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.

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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.

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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.

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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 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 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 tray. 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.

5.1 Hypersensitivity Reactions

Hypersensitivity reactions were observed in the clinical trials (e.g., rash and allergic conjunctivitis) following the administration of TEZSPIRE. Postmarketing cases of anaphylaxis have also been reported [see Contraindications (4) and Adverse Reactions (6)]. These reactions can occur within hours of administration, but in some instances have a delayed onset (i.e., days). In the event of a 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 a 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 a patient’s 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.

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.

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 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)].

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.

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)] 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.

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

8.1 Pregnancy

Risk Summary

There 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 a 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 a 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 Considerations

Disease-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.

Data

Animal Data

In 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 7 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 Summary

There 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 a human monoclonal antibody immunoglobulin G2λ (IgG2λ), and immunoglobulin G (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 mother's clinical need for TEZSPIRE and any potential adverse effects on the breastfed infant from TEZSPIRE or from the underlying maternal condition.

Data

Animal Data

In a 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 a total of 82 pediatric patients aged 12 to 17 years enrolled in NAVIGATOR and received treatment with TEZSPIRE 210 mg subcutaneously every 4 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)].

12.1 Mechanism of Action

Tezepelumab-ekko is a thymic stromal lymphopoietin (TSLP) blocker, human monoclonal antibody IgG2λ that binds to human TSLP with a dissociation constant of 15.8 pM and blocks its interaction with the heterodimeric TSLP receptor. TSLP is a 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 4 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 2 weeks after initiation of treatment and sustained reduction on treatment to 52 weeks. TEZSPIRE caused a 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 a single subcutaneous dose over a dose range from 2.1 mg to 420 mg (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 Ctrough 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.

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.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tezepelumab-ekko or of other tezepelumab products.

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 1 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic potential of tezepelumab-ekko. The malignancy risk in humans from an antibody that blocks TSLP ligand, such as tezepelumab-ekko, is currently unknown.

Male and female fertility was unaffected based upon no observed adverse histopathological findings in the reproductive organs and no changes in menstrual cycle or semen analysis in sexually mature cynomolgus monkeys that received tezepelumab-ekko for 26 weeks at subcutaneous doses up to 300 mg/kg/week (approximately 134 times the MRHD on an AUC basis).