Prolastin-C

Generic Name: alpha-1-proteinase inhibitor human

Indications and Usage for Prolastin-C

Prolastin-C is a preparation of alpha1-proteinase inhibitor that is indicated for chronic augmentation and maintenance therapy in adults with emphysema due to deficiency of alpha1-proteinase inhibitor (Alpha1-PI, alpha1-antitrypsin deficiency). The effect of augmentation therapy with any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in alpha1-antitrypsin deficiency has not been demonstrated in adequately powered, randomized, controlled, clinical trials. Prolastin-C is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established.

Prolastin-C Dosage and Administration

For intravenous use only.

The recommended dose of Prolastin-C is 60 mg/kg body weight administered once weekly. Dose ranging studies using efficacy endpoints have not been performed with any alpha1-proteinase inhibitor product. Each vial of Prolastin-C contains the labeled amount of functionally active Alpha1-PI in milligrams (as determined by the capacity to neutralize porcine pancreatic elastase) as stated on the label.

Prolastin-C should be given 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 takes approximately 15 minutes to infuse.

Preparation and Handling

  • Do not freeze. Breakage of the diluent bottle may occur.
  • Prolastin-C and diluent should be at room temperature before reconstitution.
  • Inspect reconstituted Prolastin-C visually for particulate matter and discoloration prior to pooling and use.
  • Prolastin-C should be kept at room temperature after reconstitution and should be administered within 3 hours.
  • Prolastin-C should be given alone, without mixing with other agents or diluting solutions.
  • Reconstituted product from several vials may be pooled into an empty, sterile IV solution container by using aseptic technique.
  • Do not use after expiration date.

Administration

Each product package contains one Prolastin-C single use vial, one 20 mL vial of Sterile Water for Injection (diluent), one color-coded sterile transfer needle, and one sterile filter needle. Administer within three hours after reconstitution.

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Reconstitution

Use aseptic technique.

  1. Prolastin-C and diluent should be at room temperature before reconstitution.
  2. Remove the plastic flip tops from each vial.
  3. Swab the exposed stopper surfaces with alcohol and allow surface to dry.
  4. Remove the plastic cover from the short end of the transfer needle. Insert the exposed end of the needle through the center of the stopper in the DILUENT vial.
  5. Remove the cover at the other end of the transfer needle by twisting it carefully.
  6. Invert the DILUENT vial and insert the attached needle into the PRODUCT vial at a 45° angle (Figure A below). This will direct the stream of diluent against the wall of the product vial and minimize foaming. The vacuum will draw the diluent into the PRODUCT vial.
  7. Remove the DILUENT bottle and transfer needle.
  8. Immediately after adding the diluent, swirl vigorously for 10-15 seconds to thoroughly break up cake then swirl continuously until the powder is completely dissolved (Figure B below). Some foaming will occur, but does not affect the quality of the product.
  9. Inspect the vial visually for particulate matter and discoloration prior to pooling and administration. A few small particles may occasionally remain after reconstitution. If particles are visible, remove by passage through a sterile filter (e.g., 15 micron filter) used for administering blood products (not supplied).
  10. Reconstituted product from several vials may be pooled into an empty, sterile IV solution container by using aseptic technique. A sterile filter needle is provided for this purpose.

Described here is one acceptable method of reconstitution.  The product could also be reconstituted with other appropriate devices according to the manufacturer’s accepted procedure. 

Shelf Life

Prolastin-C should be stored at temperatures not to exceed 25°C (77°F) for the period indicated by the expiration date on its label.

Special Precautions for Storage

Freezing should be avoided as breakage of the diluent bottle might occur.

Dosage Forms and Strengths

Prolastin-C is supplied in 1000 mg single use vials with a separate 20 mL vial of Sterile Water for Injection, USP.

Contraindications

Prolastin-C is contraindicated in IgA deficient patients with antibodies against IgA, due to the risk of severe hypersensitivity.

Warnings and Precautions

Sensitivity

Hypersensitivity reactions may occur. Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly and appropriate countermeasures and supportive therapy should be administered. (See Patient Counseling Information [17])

Prolastin-C 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 potentially severe hypersensitivity and anaphylactic reactions. Prolastin-C is contraindicated in patients with antibodies against IgA.

