2.1 Dosage

• Dose ranging studies using efficacy endpoints have not been performed.
• Administer 60 mg/kg body weight of ARALAST NP once weekly by intravenous infusion.

2.2 Reconstitution

1. Use aseptic technique.
2. Allow ARALAST NP and diluent to reach room temperature before reconstitution.
3. Remove caps from the diluent and product vials.
4. Swab the exposed stopper surfaces with alcohol.
5. Remove cover from one end of the double-ended transfer needle. Insert the exposed end of the needle through the center of the stopper in the diluent vial.
6. Remove plastic cap from the other end of the double-ended transfer needle now seated in the stopper of the diluent vial. To reduce any foaming, invert the vial of diluent and insert the exposed end of the needle through the center of the stopper in the product vial at an angle, making certain that the diluent vial is always above the product vial. The angle of insertion directs the flow of diluent against the side of the product vial. Refer to Figure 1 below. The vacuum in the vial is sufficient to allow transfer of all of the diluent.
   

   Figure 1

7. Disconnect the two vials by removing the diluent vial from the transfer needle. This allows any remaining low pressure in the product vial to equalize. Next, remove the double-ended transfer needle from the product vial and discard the needle into the appropriate safety container.
8. Let the vial stand until most of the contents is in solution, then GENTLY swirl until the powder is completely dissolved. Reconstitution requires no more than five minutes for a 0.5 gram vial and no more than 10 minutes for a 1 gram vial.
   Note: Do not shake the content of the vial. Do not invert the vial until ready to withdraw content.
9. Reconstituted product is a colorless or slightly yellow to yellow-green solution.
10. A few small visible particles may occasionally remain in the reconstituted product. These will be removed by the sterile 20 micron filter needle supplied with the product.
11. Place the product vial on a stable flat surface.
12. Open the blister pack of the 20 micron filter needle.
13. Twist to remove the protective cap from the Luer adapter of the filter needle.
14. Attach a single-use syringe (not provided) to the Luer adapter of the filter needle.
15. Remove the protective cap from the filter needle and draw back plunger of the syringe to admit air into syringe. Insert the filter needle through the center of the stopper in product vial.
16. Push the plunger to admit air in the product vial.
17. Invert the system (product vial with syringe attached) so that product vial is on top.
18. Withdraw the reconstituted product into the syringe.
19. Remove the syringe from the filter needle and product vial. Remove filter needle from product vial and discard the needle into the appropriate sharps container.

2.3 Administration

5.1 Hypersensitivity Reactions

ARALAST NP may contain trace amounts of IgA. Patients with known antibodies to IgA, which can be present in patients with selective or severe IgA deficiency, have a greater risk of developing severe hypersensitivity and anaphylactic reactions. Closely follow the recommended infusion rate [see Dosage and Administration (2.3)]. Monitor vital signs continuously and observe the patient carefully throughout the infusion. Discontinue the infusion if hypersensitivity symptoms occur and administer appropriate emergency treatment. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.

5.2 Transmission of Infectious Agents

Because this product is made from human plasma, it may carry a risk of transmitting infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. The risk of transmitting an infectious agent has been minimized by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain virus infections and by inactivating and removing certain viruses during the manufacturing process. Despite these measures, such products may still potentially transmit human pathogenic agents.

No seroconversions for hepatitis B or C (HBV or HCV) or human immunodeficiency virus (HIV) or any other known infectious agent were reported with the use of ARALAST NP during clinical studies.

All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Takeda Pharmaceuticals U.S.A., Inc., at 1-877-TAKEDA-7 (1-877-825-3327) (in the U.S.).

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety of ARALAST NP was evaluated in a total of 38 subjects with severe congenital Alpha1-PI deficiency (pre-augmentation therapy serum levels of Alpha1-PI of less than 11 microM) in two clinical trials. The crossover trial was a multicenter, randomized, double-blind, single-dose pharmacokinetic (PK) comparability trial conducted in 25 subjects with severe congenital Alpha1-PI deficiency to evaluate the pharmacokinetics of ARALAST NP (test drug, 60 mg/kg body weight) as compared to ARALAST (reference drug, 60 mg/kg body weight), each infused at a rate of 0.2 mL/kg body weight/minute. The BAL trial was a multicenter, open-label, non-randomized trial in 13 subjects with severe congenital Alpha1-PI deficiency to determine the safety and effects of weekly augmentation therapy with ARALAST NP (60 mg/kg body weight/week) administered at a rate of 0.2 mL/kg body weight/minute in elevating Alpha1-PI levels in serum and epithelial lining fluid (ELF).

In both trials, there were no deaths and no serious adverse reactions associated with ARALAST NP or ARALAST administration. None of the subjects withdrew from the trial due to an adverse reaction. There was no reduction in infusion rate at 0.2 mL/kg body weight/min or infusion discontinuation/interruption due to an adverse reaction, except for one subject in the crossover trial who experienced pain at infusion site during ARALAST administration.

Table 1 summarizes the number of subjects, the total number of infusions, and the rate of adverse reactions (ARs) associated with ARALAST NP or ARALAST treatment for each clinical trial.

The most common ARs (defined as adverse reactions occurring in ≥5% of infusions) in each clinical trial are shown in Table 2.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ARALAST NP. 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.

