Prolastin (Alpha1-Proteinase Inhibitor)

PROLASTIN®

Bayer

Alpha1-Proteinase Inhibitor (Human)

Alpha1-Antitrypsin Replenisher

Action And Clinical Pharmacology: Alpha1-antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha1-Pl (alpha1-antitrypsin) is associated with slowly progressive, severe panacinar emphysema that most often manifests itself in the third to fourth decades of life. (Although the terms alpha1-proteinase inhibitor and alpha1-antitrypsin are used interchangeably in the scientific literature, the hereditary disorder associated with a reduction in the serum level of alpha1-Pl is conventionally referred to as alpha1-antitrypsin deficiency while the deficient protein is referred to as alpha1-proteinase inhibitor). The emphysema is typically worse in the lower lung zones. The pathogenesis of development of emphysema in alpha1-antitrypsin deficiency is not well understood at this time. It is believed, however, to be due to a chronic biochemical imbalance between elastase (an enzyme capable of degrading elastin tissues, released by inflammatory cells, primarily neutrophils, in the lower respiratory tract) and alpha1-Pl (the principal inhibitor of neutrophil elastase), which is deficient in alpha1-antitrypsin disease. As a result, it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic, low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation of elastin tissues. The eventual outcome is the development of emphysema. Neonatal hepatitis with cholestatic jaundice appears in approximately 10% of newborns with alpha1-antitrypsin deficiency. In some adults, alpha1-antitrypsin deficiency is complicated by cirrhosis.

A large number of phenotypic variants of alpha1-antitrypsin deficiency exists. The most severely affected individuals are those with the PiZZ variant, typically characterized by alpha1-Pl serum levels 80% of developing emphysema over a lifetime. However, individuals with endogenous alpha1-Pl levels >80 mg/dL, in general, do not manifest an increased risk for development of emphysema above the general population background risk. From these observations, it is believed that the threshold level of alpha1-Pl in the serum required to provide adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency is about 80 mg/dL (based on commercial standards for immunologic assay of alpha1-Pl).

In clinical studies of alpha1-proteinase inhibitor (human), 23 subjects with the PiZZ variant of congenital deficiency of alpha1-antitrypsin deficiency and documented destructive lung disease participated in a study of acute and/or chronic replacement therapy with alpha1-proteinase inhibitor (human). The mean in vivo recovery of alpha1-Pl was 4.2 mg (immunologic)/dL/mg (functional)/kg body weight administered. The half-life of alpha1-Pl in vivo was approximately 4.5 days. Based on these observations, a program of chronic replacement therapy was developed. Nineteen of the subjects in these studies received alpha1-proteinase inhibitor (human) replacement therapy, 60 mg/kg body weight, once weekly for up to 26 weeks (average 24 weeks of therapy). With this schedule of replacement therapy, blood levels of alpha1-Pl were maintained above 80 mg/dL (based on the commercial standards for alpha1-Pl immunologic assay). Within a few weeks of commencing this program, bronchoalveolar lavage studies demonstrated significantly increased levels of alpha1-Pl and functional antineutrophil elastase capacity in the epithelial lining fluid of the lower respiratory tract of the lung, as compared to levels prior to commencing the program of chronic replacement therapy with alpha1-proteinase inhibitor (human).

All 23 individuals who participated in the investigations were immunized with hepatitis B vaccine and received a single dose of hepatitis B immune globulin (human) on entry into the investigation. Although no other steps were taken to prevent hepatitis, neither hepatitis B nor non-A, non-B hepatitis occurred in any of the subjects. All subjects remained seronegative for HIV antibody. None of the subjects developed any detectable antibody to alpha1-Pl or other serum protein.

Long-term controlled clinical trials to evaluate the effect of chronic replacement therapy with alpha1-proteinase inhibitor (human) on the development of or progression of emphysema in patients with congenital alpha1-antitrypsin deficiency have not been performed. Estimates of the sample size required of this rare disorder and the slow, progressive nature of the clinical course have been considered impediments in the ability to conduct such a trial. Studies to monitor the long-term effects will continue as part of the post-approval process.