Viral Clearance

Products made from human plasma may carry a risk of transmitting infectious agents, e.g., viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. In each of 2 randomized, double-blind studies in which the predecessor product, PROLASTIN® (Alpha1-Proteinase Inhibitor [Human]), was compared to other Alpha1 products, there was a single case of parvovirus B19 seroconversion in the PROLASTIN arms of each trial. In each case, it could not be determined whether parvovirus B19 had been acquired from PROLASTIN or from the community. However, during clinical studies with Prolastin-C, there were no reported treatment emergent cases of hepatitis B, hepatitis C, HIV or parvovirus B19 viral infections. Furthermore, the Prolastin-C process incorporates additional plasma safety and virus reduction measures that minimize the residual risk of virus transmission (See Description [11]).

The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to a patient. (See Patient Counseling Information [17]). 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 Talecris Biotherapeutics, Inc. [1-800-520-2807].

Adverse Reactions

The most serious adverse reaction observed during clinical studies with Prolastin-C was an abdominal and extremity rash in one subject. The rash resolved subsequent to outpatient treatment with antihistamines and steroids. Two instances of a less severe, pruritic abdominal rash were observed upon rechallenge despite continued antihistamine and steroid treatment, which led to withdrawal of the subject from the trial.

The most common drug-related adverse reactions observed at a rate of ≥ 1% in subjects receiving Prolastin-C were chills, malaise, headache, rash, hot flush and pruritus.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.

Two separate clinical studies were conducted with Prolastin-C: (1) A 20 week, open-label, single arm safety study in 38 subjects, and (2) A 16 week, randomized, double-blind, crossover pharmacokinetic comparability study vs. PROLASTIN in 24 subjects, followed by an 8 week open-label treatment with Prolastin-C. Thus, 62 subjects were exposed to Prolastin-C in clinical trials.

Adverse reactions considered drug related by the investigators occurring in 1.6% of subjects (one subject each) treated with Prolastin-C were malaise, headache, rash, hot flush, and pruritus. Drug related chills occurred in 3.2% (2 subjects) of Prolastin-C subjects.

Adverse events occurring irrespective of causality in ≥ 5% of subjects in the first 8 weeks of treatment are shown in Table 1. Adverse events which occurred in the first 8 weeks of treatment are shown in the table in order to control for the differing treatment durations of the safety and PK studies (20 weeks vs. two 8 week periods).

Table 1: Adverse Events Occurring in ≥ 5% of Subjects in the First 8 Weeks of Treatment Irrespective of Causality
  PROLASTIN® -C
No. of subjects: 62
PROLASTIN®
No. of subjects: 24
Adverse Event No. of subjects with AE
(percentage of all subjects)
No. of subjects with AE
(percentage of all subjects)
Source: studies 11815 and 11816
Nausea 4 (6.5%) 0
Urinary Tract Infection 4 (6.5%) 0
Headache 3 (4.8%) 2 (8.3%)
Arthralgia 2 (3.2%) 2 (8.3%)

Table 2 below displays the overall adverse rate (> 0.5%), irrespective of causality, as a percentage of infusions received.

Table 2: Adverse Event Frequency as a % of all infusions (> 0.5%) Irrespective of Causality
  PROLASTIN® -C
No. of infusions: 1132
PROLASTIN®
No. of infusions: 192
Adverse Event No. of AE
(percentage of all infusions)
No. of AE
(percentage of all infusions)
Source: studies 11815 and 11816
Upper respiratory tract infection 9 (0.8%) 1 (0.5%)
Urinary tract infection 8 (0.7%) 0
Nausea 7 (0.6%) 0
Headache 4 (0.4%) 3 (1.6%)
Arthralgia 2 (0.2%) 2 (1.0%)

Table 3 below displays the overall rates of adverse events (≥ 5%), in the first eight weeks of treatment, that began during or within 72 hours of the end of an infusion of Prolastin-C or PROLASTIN.

