GLASSIA

Baxter Healthcare Corporation
Kamada Ltd.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use GLASSIA safely and effectively. See full prescribing information for GLASSIA.GLASSIA (Alpha-Proteinase Inhibitor (Human)) Injection Solution- For Intravenous Use OnlyInitial U.S. Approval: July 2010 RECENT MAJOR CHANGESDosage and Administration (2.3) 03/2014 INDICATIONS AND USAGEGLASSIA is an Alpha1-Proteinase Inhibitor (Human) (Alpha1-PI) indicated for chronic augmentation and maintenance therapy in adults with clinically evident emphysema due to severe congenital deficiency of Alpha1-PI (alpha1-antitrypsin deficiency). GLASSIA increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha1-PI. (1) The effect of augmentation therapy with any Alpha1-PI, including GLASSIA, on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been conclusively demonstrated in randomized, controlled clinical trials. (1) Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with GLASSIA are not available. (1)GLASSIA is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established. (1) DOSAGE AND ADMINISTRATION For intravenous use only. (2) Dose = 60 mg/kg body weight intravenously once weekly. (2.1) Administer at a rate not to exceed 0.2 mL/kg body weight per minute, depending on patient response and comfort. (2.3) Dose ranging studies using efficacy endpoints have not been performed. (2.1) Always use a 5 micron in-line filter (not supplied) during infusion. (2.3) If adverse events occur, reduce the rate or interrupt the infusion until the symptoms subside. Resume the infusion at a rate tolerated by the patient. (2.3) DOSAGE FORMS AND STRENGTHSSingle use vial containing approximately 1 gram of functional Alpha1-PI in 50 mL of ready to use solution. (3)CONTRAINDICATIONS IgA deficient patients with antibodies against IgA.(4) History of severe immediate hypersensitivity reactions, including anaphylaxis, to Alpha1-PI products. (4) WARNINGS AND PRECAUTIONS Severe hypersensitivity and anaphylactic reactions may occur in IgA deficient patients with antibodies against IgA. (5.1) 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, despite manufacturing steps designed to minimize the risk of viral transmission. (5.2) Side EffectsThe most common adverse reactions (>0.5% of infusions) in clinical trials were headache and upper respiratory infection. (6) To report SUSPECTED ADVERSE REACTIONS, contact Kamada Ltd. at 1-866-GLASSIA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONSPregnancy: No human or animal data. Use only if clearly needed. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 GLASSIA INDICATIONS AND USAGE
• 2 GLASSIA DOSAGE AND ADMINISTRATION
  • 2.1 Dosage
  • 2.2 Preparation
  • 2.3 Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 GLASSIA CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Hypersensitivity Reactions
  • 5.2 Transmissible Infectious Agents
• 6 GLASSIA ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 11 GLASSIA DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• Principal display panel

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

GLASSIA, is an Alpha₁-Proteinase Inhibitor (Human), indicated for chronic augmentation and maintenance therapy in individuals with clinically evident emphysema due to severe congenital deficiency of Alpha₁-PI, also known as alpha₁-antitrypsin (AAT) deficiency. GLASSIA increases antigenic and functional (anti-neutrophil elastase capacity, ANEC) serum levels and antigenic lung epithelial lining fluid levels of Alpha₁-PI.

The effect of augmentation therapy with GLASSIA or any Alpha₁-PI product on pulmonary exacerbations and on the progression of emphysema in Alpha₁-PI deficiency has not been conclusively demonstrated in randomized, controlled clinical trials.

Clinical data demonstrating the long-term effects of chronic augmentation and maintenance therapy of individuals with GLASSIA are not available.

GLASSIA is not indicated as therapy for lung disease in patients in whom severe Alpha₁-PI deficiency has not been established.