Indications And Clinical Uses: For chronic replacement therapy of individuals having congenital deficiency of alpha1-Pl (alpha1-antitrypsin deficiency) with clinically demonstrable panacinar emphysema. Clinical and biochemical studies have demonstrated that with such therapy, it is possible to increase plasma levels of alpha1-Pl, and that levels of functionally active alpha1-Pl in the lung epithelial lining fluid are increased proportionately. As some individuals with alpha1-antitrypsin deficiency will not go on to develop panacinar emphysema, only those with evidence of such disease should be considered for chronic replacement therapy with alpha1-proteinase inhibitor (human). Subjects with the PiMZ or PiMS phenotypes of alpha1-antitrypsin deficiency should not be considered for such treatment as they appear to be at small risk for panacinar emphysema. Clinical data are not available as to the long-term effects derived from chronic replacement therapy of individuals with alpha1-antitrypsin deficiency with alpha1-proteinase inhibitor (human). Only adult subjects have received alpha1-proteinase inhibitor (human) to date.

Alpha1-proteinase inhibitor (human) is not indicated for use in patients other than those with PiZZ, PiZ(null) or Pi(null)(null) phenotypes.

Contra-Indications: Individuals with selective IgA deficiencies who have known antibody against IgA (anti-IgA antibody) should not receive alpha1-proteinase inhibitor (human), since these patients may experience severe reactions, including anaphylaxis, to IgA which may be present.

Manufacturers’ Warnings In Clinical States: This product is prepared from pooled human plasma which may contain the causative agents of hepatitis and other viral diseases. Prescribed manufacturing procedures utilized at the plasma collection centres, plasma testing laboratories, and the fractionation facilities are designed to reduce the risk of transmitting viral infection. However, the risk of viral infectivity from this product cannot be totally eliminated.

Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly non-A, non-B hepatitis. Alpha1-proteinase inhibitor (human), has been heat-treated in solution at 60°C for 10 hours in order to reduce the potential for transmission of infectious agents. No cases of hepatitis, either hepatitis B or non-A, non-B hepatitis have been recorded to date in individuals receiving alpha1-proteinase inhibitor (human). However, as all individuals received prophylaxis against hepatitis B, no conclusions can be drawn at this time regarding potential transmission of hepatitis B virus.

Precautions: General: 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution.

2. Administer only by the i.v. route.

3. As with any colloid solution, there will be an increase in plasma volume following i.v. administration of alpha1-proteinase inhibitor (human). Caution should therefore be used in patients at risk for circulatory overload.

4. It is recommended that in preparation for receiving alpha1-proteinase inhibitor (human), recipients be immunized against hepatitis B using a licensed Hepatitis B Vaccine, according to the manufacturer’s recommendations. Should it become necessary to treat an individual with alpha1-proteinase inhibitor (human), and time is insufficient for adequate antibody response to vaccination, individuals should receive a single dose of hepatitis B immune globulin (human), 0.06 mL/kg body weight, i.m., at the time of administration of the initial dose of Hepatitis B Vaccine.

5. Alpha1-proteinase inhibitor (human) should be given alone, without mixing with other agents or diluting solutions.

6. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs.

Place needles in sharps container after single use. Discard all equipment including any reconstituted Prolastin product in accordance with biohazard procedures.

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

Pregnancy: Animal reproduction studies have not been conducted with alpha1-proteinase inhibitor (human). It is also not known whether Prolastin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Prolastin should be given to a pregnant woman only if clearly needed.

Lactation: It is not known whether alpha1-proteinase inhibitor (human) is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alpha1-proteinase inhibitor (human) is administered to a nursing woman.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: Therapeutic administration of alpha1-proteinase inhibitor (human), 60 mg/kg weekly, has been demonstrated to be well tolerated. In clinical studies, 6 reactions were observed with 517 infusions of alpha1-proteinase inhibitor (human), or 1.16%. None of the reactions was severe. The adverse reactions reported included delayed fever (maximum temperature rise was 38.9°C, resolving spontaneously over 24 hours) occurring up to 12 hours following treatment (0.77%), lightheadedness (0.19%), and dizziness (0.19%). Mild transient leukocytosis and dilutional anemia several hours after infusion have also been noted.

Since market entry, occasional reports of other flu-like symptoms, allergic-like reactions, dyspnea, rash, tachycardia, and, rarely, hypotension have also been received.

Dosage And Administration: Each bottle of alpha1-proteinase inhibitor (human) has the functional activity, as determined by inhibition of porcine pancreatic elastase, stated on the label of the bottle.