Table 3: Adverse Events Occurring in ≥ 5% of Subjects during or within 72 hours of the end of an infusion, in the First 8 Weeks of Treatment Irrespective of Causality
  PROLASTIN® -C
No. of subjects: 62
PROLASTIN®
No. of subjects: 24
Adverse Event No. of subjects with AE
(percentage of all subjects)
No. of subjects with AE
(percentage of all subjects)
Source: studies 11815 and 11816
Urinary Tract Infection 4 (6.5%) 0
Headache 3 (4.8%) 2 (8.3%)

Ten exacerbations of chronic obstructive pulmonary disease were reported by 8 subjects in the 24 week pharmacokinetic crossover study. During the 16 week double-blind crossover phase, 4 subjects (17%) had a total of 4 exacerbations during Prolastin-C treatment and 4 subjects (17%) had a total of 4 exacerbations during PROLASTIN treatment. Two additional exacerbations in 2 subjects (8%) occurred during the 8 week open label treatment period with Prolastin-C. The overall rate of pulmonary exacerbations during treatment with either product was 0.9 exacerbations per subject-year.

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.

The following adverse reactions have been identified and reported during the post marketing use of the predecessor product, PROLASTIN:

  • Respiratory: dyspnea
  • Cardiac: tachycardia
  • Skin and Subcutaneous: rash
  • General/Body as a Whole: chest pain, chills, influenza-like illness
  • Immune: hypersensitivity
  • Vascular: hypotension, hypertension (including transient increases of blood pressure)

Drug Interactions

Prolastin-C should be given alone, without mixing with other agents or diluting solutions.

USE IN SPECIFIC POPULATIONS

Pregnancy

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

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

Clinical studies of Prolastin-C did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

Prolastin-C Description

Alpha1-Proteinase Inhibitor (Human), Prolastin-C, is a sterile, stable, lyophilized preparation of purified human alpha1-proteinase inhibitor (Alpha1-PI), also known as alpha1-antitrypsin. Prolastin-C is intended for use in therapy for patients with emphysema due to congenital alpha1-antitrypsin deficiency. Prolastin-C is produced through modifications of the PROLASTIN process that result in improved product purity and a higher concentration of the same active substance, Alpha1-PI, in the reconstituted product.

Prolastin-C is supplied as a sterile, white to beige, lyophilized powder. The specific activity of Prolastin-C is ≥ 0.7 mg functional Alpha1-PI per mg of total protein. Prolastin-C has a purity of ≥ 90% Alpha1-PI. Each vial contains approximately 1000 mg of functionally active Alpha1-PI. When reconstituted with 20 mL of Sterile Water for Injection, USP, Prolastin-C has a pH of 6.6–7.4, a sodium content of 100–210 mM, a chloride content of 60–180 mM and a sodium phosphate content of 15–25 mM.

Each vial of Prolastin-C contains the labeled amount of functionally active Alpha1-PI in milligrams per vial (mg/vial), as determined by capacity to neutralize porcine pancreatic elastase. Prolastin-C contains no preservative and must be administered by the intravenous route.

Prolastin-C is prepared by cold ethanol fractionation of pooled human plasma based on modifications and refinements of the Cohn method (1) using purification by polyethylene glycol (PEG) precipitation, anion exchange chromatography, and cation exchange chromatography. All source plasma used in the manufacture of this product is non-reactive (negative) by FDA-licensed serological test methods for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 and negative by FDA-licensed Nucleic Acid Technologies (NAT) for HCV and human immunodeficiency virus type 1 (HIV-1). In addition, all source plasma is negative for hepatitis B virus (HBV) by either an FDA-licensed or investigational NAT assay. The goal of the investigational HBV NAT test is to detect low levels of viral nucleic acid; however, the significance of a negative result for the investigational HBV NAT test has not been established. By in-process NAT, all source plasma is negative for hepatitis A virus (HAV). As a final plasma safety step, all plasma manufacturing pools are tested by serological test methods and NAT.