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

2.1 Dosage

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

2.2 Preparation

• Use aseptic technique.
• Allow the product to reach room temperature prior to infusing and administer within three hours of entering the vials.
• Inspect the vial of GLASSIA. The solution should be clear and colorless to yellow-green and may contain a few protein particles. Do not use if the product is cloudy.
• Infuse directly from the vial or, alternatively for large dose, pool vials into an empty, sterile container for intravenous infusion using the supplied filter needle. In the latter case, use a vented filter spike (not supplied) to withdraw the material from the vial and then use the supplied 5 micron filter needle to transfer the product into the intravenous infusion container.

2.3 Administration

For intravenous infusion only.

• Use aseptic technique.
• Inspect parenteral products visually for particulate matter and discoloration prior to administration whenever solution and container permit.
• Administer GLASSIA alone. Do not mix with other agents or diluting solutions.
• When infusing directly from the vials, use a vented filter spike (not supplied). If the contents of vials have been pooled to a sterile intravenous container, use an appropriate intravenous administration set.
• Always use a 5 micron in-line filter (not supplied) during infusion.
• Administer GLASSIA within three hours of entering the vials to avoid the potential ill effect of any inadvertent microbial contamination.
• Administer GLASSIA at room temperature through an appropriate intravenous administration set at a rate not to exceed 0.2 mL/kg body weight per minute, and as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg at a rate of 0.2 mL/kg/min will take approximately 15 minutes to infuse.
• Monitor the infusion rate closely during administration and observe the patient for signs of infusion related reactions. If infusion related adverse reactions occur, reduce the rate or interrupt the infusion as appropriate until the symptoms subside. Resume the infusion at a rate tolerated by the patient, except in the case of severe reaction.
• Following administration, discard all open vials, unused solution and administration equipment.

3 DOSAGE FORMS AND STRENGTHS

GLASSIA is available as a single-use vial containing approximately 1 gram of functional Alpha₁-PI in 50 mL of ready to use solution.

4 CONTRAINDICATIONS

GLASSIA is contraindicated in:

• immunoglobulin A (IgA) deficient patients with antibodies against IgA.
• individuals with a history of severe immediate hypersensitivity reactions, including anaphylaxis, to Alpha₁-PI products.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

GLASSIA 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. 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 Transmissible 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 current 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.

All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Kamada Ltd. at 1-866-GLASSIA or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 GLASSIA during the clinical trials.

6 ADVERSE REACTIONS

The serious adverse reaction observed during clinical trials with GLASSIA was exacerbation of chronic obstructive pulmonary disease (COPD). This reaction occurred in one subject and was considered possibly related to treatment with GLASSIA due to its temporal association.

The most common adverse reactions (>0.5% of infusions) in clinical trials were headache and upper respiratory infection.

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.

A total of 65 subjects with severe Alpha₁-PI deficiency (with pre-augmentation therapy serum Alpha₁-PI levels less than 11 microM) have received treatment in two clinical trials. However, because of the large temporal difference between trials (> 5 years) and major difference in study designs, each study was analyzed separately without excluding these three subjects who participated in both trials from either study analysis. Thus, safety and efficacy of GLASSIA are reported on all 18 subjects in the dose-escalation trial and all 50 subjects in the active-control trial, for a total of 68 subjects, representing 65 individual subjects.

In the open label, non-parallel, dose-escalation trial, 18 subjects received a single infusion of GLASSIA at dosages of 30, 60 or 120 mg/kg.

In the randomized, double-blind, active-control trial, 50 subjects were scheduled to receive weekly infusions of GLASSIA or the comparator Alpha₁-PI product, Prolastin, at a dosage of 60 mg/kg for a total of 12 doses after which all subjects remaining in the trial were treated for another 12 weeks with GLASSIA only. Overall, 17 subjects received 12 doses and 32 subjects received 22 - 24 doses of GLASSIA during the trial. (One subject randomized to the comparator Alpha₁-PI product did not receive any treatment with GLASSIA during the last 12 weeks of the trial.)

The population treated with GLASSIA in these two trials was 40-74 years old, 54% male, 100% Caucasian and had congenital Alpha₁-PI deficiency with clinical evidence of emphysema.

