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GLASSIA
[Alpha1-Proteinase Inhibitor (Human)] Liquid
for Intravenous Infusion
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 10 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
| Process Step | Enveloped Viruses | Non-enveloped Viruses | ||||
| HIV-1 | PRV | BVDV | WNV | HAV | PPV | |
| Nanofiltration | > 5.59 | > 5.57 | > 5.74 | ND | > 4.99 | 4.04 |
| S/D treatment | > 6.41 | > 6.14 | > 5.61 | > 6.32 | N/A | N/A |
| Global Reduction Factor | > 12.00 | > 11.71 | > 11.35 | > 6.32 | > 4.99 | 4.04 |
| N/A - Not Applicable. The S/D treatment is not relevant for non-enveloped viruses. ND - Not Done HIV-1 Human immunodeficiency virus Type 1 WNV West Nile virus PRV Pseudorabies virus HAV Hepatitis A virus BVDV Bovine viral diarrhea virus PPV Porcine parvovirus |
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GLASSIA, is an Alpha1 -Proteinase Inhibitor (Human), indicated for chronic augmentation and maintenance therapy in individuals with clinically evident emphysema due to severe hereditary 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.
For intravenous use only.
The carton and label on each vial of GLASSIA show the actual amount of functionally active Alpha1 1-PI in milligrams.
For Intravenous Infusion Only.
GLASSIA should be administered by a healthcare professional or self-administered by the patient/caregiver after appropriate training. For self-administration, provide the patient/caregiver with detailed instructions and adequate training for infusion in the home or other appropriate setting [see PATIENT INFORMATION].
GLASSIA is available as a single-use vial containing approximately 1 gram of functional Alpha1 -PI in 50 mL of ready to use solution.
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).
Manufactured by: Kamada Ltd. Beit Kama, MP Negev 8532500 Israel. Revised: Jun 2016
The serious adverse reaction observed during clinical trials with GLASSIA was exacerbation of chronic obstructive pulmonary disease (COPD).
The most common adverse reactions (>0.5% of infusions) in clinical trials were headache and upper respiratory infection.
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 profile of GLASSIA was evaluated in a randomized, double-blind, active-control trial and an open-label, non-parallel, dose-escalation trial, in 65 subjects with pre-augmentation therapy serum Alpha1 -PI levels less than 11 microM. In the randomized, double-blind, active-control trial, 50 subjects received 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.). In the open label, nonparallel, dose-escalation trial, 18 subjects received a single infusion of GLASSIA at dosages of 30, 60 or 120 mg/kg. The population treated in the two trials was 40-74 years old, 54% male, 100% Caucasian.
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 Reactions* 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 |
| *An 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. | ||
Table 2: Adverse Reactions* Occurring in > 5% of Subjects during the First 12 Weeks of
Treatment
| Adverse Event (AE) | GLASSIA No. of subjects: 33 |
Prolastin No. of subjects: 17 |
| 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%) |
| *An 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. | ||
Table 3: Adverse Reactions1 Frequency as a % of all Infusions (> 0.5%)
| Adverse Event (AE) | GLASSIAa No. of infusions: 960 |
Prolastinb No. of infusions: 190 |
| No. of adverse reactions1 (AR) (percentage of all infusions) |
No. of adverse reactions1 (AR) (percentage of all infusions) |
|
| Upper respiratory tract infection | 8 (0.8%) | 0 (0.0%) |
| Headache | 6 (0.6%) | 3 (1.6%) |
| 1An 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. aThroughout entire 24-week double-blind plus open-label trial period bThroughout initial 12-week double-blind period |
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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. Testing for viral markers for HBV, HCV, HIV-1 and HIV-2 showed no seroconversions during either trial.
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to GLASSIA with the incidence of antibodies to other products may be misleading.
In the double blind, randomized, active comparator trial of GLASSIA, low level anti-GLASSIA antibodies were detected in one subject at one time point (Week 12) and returned to negative at the end of the study (Week 24) despite continuous exposure to GLASSIA. No immune system adverse reactions were reported.
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.
Dyspnea
Nausea
Fatigue
No Information Provided
Included as part of the "PRECAUTIONS" Section
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/or other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.
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.
If self-administration is deemed appropriate, ensure that the patient/caregiver receives detailed instructions and adequate training on how to administer in the home or other appropriate setting and has demonstrated the ability to independently administer GLASSIA.
There is no data with GLASSIA use in pregnant women to inform a drug-associated risk. 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.
