Alpha 1 Proteinase Inhibitor

DESCRIPTION

Alpha₁-Proteinase Inhibitor (Human), ProlastinÒ is a sterile, stable, lyophilized preparation of purified human Alpha₁-Proteinase Inhibitor (alpha₁-PI) also known as alpha₁-antitrypsin. Prolastin is intended for use in therapy of congenital alpha₁-antitrypsin deficiency.

Prolastin is prepared from pooled human plasma of normal donors by modification and refinements of the cold ethanol method of Cohn.¹ Part of the fractionation may be performed by another licensed manufacturer. In order to reduce the potential risk of transmission of infectious agents Prolastin 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 Prolastin is ³0.35 mg functional alpha1-PI mg protein and when reconstituted, as directed the concentration of alpha1 PI is ³20 mg mL. When reconstituted Prolastin has a pH of 6.6- 7.4 a sodium content of 100-210 mEq-L a chloride content of 60-180 mEq/L a sodium phosphate content of 0.015- 0.025 M, a polyethylene glycol content of not more than (NMT) 5 ppm, and NMT 0.1% sucrose. Prolastin contains small amounts of other plasma proteins including alpha₂ plasmin inhibitor, alpha1-antichymotrypsin, C₁- esterase inhibitor, haptoglobin, antithrombin III, alpha₁-lipoprotein albumin and IgA. ¹

Each vial of Prolastin contains the labeled amount of functionally active alpha₁-PI in milligrams per vial (mg/vial), as determined by capacity to neutralize porcine pancreatic elastase.¹ Prolastin contains no preservative and must be administered by the intravenous route.

CLINICAL PHARMACOLOGY

Alpha1 antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha₁-PI (alpha₁-antitrypsin) is associated with slowly progressive, severe panacinar emphysema that most often manifests itself in the third to fourth decades of life.^2-9 [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 alpha-PI is conventionally referred to as "alpha-antitrypsin deficiency" while the deficient protein is referred to as "Alpha-Proteinase Inhibitor"¹⁰] The emphysema is typically worse in the lower lung zones. ^4,8,9 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 PI (the principal inhibitor of neutrophil elastase), which is deficient in alpha1 antitrypsin disease. ^11-15 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. ^11-15 The eventual outcome is the development of emphysema. Neonatal hepatitis with cholestatic jaundice appears in approximately 10% of newborns with alpha₁-antitrypsin deficiency. ¹⁵ In some adults, alpha₁-antitrypsin deficiency is complicated by cirrhosis. ¹⁵

A large number of phenotypic variants of alpha₁-antitrypsin deficiency exists.¹⁵ The most severely affected individuals are those with the PiZZ variant, typically characterized by alpha₁-PI serum levels <35 normal.¹⁵ Epidemiologic studies of individuals with various phenotypes of alpha₁-antitrypsin deficiency have demonstrated that individuals with endogenous serum levels of alpha₁-PI <50 mg/dL (based on commercial standards) have a risk of >80% of developing emphysema over a lifetime. ^{3 6,8,9,16} However individuals with endogenous alpha1 PI levels >80 mg/dL, in general, do not manifest an increased risk for development of emphysema above the general population background risk.^5,15 From these observations, it is believed that the "threshold" level of alpha₁-PI 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-PI).^12,15,17

In clinical studies of Alpha₁-Proteinase Inhibitor (Human), ProlastinÒ, 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 Prolastin.¹⁸ The mean in vivo recovery of alpha₁-PI was 4.2 mg (immunologic)/dL per mg (functional)/kg body weight administered.^18,19 The half-life of alpha₁-PI in vivo was approximately 4.5 days.^18,19 Based on these observations, a program of chronic replacement therapy was developed. Nineteen of the subjects in these studies received Prolastin 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-PI were maintained above 80 mg/dL (based on the commercial standards for alpha₁-PI immunologic assay).^18-20 Within a few weeks of commencing this program, bronchoalveolar lavage studies demonstrated significantly increased levels of alpha₁-PI 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) ProlastinÒ.^18-20

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.^18,19 All subjects remained seronegative for HIV antibody. None of the subjects developed any detectable antibody to alpha₁-PI or other serum protein.

