2.1 Preparation and Reconstitution

• Check the expiration date on the vial label and carton. Do not use ZEMAIRA after the expiration date.
• Reconstitute prior to use according to the instructions provided below.
• Reconstitute ZEMAIRA using aseptic technique to maintain product sterility.
• Total reconstitution time for a 1g vial should be obtained within 5 minutes.
• Total reconstitution time for a 4g or 5g vial should be obtained within 10 minutes.
• Inspect the reconstituted solution prior to administration. The solution should be clear, colorless to slightly yellow, and free from visible particles.
• Reconstituted ZEMAIRA may be stored at room temperature. Do not freeze the reconstituted solution.

Follow the steps provided below for the preparation and reconstitution of ZEMAIRA:

1.

Ensure that the ZEMAIRA vial and Sterile Water for Injection vial are at room temperature.

2.

Remove the plastic flip-top cap from the Sterile Water for Injection vial.

3.

Wipe the rubber stopper of the Sterile Water for Injection vial with antiseptic solution and allow it to dry.

4.

Open the Mix2Vial® filter transfer set by peeling off the lid (Fig. 1). Do not remove the transfer set from the blister package.

Fig. 1

5.

Place the Sterile Water for Injection vial on an even, clean surface and hold the vial tight. Take the transfer set together with the blister package and vertically pierce the Sterile Water for Injection vial with the blue tip of the transfer set (Fig. 2).

Fig. 2

6.

Carefully remove the blister package from the transfer set by holding at the rim, and pulling vertically upwards. Make sure that you only pull away the blister package and not the transfer set (Fig. 3).

Fig. 3

7.

Remove the plastic flip-top cap from the ZEMAIRA vial.

8.

Wipe the rubber stopper of the ZEMAIRA vial with antiseptic solution and allow it to dry.

9.

Place the ZEMAIRA vial on an even and firm surface. Invert the Sterile Water for Injection vial with the transfer set attached and vertically pierce the ZEMAIRA vial with the clear tip of the transfer set (Fig. 4). The Sterile Water for Injection will automatically flow into the ZEMAIRA vial.

Note: Ensure all water has transferred into the ZEMAIRA vial.

Fig. 4

10.

Follow steps below to remove entire transfer set from ZEMAIRA vial:

• With one hand tightly grasp the ZEMAIRA vial as shown in Fig. 5.
• With the other hand tightly grasp Sterile Water for Injection vial and blue transfer set.
• Bend the entire transfer set to the side until it disconnects from the ZEMAIRA vial (Fig. 5).
• Discard the Sterile Water for Injection vial with the entire transfer set.

Fig. 5

11.

Gently swirl the ZEMAIRA vial until the powder is completely dissolved (Fig. 6). DO NOT SHAKE. Take care not to touch the rubber vial stopper.

Fig. 6

If more than 1 vial of ZEMAIRA is needed to achieve the required dose, use aseptic technique to transfer the reconstituted solution from the vials into the administration container (e.g., empty intravenous bag or glass bottle).

2.2 Administration

For intravenous use only.

• Do not mix ZEMAIRA with other medicinal products; administer ZEMAIRA through a separate dedicated infusion line.
• Perform a visual inspection of the reconstituted solution. The solution should be clear, colorless to slightly yellow, and free from visible particles.
• Administer at room temperature within 3 hours after reconstitution.
• Filter the reconstituted solution during administration. To ensure proper filtration of ZEMAIRA, use an intravenous administration set with a suitable 5 micron infusion filter (not supplied).
• Administer ZEMAIRA intravenously at a rate of approximately 0.08 mL/kg/min as determined by the response and comfort of the patient. The recommended dosage of 60 mg/kg body weight will take approximately 15 minutes to infuse.
• Monitor closely the infusion rate and the patient's clinical state, including vital signs, throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
• ZEMAIRA is for single dose only. Following administration, discard any unused solution and all administration equipment in an appropriate manner as per local requirements.

5.1 Hypersensitivity to Other A1-PI Products

Observe any signs of hypersensitivity such as tachycardia, hypotension, confusion, syncope, oxygen consumption decrease, and pharyngeal edema when administering ZEMAIRA to patients with known hypersensitivity to an A1-PI product. If anaphylactic or severe anaphylactoid reactions occur, discontinue the infusion immediately. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction.