Tables 1 and 2 compare the adverse reactions reported during the initial 12 weeks (double-blind portion) of the randomized, active comparator trial in all subjects treated with GLASSIA with reactions in the concurrent Prolastin control group. Table 3 compares the frequency of adverse reactions as a percentage of all infusions for GLASSIA and Prolastin-treated subjects over the entire trial period.

Table 1: Number of Subjects/Infusions/Adverse ReactionsAn adverse reaction is any adverse event which met any of the following criteria: (a) an adverse event that began within 72 hours following the end of product infusion, or (b) an adverse event considered by either the investigator or sponsor to be at least possibly related to product administration, or (c) an adverse event for which causality assessment was missing or indeterminate. Occurring during the First 12 Weeks of Treatment

	GLASSIA	Prolastin
No. of subjects treated	33	17
No. of infusions	393	190
No. of subjects with serious adverse reactions (%)	1 (3%)	1 (6%)
No. of subjects experiencing an adverse reaction (%)	22 (67%)	15 (88%)
No. of adverse reactions	47	39

Table 2: Adverse ReactionsAn adverse reaction is any adverse event which met any of the following criteria: (a) an adverse event that began within 72 hours following the end of product infusion, or (b) an adverse event considered by either the investigator or sponsor to be at least possibly related to product administration, or (c) an adverse event for which causality assessment was missing or indeterminate. Occurring in > 5% of Subjects during the First 12 Weeks of Treatment

	GLASSIA No. of subjects: 33	Prolastin No. of subjects: 17
Adverse Event (AE)	No. of subjects with adverse reactions (AR) (percentage of all subjects)	No. of subjects with adverse reactions (AR) (percentage of all subjects)
Cough	3 (9%)	4 (24%)
Upper respiratory tract infection	3 (9%)	0 (0%)
Headache	3 (9%)	3 (18%)
Sinusitis	2 (6%)	1 (6%)
Chest discomfort	2 (6%)	0 (0%)
Dizziness	2 (6%)	0 (0%)
Hepatic enzyme increased	2 (6%)	0 (0%)

During the 12-week double blind portion of the randomized, active comparator trial, 4 subjects (12%) had a total of 7 exacerbations of chronic obstructive pulmonary disease (COPD) during GLASSIA treatment and 5 subjects (29%) had a total of 6 exacerbations of COPD during Prolastin treatment. Seventeen additional exacerbations in 14 subjects (28%) occurred during the 12-week open-label treatment period with GLASSIA. The overall rate of pulmonary exacerbations during treatment with either product was 1.3 exacerbations per subject per year.

Two episodes of headache were severe, defined as an inability to work or perform usual activities One subject experienced a treatment emergent serious adverse reaction (infective exacerbation of COPD), considered possibly related to treatment with GLASSIA due to its temporal association.

A total of 3 subjects (approximately 5%) receiving GLASSIA reported urticaria, irrespective of the investigator’s opinion of cause.

Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either trial.

In a trial in 30 healthy adults, in which each subject received 2 infusions of GLASSIA in a dose of 60 mg/kg body weight at either of 2 infusion rates in a crossover design, a total of 13 adverse reactions were reported. In this trial, the safety profile of GLASSIA when infused at 0.2 mL/kg/min was similar to that when infused at 0.04 mL/kg/min. The most common adverse reaction was headache, occurring in 2 [7%] subjects receiving GLASSIA at 0.2 mL/kg/min and 2 [7%] of subjects receiving GLASSIA at 0.04 mL/kg/min. No infusions were slowed, interrupted or terminated due to an adverse reaction. All adverse reactions were mild (defined as a transient discomfort that did not interfere in a significant manner with the subject’s normal functioning level, or an adverse event that resolved spontaneously or may have required minimal therapeutic intervention), and occurred during or within the first 72 hours after the completion of an infusion.