There is no information regarding the presence of GLASSIA in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GLASSIA and any potential adverse effects on the breastfed infant from GLASSIA.
Safety and effectiveness in pediatric patients have not been established.
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.
No Information Provided
GLASSIA is contraindicated in:
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 lungs1,2. 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 &Alpha1;lpha -PI deficiency (AAT deficiency), augmentation therapy with Alpha1 -Proteinase Inhibitor (Human) is indicated only in patients with severe &Alpha1;lpha -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 serum2,3. 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 risk4,5. 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 antineutrophil 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.
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.
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.
Table 5: Pharmacokinetic Parameters for Functional Alpha1 -PI (Dosage 60 mg/kg;
n=6)
| Pharmacokinetic Parameter | 60 mg/kg Dose Group |
| Terminal Half-Life (h)* | 111 ± 33 |
| Area under the curve(0-168 h) (mg·h/mL) | 89 ± 10 |
| Clearance (mL/h/kg) | 0.68 ± 0.1 |
| Volume of Distribution (L) | 3.2 ± 0.3 |
| *Any assessment of the clinical relevance of half-life in this trial should be viewed with caution, due to the short duration of blood sampling. | |
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.
REFERENCES
1. WHO. "α1 -Antitrypsin deficiency." Memorandum from a WHO meeting. 1 1997;75: 397-415.
2. Stoller JK, et al. Augmentation therapy with α1 -antitrypsin: patterns of use and adverse events. Chest 2003; 123:1425-34.
3. 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.
4. Crystal RG, et al. The alpha1 -antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest 1989;95:196-208.
5. Crystal RG. α1 -Antitrypsin deficiency: pathogenesis and treatment. Hosp Pract (Off Ed) 1991;26:81-4, 8-9, 93-4.
6. 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.
GLASSIA
[Alpha1 -Proteinase Inhibitor (Human)] for Intravenous Administration
The following summarizes important information about GLASSIA (pronounced glass-see-a). Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about GLASSIA. If you have any questions after reading this, ask your healthcare professional.
What is GLASSIA?
GLASSIA is a liquid medicine containing human Alpha1 -Proteinase Inhibitor (Alpha1 -PI) also known as alpha1 -antitrypsin (AAT), which is purified from human blood. The main purpose of infusing GLASSIA is to increase the levels of the AAT protein in your blood and lungs. AAT protein protects the lung tissue by blocking certain enzyme-caused damage. Such damage can lead to severe lung disease, such as emphysema.
Limitations of Use:
Who should not take GLASSIA?
You should not use GLASSIA if you:
What is the most important information that I should know about GLASSIA?
Severe allergic reactions can occur with GLASSIA. Your doctor will inform you about signs of allergic reactions which include hives, swelling in the mouth or throat, itching, tightness in the chest, trouble breathing, wheezing, faintness, low blood pressure, or serious allergic reaction. If you have any of these reactions, discontinue use of the product and contact your physician and/or seek immediate emergency care, depending on the severity of the reaction.
If you or your caregiver will be administering GLASSIA outside a healthcare setting, ask your doctor about an epinephrine pen and/or other supportive care for certain severe allergic reactions. Ask your doctor to make sure you receive training on how and when to use any prescribed supportive care medicine and keep it close at hand when administering GLASSIA.
How should I take GLASSIA?
What should I tell my healthcare professional before I start using GLASSIA?
Before starting GLASSIA, tell your healthcare professional if you:
What are the possible or reasonably likely side effects of GLASSIA?
These are not all of the possible side effects for GLASSIA. You can ask your healthcare professional for information that is provided to healthcare professionals. Talk to your healthcare professional about any side effects that bother you or that don’t go away.
How do I store GLASSIA?
Store GLASSIA refrigerated or at room temperature.
Check the expiration date on the carton and vial label. Do not use GLASSIA after the expiration date.
INSTRUCTIONS FOR USE
GLASSIA
[Alpha1 -Proteinase Inhibitor (Human)]
For intravenous use only
Do not attempt to do an infusion to yourself unless you or your caregiver have been taught how by your healthcare professional.
Always follow the specific instructions given by your healthcare professional. The steps listed below are general guidelines for using GLASSIA. If you are unsure of the procedures, call your healthcare professional before using.
Prepare a clean flat surface and gather all the materials you will need for the infusion. Check the expiration date, and let the vial of GLASSIA warm up to room temperature. Do not apply heat, place in hot water, or microwave. Wash your hands and put on clean exam gloves. If you are infusing yourself at home, the use of gloves is optional.
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