Vascular Disorders: Flushing

Gastrointestinal Disorders: Vomiting, Diarrhea

Skin and Subcutaneous Tissue Disorders: Urticaria

Musculoskeletal and Connective Tissue Disorders: Myalgia

General and Administration Site Conditions: Injection site reaction, Fatigue, Malaise, Asthenia, Feeling abnormal

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of ARALAST NP did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. Safety and effectiveness in patients over age 65 years of age have not been established.

12.1 Mechanism of Action

ARALAST NP administration is intended to inhibit serine proteases such as neutrophil elastase (NE), which is capable of degrading protein components of the alveolar walls and which is chronically present in the lung.

Alpha1-PI deficiency is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha1-PI.1,2,4,5 Severe forms of the deficiency are frequently associated with slowly progressive, moderate-to-severe panacinar emphysema that most often manifests in the third to fourth decades of life.1,2,3,5,6 However, an unknown percentage of individuals with severe Alpha1-PI deficiency are not diagnosed with or may never develop clinically evident emphysema during their lifetimes. Individuals with Alpha1-PI deficiency have little protection against NE released by neutrophils in their lower respiratory tract, resulting in a protease:protease inhibitor imbalance in the lung.2,7 This imbalance allows relatively unopposed destruction of the connective tissue framework of the lung parenchyma.7

There are a large number of phenotypic variants of this disorder.1,2,3 Individuals with the PiZZ variant typically have serum Alpha1-PI levels less than 35% of the average normal level.1,4 Individuals with the Pi(null)(null) variant have undetectable Alpha1-PI protein in their serum.1,2 Individuals with these low serum Alpha1-PI levels, i.e., less than 11 microM, have an increased risk of developing emphysema over their lifetimes. In addition, PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 microM,10 are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha1-PI levels are above or below 11 microM. The risk of accelerated development and progression of emphysema in individuals with severe Alpha1-PI deficiency is higher in smokers than in ex-smokers or non-smokers.2

Not all individuals with severe genetic variants of Alpha1-PI deficiency have emphysema. Augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe congenital Alpha1-PI deficiency who have clinically evident emphysema.

Augmenting the levels of functional Alpha1-proteinase inhibitor by intravenous infusion is an approach to therapy for patients with Alpha1-PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical trials. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between neutrophil elastase and protease inhibitors. Whether augmentation therapy with ARALAST NP actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Although the maintenance of blood serum levels of Alpha1-PI (antigenically measured) above 11 microM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection, this has not been proven. Individuals with severe Alpha1-PI deficiency have been shown to have increased neutrophil and neutrophil elastase concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with Alpha1-PI above 11 microM have emphysema attributed to Alpha1-PI deficiency. These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of Alpha1-PI during augmentation therapy. The clinical benefit of increased blood levels of Alpha1-PI at the recommended dose has not been established.

The clinical efficacy of ARALAST NP in influencing the course of pulmonary emphysema or the frequency, duration, or severity of pulmonary exacerbations has not been demonstrated in randomized, controlled clinical trials.

12.2 Pharmacodynamics

Chronic augmentation therapy with a weekly dose of ARALAST NP at 60 mg/kg body weight to patients with Alpha1-PI deficiency increases the level of the deficient protein in plasma and in the epithelial lining fluid (ELF) as determined by antigenic assay. Normal individuals have plasma levels of Alpha1-PI greater than 20 microM. The clinical benefit of increased blood and ELF levels of Alpha1-PI at the recommended dose has not been demonstrated in adequately powered, randomized, double-blind, placebo-controlled trials for any Alpha1-PI product.

12.3 Pharmacokinetics

The pharmacokinetic comparability of ARALAST NP and the predecessor product ARALAST was demonstrated in a randomized, double-blind, crossover trial in 25 subjects (median age: 59 years old; range: 20 to 75 years old) with severe Alpha1-PI deficiency who received a single infusion of 60 mg/kg body weight of each product. Figure 2 depicts the mean ± standard deviation (SD) plasma Alpha1-PI concentration-time profiles measured using an enzyme-linked immunosorbent assay (ELISA). Table 4 summarizes the pharmacokinetic parameters of ARALAST NP and ARALAST.

Mean (± SD) Plasma Alpha1-PI Concentration-Time Profiles After a Single Intravenous Infusion of ARALAST NP and ARALAST (60 mg/kg) in Subjects with Congenital Alpha1-PI Deficiency

Figure 2

The key pharmacokinetic parameter was AUC0-35d/dose. The 90% confidence interval (85.8% to 100.2%) for the geometric mean ratio of AUC0-35d/dose for ARALAST NP and ARALAST indicated that the 2 products are pharmacokinetically equivalent.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of ARALAST NP have not been conducted. In vitro and in vivo testing of ARALAST NP for mutagenesis or impairment of fertility was not performed.

How Supplied

ARALAST NP is available in the following kits:

Each kit contains a suitable volume of Sterile Water for Injection, USP diluent (25 mL for 0.5 gram vial; 50 mL for 1 gram vial), one sterile double-ended transfer needle, one sterile 20 micron filter needle and one package insert.

Storage and Handling

• Store ARALAST NP at temperatures not to exceed 25°C (77°F).
• Do not freeze.
• Do not use after the expiration date printed on the label.
• Store ARALAST NP in the original carton to protect from light.