Pain and Cyanosis Associated With clcl-Proteinase Inhibitor JOHN A. CLARK, M.D., M.S.P.H., THOMASP. GROSS,M.D., M.P.H., Rockviile, Maryland
PURPOSE ‘Ihe purpose of this study was to investigate adverse reaction reports of pain and/ or cyanosis attributed to al-proteinase inhibitor (AlPI), a plasma a-globulin protein used to treat AlPI deficiency. PATIENTS AND METHODS: The Food and Drug Administration’s (FDA) Spontaneous Reporting System for the collection and analysis of suspected adverse reactions to drugs and biologics was searched for all reports with dates from January 1,1988, through October 31,1989, in which AlPI was named as the suspect biologic. A case of pain and/or cyanosis was defined and characteristics of cases were compared with all other reactions. Information about the production of AlPI and results from animal studies conducted by the manufacturer were also gathered. RESULTS: Fourteen cases of acute chest pain, back pain, and/or cyanosis among patients receiving AlPI infusions were reported to the FDA. The clinical aspects of reported cases were consistent with a rapidly acting, nonallergic mechanism and were easily distinguished from other reactions associated with AlPI. The characteristics of reported cases, the epidemic curve, and lot-specific analyses suggested a point source and strongly implicated two AlPI lots. Information about the production of AlPI and results from animal studies further implicated high-molecular-weight polysaccharides associated with sucrose stabilization of the suspect lots. CONCLUSION: These cases resemble adverse reactions attributed to complexes of protamine and heparin (a mucopolysaccharide). Similar vasoactive mechanisms are suggested. Research is needed to further define the pathophysiology associated with polysaccharide moieties.
From the Office of Epidemiology and Biostatistics, Food and Drug Administration, Rockville. Maryland. The opinions expressed in this article are those of the authors and not necessarily those of the Food and Drug Administration. Requests for reprints should be addressed to Thomas P. Gross, M.D., M.P.H., Food and Drug Administration, Epidemiology Branch HFD-733, 5600 Fishers Lane, Rockville, Maryland 20857. Manuscript submitted April 19, 1991, and accepted in revised form January 27, 1992.
A
lpha-1-proteinase inhibitor (cul-antitrypsin) is a plasma a-globulin protein possessing biologic activity against neutrophil elastase and other proteinases [l]. A commercially available preparation (Prolastin*; Cutter Biological) derived from processed pooled plasma has been marketed as a treatment for al-proteinase inhibitor (AlPI) deficiency since January 1988. Although safety information was collected on AlPI prior to its marketing, knowledge of its adverse reaction profile at the time of approval was limited [Z], as is the case for many newly marketed drugs and biologics. Premarketing studies indicated that adverse reactions occurred at a low rate and were rarely life-threatening [2]. The only major safety concern prior to marketing was the infrequent occurrence of allergic reactions [l-3]. To further monitor the postmarketing safety of drugs and biologics, the Food and Drug Administration (FDA) maintains a computerized Spontaneous Reporting System (SRS) for the collection and analysis of suspected adverse reactions to drugs and biologics [4]. During the first quarter of 1989, 14 patients were reported to the FDA’s SRS to have had chest pain, back pain, and/or cyanosis during infusions of AlPI. The characteristics of reported cases, the epidemic curve, information about the production of AlPI, and ‘results from animal studies conducted by the manufacturer suggested that these reactions were due to biologically active substances, most likely high-molecular-weight polysaccharides, introduced during manufacture of some lots of AlPI.
PATIENTSAND METHODS Since 1969, about 500,000 adverse drug and biologic reaction reports have been received by the FDA’s SRS database. The majority of reports are forwarded by pharmaceutical manufacturers or distributors based on information they have received, while a minority come directly from health care professionals [5]. Each report is coded and entered into the SRS using terms from a computerized drug reaction dictionary. Once coded, a suspect report and its associated data elements can be retrieved for further analysis. The major elements of each report are: the patient’s initials or identification number, age, sex, date of birth, reaction onset date, description of the reaction, the suspect drug or bio*Trade names are provided do not imply any endorsement tion. June
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AlPI-ASSOCIATED
PAIN AND CYANOSIS
/ CLARK AN6 GROSS
other reactions in the SRS that were not cases and in which AlPI was named as the suspect biologic.
