Aralast

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

ARALAST NP is an Alpha 1 -Proteinase Inhibitor (Alpha 1 -PI) indicated for chronic augmentation therapy in adults with clinically evident emphysema due to severe congenital deficiency of Alpha 1 -PI (alpha 1 -antitrypsin deficiency). ARALAST NP increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha 1 -PI. The effect of augmentation therapy with any Alpha 1 -PI, including ARALAST NP, on pulmonary exacerbations and on the progression of emphysema in alpha 1 -antitrypsin deficiency has not been conclusively demonstrated in randomized, controlled clinical trials. Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy with ARALAST NP or ARALAST are not available. ARALAST NP is not indicated as therapy for lung disease in patients in whom severe congenital Alpha 1 -PI deficiency has not been established.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

For Intravenous Use Only

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

ARALAST NP is available as a lyophilized powder in single dose vials containing 0.5 gram or 1 gram of functional Alpha 1 -PI.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

ARALAST NP is contraindicated in immunoglobulin A (IgA) deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

Hypersensitivity reactions have been reported in patients following administration of ARALAST/ARALAST NP [see Warnings and Precautions (5.1) ] . No serious adverse reactions related to the use of ARALAST NP were reported in clinical trials. The most common adverse reactions occurring in ≥5% of infusions in clinical trials were headache, musculoskeletal discomfort, vessel puncture site bruise, nausea, and rhinorrhea.

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

11 DESCRIPTION

DESCRIPTION SECTION

ARALAST NP contains approximately 2% Alpha 1 -PI with truncated C-terminal lysine (removal of Lys394), whereas ARALAST contains approximately 67% Alpha 1 -PI with the C-terminal lysine truncation. 8 No known data suggest influence of these structural modifications on the functional activity and immunogenicity of Alpha 1 -PI. 9 ARALAST NP is a sterile, lyophilized preparation of purified human alpha 1 -proteinase inhibitor (Alpha 1 -PI), also known as alpha 1 -antitrypsin (AAT). 1 ARALAST NP is a similar product to ARALAST, containing the same active components of plasma Alpha 1 -PI with identical formulations. ARALAST NP is prepared from large pools of human plasma by using the cold ethanol fractionation process, followed by purification steps including polyethylene glycol and zinc chloride precipitations and ion exchange chromatography. To reduce the risk of viral transmission, the manufacturing process includes treatment with a solvent detergent (S/D) mixture [tri-n-butyl phosphate and polysorbate 80] to inactivate enveloped viral agents such as human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV). In addition, a nanofiltration step is incorporated into the manufacturing process to reduce the risk of transmission of enveloped and non-enveloped viral agents. Based on in vitro studies, the process used to produce ARALAST NP has been shown to inactivate and/or partition various viruses as shown in Table 3 below. Table 3: Virus Log Reduction in ARALAST NP Manufacturing Process Processing Step Virus Log Reduction Factors HIV-1 Virus Log Reduction Factors BVDV Virus Log Reduction Factors PRV Virus Log Reduction Factors HAV Virus Log Reduction Factors MMV N/A – Not applicable; study did not test for virus indicated. HIV–1: Human Immunodeficiency Virus-1; BVDV: Bovine Viral Diarrhea Virus, model for Hepatitis C Virus and other lipid enveloped RNA viruses; PRV: Pseudorabies Virus, model for lipid-enveloped DNA viruses, to which Hepatitis B also belongs; HAV: Hepatitis A Virus; MMV: Mice Minute Virus, model for small non-lipid-enveloped DNA viruses Cold ethanol fractionation 4.6 1.4 2.1 1.4 ≤1.0 Reduction factors ≤1 are not used for calculation of the overall reduction factor. Solvent Detergent-treatment >5.8 >6.0 >5.5 N/A N/A 15 N nanofiltration >5.3 >6.0 >5.6 >5.1 4.9 Overall reduction factor > 15.7 >13.4 >13.2 >6.5 4.9 The unreconstituted, lyophilized cake should be white or off-white to slightly yellow-green or yellow in color. When reconstituted as directed, the concentration of functionally active Alpha 1 -PI is 16.0 – 26.0 mg/mL and the specific activity is ≥0.55 mg active Alpha 1 -PI/mg total protein. The composition of the reconstituted product is as follows: Component Quantity/mL Elastase Inhibitory Activity 400 – 650 mg Active Alpha 1 -PI/0.5 g vial Reconstitution volume: 25 mL/0.5 g vial 800 – 1300 mg Active Alpha 1 -PI/1 g vial Reconstitution volume: 50 mL/1 g vial Albumin ≤0.6 mg/mL Polyethylene Glycol ≤112 mcg/mL Polysorbate 80 ≤20 mcg/mL Sodium ≤230 micromol/mL Tri-n-butyl Phosphate ≤1 mcg/mL Zinc ≤1.0 mg/L Each vial of ARALAST NP has the functional activity, as determined by inhibition of porcine pancreatic elastase, stated on the label. The formulation contains no preservative. The pH of the solution ranges from 7.2 to 7.8. Product must only be administered intravenously.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

