Alpha-Proteinase Inhibitor

Zemaira is a sterile, white, lyophilized preparation of purified Alpha1-Proteinase Inhibitor (Human) (A1-PI), also known as alpha1-antitrypsin, to be reconstituted and administered by the intravenous route. The specific activity of Zemaira is ≥ 0.7 mg of functional A1-PI per milligram of total protein. The purity (total A1-PI/total protein) is ≥ 90% A1-PI. Each vial contains approximately 1000 mg of functionally active A1-PI. The measured amount per vial of functionally active A1-PI as determined by its capacity to neutralize human neutrophil elastase (NE) is printed on the vial label and carton. Following reconstitution with 20 mL of Sterile Water for Injection, USP, the Zemaira solution contains 73 to 89 mM sodium, 33 to 42 mM chloride, 15 to 20 mM phosphate, and 121 to 168 mM mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust the pH. Zemaira contains no preservative.

All plasma used in the manufacture of Zemaira is obtained from US donors and is tested using serological assays for HBsAg and antibodies to HIV-½ and HCV. The plasma is tested with Nucleic Acid Testing (NAT) for HBV, HCV, HIV-1, and HAV, and found to be nonreactive (negative). The plasma is also tested by NAT for B19V. Only plasma that passed the virus screening is used for production. The limit for B19V in the fractionation pool is ≤ 104 International Units of B19V per mL.

Zemaira is manufactured from large pools of human plasma by cold ethanol fractionation according to a modified Cohn process followed by additional purification steps. The manufacturing process includes two virus clearance steps: heat treatment at 60°C for 10 hours in an aqueous solution with stabilizers; and nanofiltration. These virus clearance steps have been validated in a series of in vitro experiments for their capacity to inactivate/ remove both enveloped and non-enveloped viruses. Table 5 shows the virus clearance capacity of the Zemaira manufacturing process, expressed as mean log10 reduction factor.

Table 5: Cumulative (Log10) Virus Inactivation/Removal in Zemaira

Included as part of the PRECAUTIONS section.

Alpha 1-proteinase inhibitor is a protein, also called alpha 1-antitrypsin. This protein occurs naturally in the body and is important for preventing the breakdown of tissues in the lungs.

In people who lack the alpha 1-antitrypsin protein, breakdown of lung tissues can lead to emphysema (damage to the air sacs in the lungs).

Alpha 1-proteinase inhibitor is used to treat alpha 1-antitrypsin deficiency in people who have symptoms of emphysema.

Alpha 1-antitrypsin deficiency is a genetic (inherited) disorder and alpha 1-proteinase inhibitor will not cure this condition.

Alpha 1-proteinase inhibitor may also be used for purposes not listed in this medication guide.

Call your doctor for instructions if you miss a dose of alpha 1-proteinase inhibitor.

Your pharmacist can provide more information about alpha 1-proteinase inhibitor.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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The most common adverse reactions (ARs) occurring in at least 5% of subjects receiving Zemaira in all pre-licensure clinical trials were headache, sinusitis, upper respiratory infection, bronchitis, asthenia, cough increased, fever, injection site hemorrhage, rhinitis, sore throat, and vasodilation. Serious adverse reactions reported following administration of Zemaira in pre-licensure clinical trials included one event each in separate subjects of bronchitis and dyspnea, and one event each in a single subject of chest pain, cerebral ischemia and convulsion.

In post-licensure trials, the exposure adjusted incidence rate (EAIR) of serious exacerbations of chronic obstructive pulmonary disease (COPD) among subjects was higher during the RAPID Extension trial as compared to the rate observed during the preceding RAPID trial [see Clinical Trials Experience below].

Serious adverse reactions identified during postmarketing use were hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].

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 prelicensure clinical trials of Zemaira.

Table 1: Overall Adverse Reactions (ARs) and Serious ARs

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.

Table 2: Adverse Reactions Occurring in ≥ 5% of Subjects

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

In a retrospective analysis, during the 10-week blinded portion of the 24-week clinical trial, 6 subjects (20%) of the 30 treated with Zemaira had a total of 7 exacerbations of their chronic obstructive pulmonary disease (COPD). Nine subjects (64%) of the 14 treated with Prolastin had a total of 11 exacerbations of their COPD. The observed difference between groups was 44% (95% confidence interval [CI] from 8% to 70%). Over the entire 24-week treatment period, of the 30 subjects in the Zemaira treatment group, 7 subjects (23%) had a total of 11 exacerbations of their COPD.

In the 24-week double-blind trial, Zemaira-treated subjects were tested for HAV, HBV, HCV, HIV, and parvovirus B19 (B19V), and no evidence of virus transmission was observed. In the RAPID study 25 serious exacerbations of COPD were reported in 15 Zemaira subjects vs. 17 such events in 9 placebo subjects, corresponding to rates of 0.146 exacerbations per subject-year with Zemaira and 0.115 exacerbations per subject-year with placebo, (ratio Zemaira:Placebo [95% confidence interval]: 1.256 [0.457 - 3.454]).

Subjects who were randomized to Zemaira in the 2-year RAPID trial who then entered and received open-label Zemaira in the 2 year RAPID extension trial were in the “Early Start” group. Subjects who were randomized to Placebo in the 2-year RAPID trial who then entered and received open-label Zemaira in the 2 year RAPID extension trial were in the “Delayed Start” group. During the RAPID Extension trial 37 serious exacerbations of COPD were reported in 19 subjects (25%) in the Early Start group, corresponding to rates of 0.25 exacerbations per subject-year. In comparison, 20 serious exacerbations were reported in 11 subjects (17%) in the Delayed Start group corresponding to rates of 0.16 exacerbations per subject-year (ratio Early: Delayed [95% confidence interval]: 1.58 [0.68 - 3.66], Table 3). Among the Early Start subjects who entered the RAPID extension trial (N = 76), the exposure adjusted incidence rate of serious exacerbations during the RAPID extension trial (years 3-4) was 0.25 compared to 0.12 for those subjects during the earlier RAPID trial(years 1-2), (ratio RAPID Extension:RAPID: 2.10 [95% confidence interval: 1.21 - 3.67]). Among the Delayed Start subjects who entered the RAPID extension trial (N = 64), the exposure adjusted incidence rate of serious exacerbations during the RAPID extension trial (years 3-4) was 0.16 compared to 0.10 for those subjects during the earlier RAPID trial (years 1-2), (ratio RAPID Extension:RAPID: 1.56 [95% confidence interval: 0.80 - 3.03]).

Table 3: Comparison of Exposure-Adjusted Incidence Rates for Serious COPD Exacerbations Occurring in the RAPID study between Zemaira and Placebo subjects and in the RAPID Extension Studies between Early Start and Delayed Start subjects

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.

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 Clinical Trials Experience above].

Table 4: ARs Reported During the Postmarketing Use of Zemaira

Read the entire FDA prescribing information for Zemaira (Alpha-Proteinase Inhibitor (Human))