To provide additional assurance of the virus safety profile of Prolastin-C, in vitro studies have been conducted to validate the capacity of the manufacturing process to reduce the infectious titer of a wide range of viruses with diverse physicochemical properties. These studies evaluated the inactivation/removal of clinically relevant viruses, including human immunodeficiency virus type 1 (HIV-1) and hepatitis A virus (HAV), as well as the following model viruses: bovine viral diarrhea virus (BVDV), a surrogate for hepatitis C virus; pseudorabies virus (PRV), a surrogate for large enveloped DNA viruses (e.g., herpes viruses); vesicular stomatitis virus (VSV), a model for enveloped viruses; reovirus type 3 (Reo3), a non-specific model for non-enveloped viruses; and porcine parvovirus (PPV), a model for human parvovirus B19.

The Prolastin-C manufacturing process has several steps (Cold Ethanol Fractionation, PEG Precipitation, and Depth Filtration) that are important for purifying Alpha1-PI as well as removing potential virus contaminants. Two additional steps, Solvent/Detergent Treatment and 15 nm Virus Removal Nanofiltration, are included in the process as dedicated pathogen reduction steps. The Solvent/Detergent Treatment step effectively inactivates enveloped viruses (such as HIV-1, VSV, HBV, and HCV). The 15 nm Virus Removal Nanofiltration step has been implemented to reduce the risk of transmission of enveloped and non-enveloped viruses as small as 18 nm. The table below presents the virus reduction capacity of each process step and the accumulated virus reduction for the process as determined in viral validation studies in which virus was deliberately added to a process model in order to study virus reduction. In addition, the Solvent/Detergent Treatment step inactivates ≥ 5.4 log10 of West Nile virus, a clinically relevant enveloped virus. Studies have demonstrated that each step provides robust virus reduction across the production range for key operating parameters.

Table 4: Virus reduction (Log10 ) for the Prolastin®-C manufacturing process
Process Step Enveloped Viruses Non-enveloped Viruses
HIV-1 BVDV PRV VSV Reo3 HAV PPV
*
Not determined. VSV inactivation and/or removal was only determined for the Solvent/Detergent Treatment and 15 nm Virus Removal Nanofiltration steps.
Not applicable. This step is only effective against enveloped viruses.
Cold Ethanol Fractionation 3.4 3.5 3.9 ND* ≥2.1 1.4 1.0
PEG Precipitation 4.3 2.8 3.3 ND 3.3 3.0 3.2
Depth Filtration ≥4.7 4.0 ≥4.8 ND ≥4.0 ≥2.8 ≥4.4
Solvent/Detergent Treatment ≥6.2 ≥4.6 ≥4.3 5.1 NA NA NA
15 nm Virus Removal Nanofiltration ≥6.9 ≥4.7 ≥5.2 ≥5.1 ≥4.3 ≥5.5 4.2
Accumulated Virus Reduction ≥25.5 ≥19.6 ≥21.5 ≥10.2 ≥13.7 ≥12.7 ≥12.8

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD) and Creutzfeldt-Jakob disease (CJD) agents. Studies of the Prolastin-C manufacturing process demonstrate that a minimum of 6 log10 reduction of TSE infectivity is achieved. These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed.

Prolastin-C - Clinical Pharmacology

Alpha1-proteinase inhibitor (Alpha1-PI) deficiency (AAT deficiency) is an autosomal, co-dominant, hereditary disorder characterized by low serum and lung levels of Alpha1-PI (2-5). Smoking is an important risk factor for the development of emphysema in patients with alpha1-proteinase inhibitor deficiency (6). Because emphysema affects many, but not all individuals with the more severe genetic variants of Alpha1-PI deficiency, augmentation therapy with Alpha1-Proteinase Inhibitor (Human) is indicated only in patients with severe Alpha1-PI deficiency who have clinically evident emphysema.

Only some Alpha1-PI alleles are associated with clinically apparent AAT deficiency (7,8). Approximately 95% of all severely AAT deficient patients are homozygous for the PiZ allele (8). Individuals with the PiZZ variant typically have serum Alpha1-PI levels less than 35% of the average normal level (2,4). Individuals with the Pi(null)(null) variant have undetectable Alpha1-PI protein in their serum (2,3). Individuals with these low serum Alpha1-PI levels, i.e., less than 11 µM, have a markedly increased risk for developing emphysema over their lifetimes. In addition, PiSZ individuals, whose serum Alpha1-PI levels range from approximately 9 to 23 µM (9), are considered to have moderately increased risk for developing emphysema, regardless of whether their serum Alpha1-PI levels are above or below 11 µM.

