract infection, epistaxis, pharyngitis, back pain, influenza, injection site reaction and arthralgia. ( 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adult and Pediatric Patients 12 Years of Age and Older with Asthma The safety of TEZSPIRE in asthma 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 4 weeks. The two placebo-controlled clinical trials were of 52 weeks duration. In addition, a similar safety profile was seen in a trial that enrolled 150 adult patients with severe asthma who required treatment with daily oral corticosteroids [see Clinical Studies (14.1) ] . 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 1 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 Reaction TEZSPIRE N=665 % Placebo N=669 % Pharyngitis Pharyngitis (including Pharyngitis, Pharyngitis bacterial, Pharyngitis streptococcal and Viral pharyngitis) 4 3 Arthralgia 4 3 Back pain 4 3 Specific Adverse Reactions Cardiovascular Events In a randomized, double-blind, long term extension trial, patients 12 years and older with severe asthma from trials NAVIGATOR and the additional trial [see Clinical Studies (14.1) ] received TEZSPIRE 210 mg subcutaneously every 4 weeks or placebo for up to 104 weeks. In the trial, the incidence rates (IR) per 100 patient-years (PY) for serious cardiac adverse events in patients treated with TEZSPIRE or placebo were 1.08 and 0.21, respectively, with an incidence rate difference (IRD) of 0.88 (95% CI: 0.24, 1.53). The types of serious cardiac adverse events were heterogeneous. In the trial, the IR per 100 PY for adjudicated major adverse cardiovascular events (MACE, defined as cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with TEZSPIRE or placebo were 0.60 and 0.42, respectively, with an IRD of 0.18 (95% CI: -0.51, 0.75). Injection Site Reactions In the pooled safety population (PATHWAY and NAVIGATOR), in which TEZSPIRE or placebo was administered using the vial by a healthcare provider, injection site reactions (e.g., injection site erythema, injection site swelling, injection site pain) occurred at a rate of 3.3% in patients treated with TEZSPIRE compared with 2.7% in patients treated with placebo. In an open-label trial of 216 patients with asthma in which TEZSPIRE was administered by healthcare providers and patients or caregivers using either the pre-filled pen or pre-filled syringe, injection site reactions (e.g., injection site erythema, injection site swelling, injection site pain) were observed in 5.7% patients using the pre-filled pen and 0% using the pre-filled syringe. However, the trial was not designed to compare injection site reactions between patients who received TEZSPIRE by the pre-filled pen versus pre-filled syringe. Adverse Reactions in Adult Patients with Chronic Rhinosinusitis with Nasal Polyps The safety of TEZSPIRE in CRSwNP was based on WAYPOINT, a randomized, double-blind, parallel group, multicenter, placebo-controlled trial of 52 weeks duration, which consisted of 203 adult patients aged 18 years and older on standard of care treatment for CRSwNP who received at least one dose of TEZSPIRE 210 mg subcutaneously once every 4 weeks [see Clinical Studies (14.2) ] . Adverse reactions that occurred at an incidence greater than or equal to 3% and more common than in the placebo group from the safety population (WAYPOINT) are shown in Table 2. Table 2 Adverse Reactions with TEZSPIRE with Incidence Greater than or Equal to 3% and More Common than Placebo in Patients with CRSwNP (WAYPOINT) Adverse Reaction TEZSPIRE N=203 % Placebo N=205 % Nasopharyngitis 18 10 Upper respiratory tract infection Upper respiratory tract infection (including Upper respiratory tract infection and Viral upper respiratory tract infection) 12 8 Epistaxis 6 3 Pharyngitis Pharyngitis (including Pharyngitis, Pharyngitis bacterial, Pharyngitis streptococcal and Viral pharyngitis) 5 1 Back pain 5 2 Influenza 4 1 Injection site reaction Injection site reaction (e.g., Injection site erythema, Injection site swelling and Injection site pain) 4 2 Arthralgia 3 2 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TEZSPIRE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions : anaphylaxis

12.3 Pharmacokinetics The pharmacokinetics of tezepelumab-ekko is similar in patients with asthma and CRSwNP. The pharmacokinetics of tezepelumab-ekko were dose-proportional following administration of a single subcutaneous dose over a dose range from 0.01 to 2 times the recommended dose. With an every 4 weeks dosing regimen, tezepelumab-ekko achieves steady-state after 12 weeks and the accumulation ratio for C trough is 1.86-fold. Absorption Following subcutaneous administration, the maximum serum concentration was reached in approximately 3 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). Distribution Based on population pharmacokinetic analysis, central and peripheral volume of distribution of tezepelumab-ekko were 3.9 L and 2.2 L, respectively, for a 70 kg individual. Elimination As a 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 a 70 kg individual. The elimination half-life was approximately 26 days. Metabolism Tezepelumab-ekko is a human monoclonal antibody (IgG2λ) that is degraded by proteolytic enzymes widely distributed in the body and not metabolized by hepatic enzymes. Specific Populations Age, Sex, Race Based 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 Weight Based 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. Pediatric Patients CRSwNP Clinical studies have not been conducted in pediatric patients aged 12 years and older with CRSwNP. Tezepelumab-ekko exposures are expected to be comparable between adults and pediatric patients aged 12 years and older at the recommended subcutaneous dosage (210 mg every 4 weeks) for CRSwNP. Patients with Renal impairment No 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 Studies No 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.