Long term controlled clinical trials to evaluate the effect of chronic replacement therapy with Prolastin 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.²¹ Studies to monitor the long-term effects will continue as proof of the postapproval process.

INDICATIONS

Congenital Alpha1 Antitrypsin Deficiency

Prolastin is indicated for chronic replacement therapy of individuals having congenital deficiency of alpha₁-PI (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-PI and that levels of functionally active alpha₁-PI, in the lung epithelial lining fluid are increased proportionately.^18-20 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 Prolastin.²² 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.²² Clinical data are not available as to the long-term effects derived from chronic replacement therapy of individuals with alpha₁-antitrypsin deficiency with Prolastin. Only adult subjects have received Prolastin to date.

Prolastin is not indicated for use in patients other than those with PiZZ, PiZ (null) or Pi (null)/(null) phenotypes.

DOSAGE AND ADMINISTRATION

Each bottle of Prolastin has the functional activity, as determined by inhibition of porcine pancreatic elastase,¹ stated on the label of the bottle.

The "threshold" level of alpha₁-PI 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-PI immunologic assay).^12,15,17 However assays of alpha₁-PI based on commercial standards measure antigenic activity of alpha₁-PI whereas the labeled potency value of alpha₁-PI 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 PI determined using commercial immunologic assays may not accurately reflect actual functional alpha₁-PI levels. Therefore, although it may be helpful to monitor serum levels of alpha₁-PI in individuals receiving Prolastin, 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 Prolastin is 60 mg/kg body weight administered once weekly. This dose is intended to increase and maintain a level of functional alpha₁-PI 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), ProlastinÒ may be given at a rate of 0.08 mL/kg/min or greater and must be administered intravenously. 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.

HOW SUPPLIED

Alpha₁-Proteinase Inhibitor (Human), ProlastinÒ is supplied in the following single use vials with the total alpha₁-PI functional activity in milligrams, stated on the label of each vial. A suitable volume of Sterile Water for Injection, USP, is provided.

STORAGE

Prolastin should be stored under refrigeration (2-8°C; 36-46°F) or at temperatures not to exceed 25°C (77°F). Freezing should be avoided as breakage of the diluent bottle might occur.

CAUTION: U.S. federal law prohibits dispensing without prescription.

LIMITED WARRANTY

A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly, that the directions be followed carefully during use, and that the risk of transmitting viruses be carefully weighed before the product is prescribed.

No warranty, express or implied, including any warranty of merchantability or fitness is made. Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling, including the package insert for this product, except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof.

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. Laurell CB, Eriksson S: The electrophoretic alpha₁-globulin pattern of serum in alpha₁-antitrypsin deficiency. Scand J Clin Lab Invest 15: 132-40, 1963

3. Eriksson S: Pulmonary emphysema and alpha₁-antitrypsin deficiency. Acta Med Scand 175(2): 197-205, 1964.

4. Eriksson S: Studies in alpha₁-antitrypsin deficiency. Acta Med Scand Suppl 432: 1-85, 1965.

5. Kueppers F, Black LF: Alpha₁-antitrypsin and its deficiency. Am Rev Respir Dis 110(2): 176-94, 1974.

6. Morse JO: Alpha₁-antitrypsin deficiency. N Engl J Med 299: 1045-8; 1099-105, 1978.

7. Black LF, Kueppers F: Alpha₁-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis 117(3): 421-8, 1978.

8. Tobin MJ, Cook PJ, Hutchison DC: Alpha₁-antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest 77(1): 14-27, 1983.

9. Larsson C: Natural history and life expectancy in severe alpha₁-antitrypsin deficiency, Pi Z. Acta Med Scand 204(5) 345-51, 1978.