Augmenting the levels of functional protease inhibitor by intravenous infusion is an approach to therapy for patients with AAT deficiency. 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 any Alpha1-PI product actually protects the lower respiratory tract from progressive emphysematous changes has not been 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 (10), 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.

Mechanism of Action

The pathogenesis of emphysema is understood to evolve as described in the “protease-antiprotease imbalance” model (11). Alpha1-PI is understood to be the primary antiprotease in the lower respiratory tract, where it inhibits neutrophil elastase (NE) (12). Normal healthy individuals produce sufficient Alpha1-PI to control the NE produced by activated neutrophils and are thus able to prevent inappropriate proteolysis of the 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 Alpha1-PI are unable to maintain an appropriate antiprotease defense, and, in addition, they have been shown to have increased lung epithelial lining fluid neutrophil and NE concentrations. Because of these factors, many (but not all) individuals who are severely deficient in endogenous Alpha1-PI are subject to more rapid proteolysis of the alveolar walls leading to chronic lung disease. PROLASTIN®-C (Alpha1-Proteinase Inhibitor [Human]) serves as Alpha1-PI augmentation therapy in the patient population with severe Alpha1-PI deficiency and emphysema, acting to increase and maintain serum and lung epithelial lining fluid levels of Alpha1-PI.

Pharmacodynamics

Chronic augmentation therapy with the predecessor product, PROLASTIN® (Alpha1-Proteinase Inhibitor [Human]), administered weekly at a dose of 60 mg/kg body weight, results in significantly increased levels of Alpha1-PI and functional anti-neutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing therapy with PROLASTIN (11-13). However, the clinical benefit of the increased levels at the recommended dose has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha1-PI product.

Pharmacokinetics

The pharmacokinetic (PK) study was a randomized, double-blind, crossover trial comparing Prolastin-C to PROLASTIN conducted in 24 adult subjects age 40 to 72 with severe AAT deficiency. Ten subjects were male and 14 subjects were female. Twelve subjects were randomized to each treatment sequence. All but one subject had the PiZZ genotype and the remaining subject had PiSZ. All subjects had received prior Alpha1-PI therapy with PROLASTIN for at least 1 month.

Study subjects were randomly assigned to receive either 60 mg/kg body weight of functional Prolastin-C or PROLASTIN weekly by IV infusion during the first 8 week treatment period. Following the last dose in the first 8-week treatment period, subjects underwent serial blood sampling for PK analysis and then crossed over to the alternate treatment for the second 8-week treatment period. Following the last treatment in the second 8-week treatment period, subjects underwent serial blood sampling for PK analysis. In addition, blood samples were drawn for trough levels before infusion at Weeks 6, 7, and 8, as well as before infusion at Weeks 14, 15, and 16.

In the 8-week open-label treatment phase that followed the crossover period, all subjects received 60 mg/kg body weight of functional Prolastin-C.

The pharmacokinetic parameters of Alpha1-PI in plasma, based on functional activity assays, showed comparability between Prolastin-C treatment and PROLASTIN treatment, as shown in Table 5.

Table 5: Pharmacokinetic parameters of Alpha1-PI in plasma
Treatment AUC0-7 days
(hr*mg/mL)
Mean (%CV)
Cmax
(mg/mL)
Mean (%CV)
t1/2
(hr)
Mean (%CV)
PROLASTIN®-C
(n=22 or 23)
155.9
(17%)
1.797
(10%)
146.3
(16%)
PROLASTIN®
(n=22 or 23)
152.4
(16%)
1.848
(15%)
139.3
(18%)

The key pharmacokinetic parameter was the area under the plasma concentration-time curve (AUC0-7days) following 8 weeks of treatment with Prolastin-C or PROLASTIN. The 90% confidence interval (0.97-1.09) for the ratio of AUC0-7days for Prolastin-C and PROLASTIN indicated that the 2 products are pharmacokinetically equivalent. Figure 1 shows the concentration (functional activity) vs. time curves of Alpha1-PI after intravenous administration of Prolastin-C and PROLASTIN.