The threshold level of alpha1-Pl in the serum believed to provide adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency is 80 mg/dL (based on commercial standards for alpha1-Pl immunologic assay). However, assays of alpha1-Pl based on commercial standards measure antigenic activity of alpha1-Pl, whereas the labeled potency value of alpha1-Pl is expressed as actual functional activity, i.e., actual capacity to neutralize porcine pancreatic elastase. As functional activity may be less than antigenic activity, serum levels of alpha1-Pl determined using commercial immunologic assays may not accurately reflect actual functional alpha1-Pl levels. Therefore, although it may be helpful to monitor serum levels of alpha1-Pl in individuals receiving alpha1-proteinase inhibitor (human), using currently available commercial assays of antigenic activity, results of these assays should not be used to determine the required therapeutic dosage.

The recommended dosage of alpha1-proteinase inhibitor (human) is 60 mg/kg body weight administered i.v. once weekly. This dose is intended to increase and maintain a level of functional alpha1-Pl in the epithelial lining of the lower respiratory tract, providing adequate anti-elastase activity in the lung of individuals with alpha1-antitrypsin deficiency.

Alpha1-proteinase inhibitor (human) may be given at a rate of 0.08 mL/kg/min or greater and must be administered i.v. The recommended dosage of 60 mg/kg takes approximately 30 minutes to infuse.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution: 1. Warm the unopened diluent and concentrate to room temperature (not more than 37°C).

2. After removing the plastic flip-top caps, aseptically cleanse rubber stoppers of both bottles.

3. Remove the protective cover from the plastic transfer needle cartridge with tamper-proof seal and penetrate the stopper of the diluent bottle.

4. Remove the remaining portion of the plastic cartridge. Invert the diluent bottle and penetrate the rubber seal on the concentrate bottle with the needle at an angle.

5. The vacuum will draw the diluent into the concentrate bottle. For best results, and to avoid foaming, hold the diluent bottle at an angle to the concentrate bottle in order to direct the jet of diluent against the wall of the concentrate bottle.

6. After removing the diluent bottle and transfer needle, gently swirl the concentrate bottle until the powder is completely dissolved.

7. Swab top of reconstituted bottle of alpha1-proteinase inhibitor (human), again.

8. Attach the sterile filter needle provided to syringe. With filter needle in place, insert syringe into reconstituted bottle and withdraw solution into syringe.

9. To administer alpha1-proteinase inhibitor (human), replace filter needle with appropriate injection needle and follow procedure for i.v. administration.

10. The contents of more than 1 bottle may be drawn into the the same syringe before administration. If more than 1 bottle is used, withdraw contents from bottles using aseptic technique. Place contents into an administration container (plastic minibag or glass bottle) using a syringe. Avoid pushing an i.v. administration set spike into the product container stopper as this has been known to force the stopper into the vial, with a resulting loss of sterility.

Availability And Storage: Each single use vial of sterile, stable, lyophilized preparation contains: purified human alpha1-proteinase inhibitor with a functional activity of 500 or 1 000 mg. A suitable volume of Sterile Water for Injection USP (20 or 40 mL, respectively), a sterile double-ended transfer needle and a sterile filter needle are provided. Preservative-free. Must be administered by the i.v. route.

Alpha1-proteinase inhibitor (human) is prepared from pooled human plasma of normal donors by modification and refinements of the cold ethanol method of Cohn. In order to reduce the potential risk of transmission of infectious agents, alpha1-proteinase inhibitor (human) has been heat-treated in solution at 60±0.5°C for not less than 10 hours. However, no procedure has been found to be totally effective in removing viral infectivity from plasma fractionation products.

The specific activity of alpha1-proteinase inhibitor (human) is ³0.35 mg functional alpha1-Pl/mg protein and when reconstituted as directed, the concentration of alpha1-Pl is ³20 mg/mL. When reconstituted, alpha1-proteinase inhibitor (human) has a pH of 6.6 to 7.4, a sodium content of 100 to 210 mEq/L a chloride content of 60 to 180 mEq/L, a sodium phosphate content of 0.015 to 0.025 M, a polyethylene glycol content of not more than 5 ppm, and not more than 0.1% sucrose. Alpha1-proteinase inhibitor (human) contains small amounts of other plasma proteins including alpha2-plasmin inhibitor, alpha1-antichymotrypsin, C1-esterase inhibitor, haptoglobin, antithrombin III, alpha1-lipoprotein, albumin, and IgA.

Each vial contains the labeled amount of functionally active alpha1-Pl in mg/vial, as determined by capacity to neutralize porcine pancreatic elastase.

Store under refrigeration (2 to 8°C). Freezing should be avoided as breakage of the diluent bottle might occur.

PROLASTIN® Bayer Alpha1-Proteinase Inhibitor (Human) Alpha1-Antitrypsin Replenisher

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