10. Pannell R, Johnson D, Travis J: Isolation and properties of human plasma alpha₁-proteinase inhibitor. Biochemistry 13(26): 5439-45, 1974.

11. Lieberman J: Elastase, collagenase, emphysema, and alpha₁-antitrypsin deficiency. Chest 70(1): 62-7, 1976.

12. Gadek JE, Fells GA, Zimmerman RL, et al: Antielastases of the human alveolar structures: implications for the protease antiprotease theory of emphysema. J Clin Invest 68(4): 889-98, 1981.

13. Beatty K, Bieth J, Travis J, Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem 255(9):3931-4,1980.

14. Janoff A, White R, Carp H, et al: Lung injury induced by leukocytic proteases. Am J Pathol 97(1):111-36, 1979.

15. 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

16. Larsson C, Dirksen H, Sundstrom G, et al: Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of alpha₁-antitrypsin Scand J Respir Dis 57(6): 267-80, 1976.

17. Gadek JE, Klein HG, Holland PV, et al: Replacement therapy of alpha₁-antitrypsin deficiency: reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects J Clin Invest 68(5):1158-65,1981.

18. Data on file, Bayer Corporation.

19. Wewers MD, Casolaro MA, Sellers SE, et al: Replacement therapy for alpha₁-antitrypsin deficiency associated with emphysema. N Engl J Med 316(17):1055-62,1987.

20. Wewers MD, Casolaro MA, Crystal RG: Comparison of alpha-1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha-1-antitrypsin phenotype null- null before and during alpha-1-antitrypsin augmentation therapy. Am Rev Respir Dis 135(3):539-43, 1987.

21. Burrows B: A clinical trial of efficacy of antiproteolytic therapy: can it be done? Am Rev Respir Dis 127(2:2): S42-3, 1983.

22. Cohen AB: Unraveling the mysteries of alpha₁-antitrypsin deficiency. N Engl J Med 314(12): 778-9, 1986.

23. Finlayson JS: Albumin products. Semin Thromb Hemost 6(2): 85-120, 1980.

SIDE EFFECTS

Therapeutic administration of Prolastin, 60 mg/kg weekly, has been demonstrated to be well tolerated. In clinical studies, six reactions were observed with 517 infusions of Prolastin, or 1.16%. None of the reactions were severe.¹⁸ 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%), light-headedness (0.19%) and dizziness (0.19%).¹⁸ Mild transient leukocytosis and dilutional anemia several hours after infusion have also been noted. ¹⁸ Since market entry, occasional reports of other flu-like symptoms, allergic-like reactions, chills, dyspnea, rash, tachycardia, and, rarely, hypotension have also been received.

DRUG INTERACTIONS

No information provided.

WARNINGS

Alpha₁-Proteinase Inhibitor (Human), ProlastinÒ is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. 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 Bayer Corporation [1-888-765-3203].

The physician should discuss the risks and benefits of this product with the patient before, prescribing or administering it to a patient.

Prolastin has been heat treated in solution at 60°C for 10 hours in order to reduce the potential for transmission of infectious agents.¹ No cases of hepatitis, either hepatitis B or hepatitis C, have been recorded to date in individuals receiving Prolastin.¹⁸ However, as all individuals received prophylaxis against hepatitis B, no conclusion 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 intravenous route.

3. As with any colloid solution, there will be an increase in plasma volume following intravenous administration of Prolastin. ²³ Caution should therefore be used in patients at risk for circulatory overload.

4. It is recommended that in preparation for receiving Prolastin, 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 Prolastin 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, intramuscularly, at the time of administration of the initial dose of Hepatitis B Vaccine.

5. Prolastin 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 Category C

Animal reproduction studies have not been conducted with Alpha₁-Proteinase Inhibitor (Human) ProlastinÒ. 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.

Nursing Mothers

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

Pediatric Use

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