Figure 1: Mean Plasma Alpha1-PI Concentration (functional activity) vs. Time Curves Following Treatment with Prolastin-C or PROLASTIN

Trough levels measured during the PK study via an antigenic content assay showed Prolastin-C treatment resulted in a mean trough of 16.9 ± 2.3 µM and PROLASTIN resulted in a mean trough of 16.7 ± 2.7 µM. Using the functional activity assay, Prolastin-C resulted in a mean trough of 11.8 ± 2.2 µM and PROLASTIN resulted in a mean trough of 11.0 ± 2.2 µM.

Clinical Studies

A total of 62 unique subjects were studied in 2 clinical studies. In addition to the pharmacokinetic study described in [12.3], a multi-center, open-label single arm safety study was conducted to evaluate the safety and tolerability of Prolastin-C. In this study, 38 subjects were treated with weekly IV infusions of 60 mg/kg body weight of Prolastin-C for 20 weeks. Half the subjects were naïve to previous Alpha1-PI augmentation prior to study entry and the other half were receiving augmentation with PROLASTIN prior to entering the study. A diagnosis of severe AAT deficiency was confirmed by the demonstration of the PiZZ genotype in 32 of 38 (84.2%) subjects, and 6 of 38 (15.8%) subjects presented with other alleles known to result in severe AAT deficiency. These groups were distributed evenly between the naïve and non-naïve cohorts. Results from the study are discussed in [6.2]. The clinical efficacy of Prolastin-C or any Alpha1-PI product in influencing the course of pulmonary emphysema or pulmonary exacerbations has not been demonstrated in adequately powered, randomized, controlled clinical trials.

REFERENCES

  1. Coan MH, Brockway WJ, Eguizabal H, et al: Preparation and properties of alpha1-proteinase inhibitor concentrate from human plasma. Vox Sang 48(6):333-42, 1985.
  2. Brantly M, Nukiwa T, Crystal RG: Molecular basis of alpha-1-antitrypsin deficiency. Am J Med 84(Suppl 6A):13-31, 1988.
  3. Crystal RG, Brantly ML, Hubbard RC, Curiel DT, et al: The alpha1-antitrypsin gene and its mutations: Clinical consequences and strategies for therapy. Chest 95:196-208, 1989.
  4. Hutchison DCS: Natural history of alpha-1-protease inhibitor deficiency. Am J Med 84(Suppl 6A):3-12, 1988.
  5. Hubbard RC, Crystal RG: Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency. Am J Med 84(Suppl 6A):52-62, 1988.
  6. American Thoracic Society/European Respiratory Society Statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 168:818-900, 2003.
  7. Crystal RG: α1-Antitrypsin deficiency, emphysema, and liver disease; genetic basis and strategies for therapy. J Clin Invest 85:1343-52, 1990.
  8. World Health Organization: Alpha-1-antitrypsin deficiency: Memorandum from a WHO meeting. Bull World Health Organ 75:397-415, 1997.
  9. Turino GM, Barker, AF, Brantly, ML et al: Clinical features of individuals with PI*SZ phenotype of α1-antitrypsin deficiency. Am J Respir Crit Care Med 154: 1718-25, 1996.
  10. American Thoracic Society: Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency. Am Rev Respir Dis 140:1494-7, 1989.
  11. Stockley RA: Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 160:S49-S52, 1999.
  12. Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal RG: Antielastases of the human alveolar structures; Implications for the protease-antiprotease theory of emphysema. J Clin Invest 68:889-98, 1981.
  13. Gadek JE, Crystal RG: Alpha1-antitrypsin deficiency. In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al, eds.: The Metabolic Basis of Inherited Disease. 5th ed. New York, McGraw-Hill, 1983, p.1450-67.