5.2 Hypersensitivity to IgA

ZEMAIRA may contain trace amounts of IgA. Patients with selective or severe IgA deficiency can develop antibodies to IgA and, therefore, have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. If anaphylactic or severe anaphylactoid reactions occur, discontinue the infusion immediately. Have epinephrine and other appropriate supportive therapy available for the treatment of any acute anaphylactic or anaphylactoid reaction. ZEMAIRA is contraindicated in IgA-deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

5.3 Transmissible Infectious Agents

Because ZEMAIRA is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for ZEMAIRA [see Description (11)]. Despite these measures, ZEMAIRA, like other products made from human blood, may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated.

All infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The following clinical trials were conducted with ZEMAIRA:

• Controlled, double-blind trial in 44 subjects, who received a weekly 60 mg/kg body weight dose of either ZEMAIRA (30 subjects) or Prolastin® (a commercially available Alpha1-Proteinase Inhibitor [Human] product) (14 subjects) for 10 weeks, followed by an open-label phase in which 43 subjects received ZEMAIRA weekly for 14 weeks;
• Open-label trial in 9 subjects who received a weekly 60 mg/kg body weight dose of ZEMAIRA for 26 weeks, followed by a 7-week to 22-week extension;
• Crossover, double-blind trial in 18 subjects who received a single 60 mg/kg dose of ZEMAIRA and a single 60 mg/kg dose of Prolastin;
• Open-label trial of 19 subjects who received a single 15 mg/kg (2 subjects), 30 mg/kg (5 subjects), 60 mg/kg (6 subjects), or 120 mg/kg (6 subjects) dose of ZEMAIRA; and
• Post-Licensure Randomized, Placebo-Controlled Trial of Augmentation Therapy in Alpha-1 Protease Inhibitor Deficiency (RAPID), in 180 subjects who received a weekly 60 mg/kg body weight dose of either ZEMAIRA (93 subjects) or placebo (87 subjects) for 24 months (referred to as years 1 and 2 in Table 3).
• Post-Licensure Open-label extension of the RAPID trial involving 140 subjects who had completed blinded treatment with ZEMAIRA or placebo for 24 months in the RAPID trial and who entered the extension trial and received open-label ZEMAIRA for up to an additional 24 months (referred to as years 3 and 4 in Table 3).

Table 1 summarizes the ARs, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in pre-licensure clinical trials of ZEMAIRA.

Table 2 summarizes the ARs occurring in 5% or more (>3) subjects, expressed as events per subject-year, and the corresponding number of ARs per infusion, expressed as % of all infusions, for each treatment in clinical trials of ZEMAIRA.

Diffuse interstitial lung disease was noted on a routine chest x-ray of one subject at Week 24. Causality could not be determined.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. No anti-A1PI antibodies have been detected in clinical trials of ZEMAIRA. 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 ZEMAIRA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Table 4 lists the ARs that have been identified during postmarketing use of ZEMAIRA. This list does not include reactions already reported in clinical trials with ZEMAIRA [see Adverse Reactions (6.1)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

8.5 Geriatric Use

The safety and efficacy of ZEMAIRA in the geriatric population have not been established due to an insufficient number of subjects.

12.1 Mechanism of Action

A1-PI deficiency is a chronic, hereditary, autosomal, co-dominant disorder that is usually fatal in its severe form. Low blood levels of A1-PI (i.e., below 11 µM) are most commonly associated with progressive, severe emphysema that becomes clinically apparent by the third to fourth decade of life. In addition, PiSZ individuals, whose serum A1-PI levels range from approximately 9 to 23 µM, are considered to have a moderately increased risk for developing emphysema, regardless of whether their serum A1-PI levels are above or below 11 µM.2 Not all individuals with severe genetic variants of A1-PI deficiency have emphysema. Augmentation therapy with alpha1-proteinase inhibitor (human) is indicated only in patients with severe congenital A1-PI deficiency who have clinically evident emphysema. A registry study showed 54% of A1-PI deficient subjects had emphysema.3 Another registry study showed 72% of A1-PI deficient subjects had pulmonary symptoms.4 Smoking is an important risk factor for the development of emphysema in patients with A1-PI deficiency.