A clinical trial (ARALAST versus PROLASTIN trial) was conducted to compare the predecessor product ARALAST to a commercially available preparation of Alpha 1 -PI (PROLASTIN) in 28 subjects with congenital Alpha 1 -PI deficiency and emphysema, who had not received Alpha 1 -PI augmentation therapy within the preceding six months. Subjects were randomized to receive either ARALAST or PROLASTIN, 60 mg/kg intravenously per week for 10 consecutive weeks. Following their first 10 weekly infusions, the subjects who were receiving PROLASTIN were switched to ARALAST while those who already were receiving ARALAST continued to receive it. Table 5 summarizes the mean serum antigenic and functional Alpha 1 -PI trough levels measured prior to infusion at steady state (Weeks 8 through 11). Table 5: Steady-State Serum Antigenic and Functional Alpha 1 -PI Trough Levels Following Intravenous Augmentation Therapy with ARALAST or PROLASTIN ARALAST Mean ± SD (Range of means) (No. of Subjects = 13) PROLASTIN Mean ± SD (Range of means) (No. of Subjects = 13) Antigenic Alpha 1 -PI 15.3 ± 2.5 (14.7 to 15.5) microM 16.9 ± 2.3 (16.2 to 17.2) microM Functional Alpha 1 -PI 15.3 ± 2.4 (14.8 to 15.6) microM 15.7 ± 2.6 (14.4 to 16.4) microM Following weekly augmentation therapy with ARALAST or PROLASTIN, a gradual increase in peak and trough serum Alpha 1 -PI levels was noted, with stabilization after several weeks. The metabolic half-life of ARALAST was 5.9 days. Serum ANEC trough levels rose substantially in all subjects by Week 2, and by Week 3, serum ANEC trough levels exceeded 11 microM in the majority of subjects. With few exceptions, levels in both treatment groups remained above this level in individual subjects for the duration of the period Weeks 3 through 24. Although only five of fourteen subjects (35.7%) receiving ARALAST had BALs meeting acceptance criteria for analysis at both baseline and Week 7, a statistically significant increase in the antigenic level of Alpha 1 -PI in epithelial lining fluid (ELF) was observed. No statistically significant increase in the ANEC in the ELF was detected. It was concluded that at a dose of 60 mg/kg administered intravenously once weekly, ARALAST and PROLASTIN had similar effects in maintaining target serum Alpha 1 -PI trough levels and increasing antigenic levels of Alpha 1 -PI in the ELF with maintenance augmentation therapy. The pharmacokinetic comparability of ARALAST NP and the predecessor product ARALAST was demonstrated in a randomized, double-blind, crossover trial in 25 subjects with severe Alpha 1 -PI deficiency [see Clinical Pharmacology (12.3) ] . Another clinical trial (BAL TRIAL) was conducted to determine the effects of open-label, weekly intravenous augmentation therapy with 60 mg/kg ARALAST NP on ELF levels of Alpha 1 -PI, ANEC, and Alpha 1 -PI: human neutrophil elastase (HNE) complexes in subjects with severe, congenital Alpha 1 -PI deficiency. A total of 13 subjects completed 8 weekly infusions of ARALAST NP at a median dose of 63 (range: 58 to 67) mg/kg body weight at an infusion rate of 0.2 mL/kg/min. Of the 13 subjects, 12 had both baseline and post-treatment bronchoalveolar lavage samples. ARALAST NP augmentation therapy resulted in a significant increase (p