How Supplied/Storage and Handling

Prolastin-C is supplied in single-use vials with the total Alpha1-PI functional activity, in milligrams, stated on the label of each vial. Each product package contains a single vial of Prolastin-C, one 20 mL vial of Sterile Water for Injection, USP, a transfer needle, and a filter needle. Prolastin-C is supplied in the following size:

NDC Number Approximate Alpha1 -PI
Functional Activity
Diluent
13533-700-01 1000 mg 20 mL

Prolastin-C should be stored at temperatures not to exceed 25°C (77°F) for the period indicated by the expiration date on its label. Freezing should be avoided as breakage of the diluent bottle might occur.

Patient Counseling Information

Inform patients of the signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, dyspnea, wheezing, faintness, hypotension, and anaphylaxis. Patients should be advised 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 Prolastin-C is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Inform patients of the risk that Prolastin-C may transmit an infectious agent, but that this risk has been reduced by screening plasma donors for prior exposure to certain viruses, by testing the donated plasma for certain virus infections and by inactivating and/or removing certain viruses during manufacturing. (See Warnings and Precautions [5.2]). Inform patients that administration of Prolastin-C has been demonstrated to raise the plasma level of Alpha1-PI, but that the effect of this augmentation on pulmonary exacerbations and on the rate of progression of emphysema has not been demonstrated in adequately powered, randomized, controlled clinical trials for any Alpha1-PI product.

 

Manufactured by: 

Talecris Biotherapeutics, Inc.

Research Triangle Park, NC 27709 USA
U.S. License No. 1716

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 13533-700-01

Alpha1-Proteinase Inhibitor (Human)

PROLASTIN® C

Solvent detergent treated

Nanofiltered

Talecris Biotherapeutics

The patient and physician should discuss the risks and benefits of this product.

No preservative

For intravenous administration only

Sterile—nonpyrogenic

Reconstitute with 20 mL diluent sterile water for injection, USP.

Store at temperatures not to exceed 25°C (77°F). Do not freeze.

Dosage and administration:

Read package insert.

Rx only

Talecris Biotherapeutics, Inc.

Research Triangle Park, NC 27709 USA

U.S. License No. 1716

Alpha1-Proteinase Inhibitor (Human)

Prolastin® C

Sovent detergent treated

Nanofiltered

Dosage and administration:

Read enclosed package insert.

Store at temperatures not to exceed not to exceed 25(degrees)C (77(degrees)F.

Do not freeze.

Talecris Biotherapeutics

NDC 13533-700-01

Prolastin-C  
alpha-1-proteinase inhibitor human kit
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:13533-700
Packaging
# Item Code Package Description
1 NDC:13533-700-01 1 KIT (KIT) in 1 CARTON
Quantity of Parts
Part # Package Quantity Total Product Quantity
Part 1 1 VIAL, SINGLE-DOSE 20 mL
Part 2 1 VIAL, SINGLE-DOSE 20 mL
Part 1 of 2
ALPHA-1-PROTEINASE INHIBITOR HUMAN  
alpha-1-proteinase inhibitor human injection, powder, lyophilized, for solution
Product Information
     
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Alpha-1-proteinase Inhibitor Human (Alpha-1-proteinase Inhibitor Human) Alpha-1-proteinase Inhibitor Human 1000 mg  in 20 mL
Inactive Ingredients
Ingredient Name Strength
Sodium Phosphate  
Sodium Chloride  
Product Characteristics
Color WHITE (White to Beige) Score     
Shape Size
Flavor Imprint Code
Contains         
Packaging
# Item Code Package Description
1 20 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103174 01/31/1987
Part 2 of 2
STERILE WATER  
water injection
Product Information
     
Route of Administration INTRAVENOUS DEA Schedule     
Inactive Ingredients
Ingredient Name Strength
Water  
Packaging
# Item Code Package Description
1 20 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103174 01/01/1987
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA103174 01/31/1987
Labeler - TALECRIS BIOTHERAPEUTICS, INC. (839731507)
Establishment
Name Address ID/FEI Operations
TALECRIS BIOTHERAPEUTICS HOLDINGS CORP 611019113 MANUFACTURE
Revised: 10/2009
 
TALECRIS BIOTHERAPEUTICS, INC.
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