In the trial in healthy adults, testing for viral markers for HBV, HCV, HIV-1, HIV-2, HAV and PVB19 showed no seroconversions.

6.2 Postmarketing Experience

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

Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea

Gastrointestinal Disorders: Nausea

General Disorders and Administration Site Conditions: Fatigue

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C
Animal reproduction studies have not been conducted with GLASSIA. It is also not known whether GLASSIA can cause fetal harm when administered to pregnant women or can affect reproductive capacity. GLASSIA should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether Alpha₁-PI is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GLASSIA is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical trials of GLASSIA included 11 subjects of 65 years of age or older. This number of subjects was not sufficient 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 65 years of age have not been established.

11 DESCRIPTION

GLASSIA  is a sterile, ready to use, liquid preparation of purified human alpha₁-proteinase inhibitor (Alpha₁-PI), also known as alpha₁-antitrypsin (AAT). The solution contains 2% active Alpha₁-PI in a phosphate-buffered saline solution. The specific activity of GLASSIA is ≥ 0.7 mg functional Alpha₁-PI per mg of total protein. Not less than 90% of the Alpha₁-PI in GLASSIA is of the monomeric form as measured by size-exclusion chromatography.

GLASSIA  is prepared from human plasma obtained from US-licensed plasma collection centers by a modified version of the cold ethanol fractionation process and the Alpha₁-PI is then purified using chromatographic methods.

Individual plasma units used for production of GLASSIA  are tested using FDA- licensed serological assays for hepatitis B surface antigen (HBsAg) and for antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2), as well as by FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1. Each plasma unit must be non-reactive (negative) in all tests. Plasma is also tested by in-process NAT procedures for parvovirus B19 and the limit for B19 DNA in the manufacturing pool is set not to exceed 10⁴ IU per mL.

To reduce the risk of viral transmission, the manufacturing process for GLASSIA includes two steps specifically designed to remove or inactivate viruses. The first of these is nanofiltration (NF) through a 15 nm filter which can remove both enveloped and non–enveloped viral agents and the second is solvent/detergent (S/D) treatment with a mixture of tri-(n-butyl) phosphate (TNBP) and Polysorbate 80 (Tween 80) which inactivates enveloped viral agents such as HIV, HBV and HCV.

The effectiveness of the S/D treatment and nanofiltration procedures for reducing virus content has been assessed using a series of viruses with a range of physico-chemical characteristics. The results of the viral challenge studies are summarized in Table 4.

• Table 4: Log₁₀ Virus Reduction during Manufacture of GLASSIA

  HIV-1: Human immunodeficiency virus Type 1, PRV; Pseudorabies virus, BVDV: Bovine viral diarrhea virus, WNV: West Nile virus, HAV: Hepatitis A virus, PPV; Porcine parvovirus
  	Enveloped Viruses				Non-enveloped Viruses
  Process Step	HIV-1	PRV	BVDV	WNV	HAV	PPV
  Nanofiltration	> 5.59	> 5.57	> 5.74	NDND - Not Done	> 4.99	4.04
  S/D treatment	> 6.41	> 6.14	> 5.61	> 6.32	N/AN/A - Not Applicable. The S/D treatment is not relevant for non-enveloped viruses.	N/A
  Global Reduction Factor	> 12.00	> 11.71	> 11.35	> 6.32	> 4.99	4.04

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

GLASSIA 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 a chronic, autosomal, co-dominant hereditary disorder characterized by reduced levels of Alpha₁-PI in the blood and lungs^{1, 2}. Smoking is an important risk factor for the development of emphysema in patients with Alpha₁-PI deficiency³. Because emphysema affects many, but not all individuals with the more severe genetic variants of Αlpha₁-PI deficiency (AAT deficiency), augmentation therapy with Alpha₁-Proteinase Inhibitor (Human) is indicated only in patients with severe Αlpha₁-PI deficiency who have clinically evident emphysema.