15 REFERENCES

REFERENCES SECTION

Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin deficiency. Am J Med 1988 (Suppl 6A); 84:13–31. Crystal RG, Brantly ML, Hubbard RC, Curiel DT, et al . The alpha 1 -antitrypsin gene and its mutations: Clinical consequences and strategies for therapy. Chest 1989; 95:196–208. Crystal RG. α 1 -Antitrypsin deficiency: pathogenesis and treatment. Hospital Practice 1991; Feb.15:81–94. Hutchison DCS. Natural history of alpha-1-protease inhibitor deficiency. Am J Med 1988; 84(Suppl 6A):3–12. Hubbard RC, Crystal RG. Alpha-1-antitrypsin augmentation therapy for alpha-1- antitrypsin deficiency. Am J Med 1988; 84(Suppl 6A):52–62. Buist SA, Burrows B, Cohen A, et al . Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency. Am Rev Respir Dis 1989; 140:1494–1497. Gadek JE, Fells GA, Zimmerman RL, et al . Antielastases of the human alveolar structures: Implications for the protease-antiprotease theory of emphysema. J Clin Invest 1981; 68:889–898. Kolarich D, et al . Biochemical, molecular characterization, and glycoproteomic analyses of α 1 -proteinase inhibitor products used for replacement therapy. Transfusion 2006; 46:1959–1977. Transcript of Blood Products Advisory Committee (BPAC) 85 th Meeting; 3-4 Nov 2005. Turino GM, Barker AF, Brantly ML, et al : Clinical features of individuals with Pi*SZ phenotype of α 1 -antitrypsin deficiency. Am J Respir Crit Care Med 154: 1718–25, 1996.

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Inform patients of the early signs of hypersensitivity reactions, including hives, generalized urticaria, chest tightness, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care, depending on the severity of the reaction, if these symptoms occur. Inform patients that ARALAST NP is made from human plasma, therefore the possibility of transmitting infectious agents cannot be totally excluded. Explain that the risk of transmitting an infectious agent has been reduced by screening donors, testing plasma for certain virus infections, and a manufacturing process to inactivate and/or remove certain viruses. Inform patients that administration of ARALAST NP has been demonstrated to raise the levels of Alpha 1 -PI in the blood and in the lung, but that the effect of this augmentation on the frequency of pulmonary exacerbations and on the rate of progression of emphysema has not been established by clinical trials. Takeda Pharmaceuticals U.S.A., Inc. Cambridge, MA 02142 U.S. License No. 1898 ARALAST is a registered trademark of Baxalta Incorporated. Takeda and are registered trademarks of Takeda Pharmaceutical Company Limited. PROLASTIN ® is a registered trademark of Grifols Therapeutics LLC. ©2025 Takeda Pharmaceutical Company Limited. All rights reserved.

PRINCIPAL DISPLAY PANEL - Kit Carton - 0.5 gram

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 0944-2814-01 0.5 gram Alpha 1 -Proteinase Inhibitor (Human) Aralast ® NP Solvent Detergent Treated Nanofiltered Lyophilized powder for solution For intravenous use only Rx only Takeda

PRINCIPAL DISPLAY PANEL - 0.5 gram Vial Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 0944-2803-03 0.5 gram Alpha 1 -Proteinase Inhibitor (Human) Aralast ® NP Solvent Detergent Treated Nanofiltered Lyophilized powder for solution ARALAST is a registered trademark of Baxalta Incorporated. Rx only Takeda

PRINCIPAL DISPLAY PANEL - Kit Carton - 1 gram

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 0944-2815-01 1 gram Alpha 1 -Proteinase Inhibitor (Human) Aralast ® NP Solvent Detergent Treated Nanofiltered Lyophilized powder for solution For intravenous use only Rx only Takeda

PRINCIPAL DISPLAY PANEL - 1 gram Vial Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 0944-2804-04 1 gram Alpha 1 -Proteinase Inhibitor (Human) Aralast ® NP Solvent Detergent Treated Nanofiltered Lyophilized powder for solution ARALAST is a registered trademark of Baxalta Incorporated. Rx only Takeda