TABLE I Incidence of CommonlyReported Symptomsin Casesand Noncases
RESULTS
No. (%I Cases (n = 14) Pain Chest pain&back pain Chest pain & dyspnea Back pain & dyspnea
2 (14) 2 (14)
Cyanosis Cyanosis & dyspnea Cyanosis alone
1 (7)
Pain &cyanosis Back pain & cyanosis & dyspnea
1 (7) 1 (7)
Noncases
(n = 29)
Constitutional Fever &/or chills Faintness &/or dizziness Nausea &/or vomiting
8 (28) 4 (14)
Urticaria Alone Urticaria & hypotension
7 (24) 6(21) 1 (3)
Pain Chest pain & dyspnea Flank pain &cyanosis & dyspnea Arm pain & dyspnea Chest pain & back pain &cyanosis dyspnea Flu-like reaction with myalgias
7 (24)
Respiratory Dyspnea Respiratory failure Dyspnea & pallor
i I:; &
i Iii 3 (10) 5 (17) 3 (10)
. i I;;
Other Tinnitus Circumoral paresthesia
:1371 1 (3)
logic, date(s) of administration, pertinent laboratory values, and relevant past medical history. The, name of the suspect drug or biologic’s manufacturer and lot number(s) may also be provided. The SRS was searched for all reports with dates from January 1,1988, through October 31,1989, in which AlPI was named as the suspect biologic. A case of pain and/or cyanosis was defined as: (1) the sudden occurrence of chest pain, back pain, and/or cyanosis during infusion of AlPI; (2) the absence of indicators of bronchospasm such as wheezing; (3) the absence of signs suggestive of histamine release such as urticaria, angioedema, laryngeal edema, or hypotension; and (4) the resolution of signs and symptoms upon withdrawal of the infusion. Although a common symptom among cases, dyspnea was not included in the case definition in order to increase its specificity. Therefore, reports of individuals without pain and/or cyanosis but with dyspnea, which might well be explained as an exacerbation of their underlying emphysema, were not counted as cases. Noncases were defined as all 622
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Adverse Reaction Reports Of the 43 reports forwarded to the SRS during the study interval, 14 met the case definition. Pain (chest pain, back pain, or a combination) was reported in nine of 14 patients (64%), cyanosis in four (29%), and a combination of both pain and cyanosis in one (7%) (Table I). Dyspnea was mentioned in eight patients (57%). Other less commonly reported signs and symptoms included pallor (three patients), dizziness/faintness/lightheadedness (three), and one each of chills, cold sensation, diaphoresis, dysgeusia, fever, throbbing headache, hot sensation, hypertension, leukocytosis, pressure sensation in the ears, and tachycardia. Of the six case reports that mentioned vital signs, four noted increased respiratory rates, all in patients with cyanosis and/or dyspnea. Due to the acute nature of the reaction, blood gas values were not obtained prior to oxygen therapy in these or other cases with cyanosis and/or dyspnea. The most commonly reported adverse reactions among the 29 noncases were constitutional signs and symptoms (28%), such as fever or nausea, or reactions characteristic of histamine release, such as urticaria (24%) (Table I). Of the seven reports that described pain, four resembled, but did not satisfy, the case definition. One was an instance of chest pain and dyspnea and another of flank pain, cyanosis, and dyspnea. Both were excluded as cases because of concomitant bronchospastic signs. A third patient experienced arm pain, dyspnea, and chest tightness. A fourth patient had chest pain, back pain, cyanosis, and dyspnea, but symptoms did not improve with cessation of exposure. Five noncase reports described reactions presumed to be of respiratory origin, four of which listed dyspnea. The overall prevalence of dyspnea among noncases (eight of 29, or 28%) was not significantly different from that of cases (p = 0.06). Other reported signs and symptoms included single reports of blurry vision, circumoral paresthesia, coldness, convulsion, dry mouth, infection, nervousness, pain in the apical lung area, palpitations, petechiae, sensation of heat, sensation of lip swelling, tinnitis, and transient paralysis. The month of occurrence and associated AlPI retail lot for cases and noncases are presented in Figure 1. All cases occurred during the first quarter of 1989 and the majority (13 of 14) were associated with lots i or j. These lots were released from the manufacturer for distribution on January 17,1989,, and January 19, 1989, respectively (lots h and k were released on October 27, 1988, and December
