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

1. Use aseptic technique.
2. Allow the product to reach room temperature prior to infusing and administer within three hours of entering the vials.
3. 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.
4. 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.

1. Use aseptic technique.
2. Inspect parenteral products visually for particulate matter and discoloration prior to administration whenever solution and container permit.
3. Administer GLASSIA alone. Do not mix with other agents or diluting solutions.
4. 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.
5. Always use a 5 micron in-line filter (not supplied) during infusion.
6. Administer GLASSIA within three hours of entering the vials to avoid the potential ill effect of any inadvertent microbial contamination.
7. 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.
8. 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.
9. Following administration, discard all open vials, unused solution and administration equipment.

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.

6.1 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.

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

8.1 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.

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 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 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 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 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.

13.1 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.