A large number of phenotypic variants of Alpha₁-PI deficiency exist, not all of which are associated with the clinical disease. Approximately 95% of identified Alpha₁-PI deficient individuals have the PiZZ variant, typically characterized by Alpha₁-PI serum levels < 35% of normal. Individuals with the Pi(null)(null) variant have no Alpha₁-PI protein in their serum^{2, 3}. Individuals with the lack of, or low, endogenous serum levels of Alpha₁-PI, i.e., below 11 µM, manifest a significantly increased risk for development of emphysema above the general population background risk^{4, 5}. In addition, PiSZ individuals, whose serum Alpha₁-PI levels range from approximately 9 to 23 µM are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha₁-PI levels are above or below 11 µM⁶.

Augmenting the levels of functional protease 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 GLASSIA or any Alpha₁-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been conclusively demonstrated in adequately powered, randomized controlled clinical trials. Although the maintenance of blood serum levels of Alpha₁-PI (antigenically measured) above 11 µM 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 µM 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.

12.2 Pharmacodynamics

Administration of GLASSIA to patients with Alpha₁-PI deficiency augments the level of the deficient protein. Normal individuals have levels of Alpha₁-PI greater than 22 µM. The clinical benefit of the increased blood levels of Alpha₁-PI at the recommended dose has not been established.

The clinical efficacy of GLASSIA 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.

12.3 Pharmacokinetics

A prospective, open-label, uncontrolled multicenter pharmacokinetic trial was conducted in 7 females and 11 males with congenital Alpha₁-PI deficiency, ranging in age from 40 to 69 years. Subjects received a single dose of GLASSIA either 30 mg/kg, 60 mg/kg or 120 mg/kg. Blood samples for pharmacokinetic study were taken prior to and within 5 minutes of completion of the infusion, and then at 1 hour, 6 hours, 12 hours, 24 hours, 3 days and 7 days.

The mean results for pharmacokinetic parameters in the 60 mg/kg dosage group are shown in Table 5. The pharmacokinetics of GLASSIA were linear over the dose range of 30-120 mg/kg.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14 CLINICAL STUDIES

A randomized, double-blind trial with a partial cross-over was conducted to compare GLASSIA to a commercially available preparation of Alpha₁-PI (Prolastin) in 50 Alpha₁-PI-deficient subjects. The trial objectives were to demonstrate that the pharmacokinetics of antigenic and/or functional Alpha₁-PI in GLASSIA were not inferior to those of the control product, to determine whether GLASSIA maintained antigenic and/or functional plasma levels of at least 11 microM (57 mg/dL) and to compare Alpha₁-PI trough levels (antigenic and functional) over 6 infusions.

For inclusion in the trial, subjects were required to have lung disease related to Alpha₁-PI deficiency and ‘at-risk’ alleles associated with Alpha₁-PI plasma levels < 11 microM. Subjects already receiving Alpha₁-PI therapy were required to undergo a 5-week wash-out period of exogenous Alpha₁-PI prior to dosing.

Fifty subjects received either GLASSIA (33 subjects) or the comparator product (17 subjects) at a dose of 60 mg/kg intravenously per week for 12 consecutive weeks. From Week 13 to Week 24 all subjects received open-label weekly infusions of GLASSIA at a dose of 60 mg/kg.

Trough levels of functional and antigenic Alpha₁-PI were measured prior to treatment, at baseline and throughout the trial until Week 24. The median trough Alpha₁-PI values for Weeks 7-12 for subjects receiving GLASSIA were 14.5 microM (range: 11.6 to 18.5 microM) for antigenic and 11.8 microM (range: 8.2 to 16.9 microM) for functional Alpha₁-PI. Eleven of 33 subjects (33.3%) receiving GLASSIA had mean steady-state functional Alpha₁-PI levels below 11 microM. GLASSIA was shown to be non-inferior to the comparator product.

Serum Alpha₁-PI trough levels rose substantially in all subjects by Week 2 and were comparatively stable during Weeks 7 to 12. All subjects receiving GLASSIA had mean serum trough antigenic Alpha₁-PI levels greater than 11 microM during Weeks 7-12.