I
I
I
JAN
I
MAR
I
I
I
MAY
I
JUL
I
I
SEPT
I
I
I
NOV
I,
I
JAN
MAR
I
I
I
MAY
I
I
JUL
I
SEPT
l-lj i
u I JAN
1. Cases and noncases by month of onset and lot, January 1988 through October 1989.
b/c I I
I
MAR
I
I
MAY
d I JUL
Figure
b I
f I SEPT
g/h f b
u I
I
NOV
JAN
u
j
i I
i I MAR
h I
I MAY
P
P
o I
q I JUL
r I
II v
I
SEPT
1988 - 1989 *u-unknown
13, 1988, respectively). Lots i and j were later recalled on March 22,1989 (personal communication, Cutter Biological). Cases originated in 11 states, three of which reported two. In all three states, the two reports were forwarded by different individuals and institutions. In contrast to cases, noncases were first reported to have occurred in January 1988, shortly after initial marketing of AlPI (Figure 1). An increase in noncase reports was noted in March 1989, followed by a single report in April, during which AlPI was not being distributed. Reporting of noncases resumed after remarketing of AlPI in June 1989. Compared with cases, noncases were significantly less likely to have been exposed to lots i or j (p = 0.00004, Table
II
e b/c
II).
Further characteristics of reported case- and noncase-patients are noted in Table II. Their average age was comparable, reflecting the age at onset of significant respiratory impairment from AlPI deficiency [6]. Compared with noncase-patients, case-patients were as likely to be male, to have started infusions with doses consistent with the 60
mg/kg weekly regimen recommended in the package insert (the total dose administered prior to reaction onset was not available), and to have had rates of infusion consistent with package insert recommendations (0.08 mL/kg/min or 60 mg/kg administered over approximately 30 minutes). Case-patients compared with noncase-patients reported a sixfold greater median number of treatments prior to the adverse reaction, although the difference was not statistically significant. The lack of statistical significance may have been influenced by the limited number of case reports with this information (n = 5). Median time to onset of reaction was significantly different in cases (9 minutes) and in noncases (2 hours). Although a greater proportion of case-patients (43% versus 24%) had a medical intervention for their symptoms, the difference was not statistically significant. Although, by definition, all case-patients indicated resolution of their symptoms following interruption of the AlPI infusion, the time to resolution was generally not reported. Eight reports noted an “unJune
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AND GROSS
TABLE II
Characteristicsof Repotted Casesand Noncases Characteristic Aget (Y)
CaseRate(%) 50.5
Mean Range
41-66
Sex Male Female AlPl Treatments Standard doset: Standard ratet No. prior to onset5 Median Range
Noncase Rate(%)
p Value*
49.0
NS
32-71
9114 (64)
13/28 (46)
NS
5114 (36)
15/28 (54)
NS
13/14 (93) 12/14 (86)
26129 (89) 9112 (75)
Ii:
2j33
1%
NS
Time to onset (min)
1 min120 to 10 d
2T20 Patient treatment Hospitalized Prescription drug None Associated lot Lot i
Lotj Lotiorj All others Unknown
1114 (7) 4114 (29) 8/14 (57) 6114 (43) 7i14 i5Oj 13/14 (93)
0.009
l/29 (3)
NS
6/29 (21) 22/29 (76)
rig
3129 3/29 6129 21/29 7129
(10) iloi (21) (72) (24)
0.04 0.0007 0.00004 0.005 NS I
IS = nonsignificant if p value >0.05. Tests used: Student’s t-test for differences in means; ?dian test for differences in medians, chi-square with Yates’ _. correction for differences in ropottions If expected values for all cells were 2 5, the two-tailed Fisher exact test It not. Ages 40 to 59 years: case-patients 12/14, noncase-patients 24/29. %tandard dose = 60 mgikg. Standard rate = 0.08 mL/kg/min or 60 mgikg administered over approximately 30 minutes (nonstandard definedas over 40 minutes). SEasedon five case reports, 22 noncase reports. l!Basedon six case reports, 11 noncase reports.