Approximately 100 genetic variants of A1-PI deficiency can be identified electrophoretically, only some of which are associated with the clinical disease.5,6 Ninety-five percent of clinically symptomatic A1-PI deficient individuals are of the severe PiZZ phenotype. Up to 39% of A1-PI deficient patients may have an asthmatic component to their lung disease, as evidenced by symptoms and/or bronchial hyperreactivity.3 Pulmonary infections, including pneumonia and acute bronchitis, are common in A1-PI deficient patients and contribute significantly to the morbidity of the disease.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with A1-PI deficiency. However, the efficacy of augmentation therapy in affecting the progression of emphysema has not been demonstrated in randomized, controlled clinical studies. The intended theoretical goal is to provide protection to the lower respiratory tract by correcting the imbalance between NE and protease inhibitors. Whether augmentation therapy with ZEMAIRA or any A1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been evaluated. Individuals with endogenous levels of A1-PI below 11 µM, in general, manifest a significantly increased risk for development of emphysema above the general population background risk.6,7,8,9 Although the maintenance of blood serum levels of A1-PI (antigenically measured) above 11 µM has been historically postulated to provide therapeutically relevant anti-neutrophil elastase protection10, this has not been proven. Individuals with severe A1-PI deficiency have been shown to have increased neutrophil and NE concentrations in lung epithelial lining fluid compared to normal PiMM individuals, and some PiSZ individuals with A1-PI above 11 µM have emphysema attributed to A1-PI deficiency.2 These observations underscore the uncertainty regarding the appropriate therapeutic target serum level of A1-PI during augmentation therapy.

Pulmonary disease, particularly emphysema, is the most frequent manifestation of A1-PI deficiency.6 The pathogenesis of emphysema is understood to evolve as described in the "protease-antiprotease imbalance" model. A1-PI is now understood to be the primary antiprotease in the lower respiratory tract, where it inhibits NE.11 Normal healthy individuals produce sufficient A1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of lung tissue by NE. Conditions that increase neutrophil accumulation and activation in the lung, such as respiratory infection and smoking, will in turn increase levels of NE. However, individuals who are severely deficient in endogenous A1-PI are unable to maintain an appropriate antiprotease defense and are thereby subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. ZEMAIRA serves as A1-PI augmentation therapy in this patient population, acting to increase and maintain serum levels and ELF levels of A1-PI.

12.2 Pharmacodynamics

Weekly repeated infusions of A1-PI at a dose of 60 mg/kg lead to serum A1-PI levels above the historical target threshold of 11 µM.

The clinical benefit of the increased blood levels of A1-PI at the recommended dose has not been established for any A1-PI product.

12.3 Pharmacokinetics

A double-blind, randomized, active-controlled, crossover pharmacokinetic study was conducted in 13 males and 5 females with A1-PI deficiency, ranging in age from 36 to 66 years. Nine subjects received a single 60 mg/kg dose of ZEMAIRA followed by Prolastin, and 9 subjects received Prolastin followed by a single 60 mg/kg dose of ZEMAIRA, with a wash-out period of 35 days between doses. A total of 13 post-infusion serum samples were taken at various time points up to Day 21. Table 6 shows the mean results for the ZEMAIRA pharmacokinetic parameters.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenesis, mutagenesis, or impairment of fertility have not been conducted.

13.2 Animal Toxicology and/or Pharmacology

In a safety pharmacology study, dogs were administered a 60 or 240 mg/kg intravenous dose of ZEMAIRA. At the clinical dose of 60 mg/kg, no changes in cardiovascular and respiratory parameters or measured hematology, blood chemistry, or electrolyte parameters were attributed to the administration of ZEMAIRA. A minor transient decrease in femoral resistance and increase in blood flow were observed after administration of the 240 mg/kg dose.

In single-dose studies, mice and rats were administered a 0, 60, 240, or 600 mg/kg intravenous dose of ZEMAIRA and observed twice daily for 15 days. No signs of toxicity were observed up to 240 mg/kg. Transient signs of distress were observed in male mice and in male and female rats after administration of the highest dose (600 mg/kg).

In repeat-dose toxicity studies, rats and rabbits received 0, 60, or 240 mg/kg intravenous doses of ZEMAIRA once daily for 5 consecutive days. No treatment-related effects on clinical signs, body weight, hematology, coagulation, or urinalysis were observed in rats administered up to 240 mg/kg. No signs of toxicity were observed in rabbits administered 60 mg/kg. Changes in organ weights and minimal epidermal ulceration were observed in rabbits administered 240 mg/kg, but had no clinical effects.

The local tolerance of ZEMAIRA was evaluated in rabbits following intravenous, perivenous, and intraarterial administration. No treatment-related local adverse reactions were observed.

Storage and Handling

• When stored up to 25°C (77°F), ZEMAIRA is stable for the period indicated by the expiration date on its vial label and carton.
• Avoid freezing, which may damage the diluent vial.
• Discard any unused product and all used disposable supplies.