A subset of subjects in both treatment groups (n = 7 for subjects receiving GLASSIA) underwent broncho-alveolar lavage (BAL) and were shown to have increased levels of antigenic Alpha₁-PI and Alpha₁-PI - neutrophil elastase complexes in the epithelial lining fluid at Week 10-12 over levels found at baseline, demonstrating the ability of the product to reach the lung.

The clinical efficacy of GLASSIA 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.

A prospective, randomized, double-blind, active-controlled, crossover trial was conducted in thirty healthy adult subjects (23 [77%] male and 7 [23%] female; median age of 24 years [range: 19 to 61 years]), each receiving 2 infusions of GLASSIA at a dosage of 60 mg/kg. The objective of the trial was to assess the safety and tolerability of GLASSIA at an intravenous infusion rate of 0.2 mL/kg/min. On Day 1, 15 subjects received GLASSIA at 0.04 mL/kg/min with a simultaneous administration of placebo (2.5% human albumin in normal saline, for the purpose of masking infusion) at 0.2 mL/kg/min (Cohort 1), and 15 subjects received GLASSIA at 0.2 mL/kg/min with a simultaneous administration of placebo at 0.04 mL/kg/min (Cohort 2). Two weeks later (Day 15), the 15 subjects in Cohort 1 received the second infusion of GLASSIA at 0.2 mL/kg/min with a simultaneous administration of placebo at 0.04 mL/kg/min, and the 15 subjects in Cohort 2 received GLASSIA at 0.04 mL/kg/min with a simultaneous administration of placebo at 0.2 mL/kg/min. Neither efficacy nor exposure (antigenic or functional AAT) was measured in this trial.

15 REFERENCES

• WHO. "α₁-Antitrypsin deficiency." Memorandum from a WHO meeting. 1997;75: 397-415.
• Stoller JK, et al. Augmentation therapy with α₁-antitrypsin: patterns of use and adverse events. Chest 2003;123:1425-34.
• Cox DW. α₁-Antitrypsin Deficiency. In: Scriver C, Sly W, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2002:5559-78.
• Crystal RG, et al. The alpha₁-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest 1989;95:196-208.
• Crystal RG. α₁-Antitrypsin deficiency: pathogenesis and treatment. Hosp Pract (Off Ed) 1991;26:81-4, 8-9, 93-4.
• Turino GM, et al. Clinical features of individuals with PI*SZ phenotype of α₁-antitrypsin deficiency. Am J Respir Crit Care Med 1996;154:1718-25.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Each carton of GLASSIA contains a single use vial containing approximately 1 gram of functional Alpha₁-PI in 50 mL of solution and a sterile filter needle (NDC 0944-2884-01).

Storage and Handling

• Store GLASSIA at 2-8 °C (36-46 °F). Do not freeze.
• Product may be stored at room temperatures not exceeding 25 °C (77 °F) for up to one month.
• Use product removed from refrigeration within one month.
• Keep vial in carton until required for use.
• Do not use after the expiration date printed on the label.
• GLASSIA contains no preservatives and no latex.

   

17 PATIENT COUNSELING INFORMATION

• 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 GLASSIA is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk of GLASSIA transmitting an infectious agent has been reduced by screening the plasma donors, by testing the donated plasma for certain virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing [see Warnings and Precautions (5.2)]. Symptoms of a possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice.
• Inform patients that administration of GLASSIA has been demonstrated to raise the plasma level of Alpha₁-PI, 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.

Manufactured by:

Kamada Ltd.
Beit Kama
MP Negev 85325
Israel

U.S. License No. 1826

Distributed by:

Baxter Healthcare Corporation
Westlake Village, CA 91362
USA

Principal display panel

ALPHA-1 PROTEINASE INHIBITOR (HUMAN)

GLASSIA^®

For Intravenous Administration Only

Injection Solution

50 mL