P
eventful recovery,” five noted that “symptoms cleared,” and one noted resolution of symptoms in 28 minutes. Of the five case-patients in whom administration of the same lot of AlPI was known to have been resumed during the same treatment session, two reported recurrence of symptoms. The infusion rate for the three who did not report recurrence had been decreased. Six other case-patients were reexposed to the same lot of AlPI 1 week later; four reported recurrence of symptoms (one of whom discontinued treatment). Of the two who did not, one had received a lower dose and the other’s dose and rate of infusion were unknown. Three of the remaining case-patients were not reexposed to the same lot, and, as was true for all case-patients, did not have recurrence of symptoms upon exposure to nonsuspect lots. Manufacturing Process, Distribution, and Results of Animal Studies AlPI is produced by a complex, multistep process that begins with plasmapheresis of screened do624
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nors. The pooled plasma then undergoes fractionation (mainly precipitation and ion-exchange chromatography) designed to separate the AlPI component from other plasma constituents [7]. After an adequate concentration of the active protein is achieved, the solution undergoes heat treatment to decrease the risk of parenterally transmitted viral infections. In preparation for this step, two stabilizing agents, sodium citrate and sucrose, are added to protect against deterioration of AlPI protein [7]. After removal of the stabilizers, the solution is adjusted to bulk form, lyophilized, assigned a lot number, and tested prior to release. At administration, AlPI is reconstituted using sterile water, generally to a concentration of 25 mg/mL. The final product volume of about 150 to 250 mL is infused over about 30 minutes [2]. This quantity corresponds to 3.75 to 6.25 g per treatment. During 1989, the manufacturer distributed 75,729 l-g equivalents in one-half and l-g vials (personal communication, Cutter Biological). Assuming a treatment dose of 5 g, the quantity distributed in 1989 corresponds to about 291 persons treated weekly for 1 year. The two suspect lots, namely i and j, comprised a combined total of 8,267 l-g equivalents, of which 2,371(29%) were returned upon recall of the lots. The remaining 5,896 l-g equivalents comprised 1,179 5-g doses. Assuming that 1,179 individuals received these 5-g doses, an estimated miltimal attack rate would be 13 of 1,179 or 1.1 of 100. Adjusting for overestimation of persons exposed (some may have received multiple doses or doses less than 5 g) and underreporting, both of which are likely, would result in a higher attack rate. In response to these unusual adverse reaction reports, the manufacturer tested suspect retain material set aside at various steps of the manufacturing sequence and performed a series of animal studies. High-pressure liquid chromatography (HPLC) columns were used for size exclusion separation of the sucrose additive used in lots i and j and in control lots. The resulting chromatograms showed detectable levels of unidentified high-molecular-weight polysaccharides (molecular weight greater than 500,000) in the suspect lots, but chromatograms of control lots showed significantly lower or no detectable levels (personal communication, Cutter Biological). The manufacturer also used a rabbit bioassay, which showed a significant increase in platelet reactivity over controls in rabbits given material from lots i and j. This effect was accompanied by a rapid, transient thrombocytopenia as evidenced by the reduction in platelet count as great as 60% to 70% in the suspect lots and no greater than 10% to 20% in
AlPI-ASSOCIATED
clinically well-tolerated lots (personal communication, Cutter Biological). HPLC of the sucrose additive was not able to consistently predict which lots would elicit an adverse response in the animal model. Only the animal model was able to consistently distinguish the suspect lots.
COMMENTS Although inferences drawn from comparisons of case- and noncase-patients in a spontaneous reporting system are potentially biased, such effects are reduced in this analysis due to the manner in which patients become selected for treatment. AlPI is unusual in that it is administered for a single disease entity, and then only in a subset where a known pulmonary complication (i.e., emphysema) has supervened. Furthermore, the age range of the treatment population is comparatively narrow, since the emphysema of AlPI deficiency usually occurs when patients reach their 40s or 50s [6]. Therefore, both case and noncase reports are likely to be representative of the underlying treatment population in terms of two important characteristics that could produce confounding bias, i.e., the disease for which treatment is indicated and age (a crude surrogate measure for disease severity). Indeed, the mean age for both case- and noncase-patients was about 50 years, and over 80% of all reported patients were aged 40 through 59 years. Furthermore, there is no evidence that the bias of most concern, i.e., that cases were more likely to be reported in association with the two suspect lots than noncases, was operative. Support for this statement comes from lack of similar case reports following recall of the suspect lots (but continued noncase reporting), despite increased awareness of the problem among health care professionals administering AlPI. The unique clinical presentation of cases, i.e., moderate to severe pain, cyanosis out of proportion to the respiratory status, and occasional indicators of vasomotor activity, such as pallor or throbbing headache, was easily distinguished from that of noncases. Furthermore, the case reports suggested that the reactions were not due to exacerbation of underlying pulmonary disease by either allergic or nonallergic mechanisms, but rather were more consistent with a vascular, rather than a respiratory, mechanism. The rapid reaction onset among cases could be consistent with exposure to an allergen. However, cases tended to occur only after several exposures, which is more compatible with a toxin-like substance (delivered at rates or doses sufficient to induce an adverse reaction). Both clinical presentation and reaction time course suggest that the case-patients experienced a
PAIN AND CYANOSIS
/ CLARK AND GROSS
nonallergic, toxin-like, reaction. Furthermore, the appearance of such a unique reaction well after initial marketing suggests that the illness could have been related to a contaminant in the product, introduced either at the time of manufacture or during reconstitution. If the latter were true, the expected geographic case-distribution would be that of reports from one or a few sites, not one or two reports each from a variety of geographic locations as was the case. The epidemic curve provides further support for a source contamination at the time of manufacture. Although cases had not previously been reported either during clinical trials or after one full postmarketing year, they were reported within 1 month of distribution of lots i and j, lots that were significantly more associated with cases than with noncases, but were no longer reported after lots i and j were withdrawn. The sudden increase in March in noncase reports can be explained either as misclassification of some cases as noncases or as “stimulated” reporting of noncases after case-finding inquiries had been made by the manufacturer. Further support for a lot-specific problem is noted in the recurrence of symptoms in the majority of casepatients reexposed to the suspect lots (reduced infusion rates or doses may explain lack of recurrence in the minority) and the lack of symptoms in all case-patients upon exposure to lots other than i or j. Potential case misclassification might explain why one case was associated with another lot. Findings by the manufacturer of an altered HPLC pattern in the sucrose additive used in suspect lots, and lot-related transient thrombocytopenia in animals, suggested the presence of biologically active substances (i.e., high-molecular-weight polysaccharides) in higher than normal concentrations. That the animal model could consistently distinguish the suspect lots is likely due to its sensitivity in detecting trace amounts of these agents remaining following removal of the sodium citrate and sucrose stabilizers after heat treatment of AlPI. HPLC was used to test the bulk sucrose additives and not the final product and therefore could not consistently predict responses in the animal model. The subsequent use of sucrose-stabilized product screened for more than trace amounts of suspect high-molecular-weight polysaccharides has not yet been associated with additional case reports to the FDA’s SRS. Although new to AlPI, reports of cyanosis, chest pain, and back pain have been associated with another therapeutic agent, protamine sulfate. This highly basic protein reverses the anticoagulant effects of heparin, an acidic mucopolysaccharide [8]. In the FDA’s SRS, the adverse reaction most comJune
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/ CLARK AND GROSS
monly reported with protamine use is back pain (10.4% of reports), which can be obviated by lowering protamine’s rate of administration. Both chest pain and cyanosis have also been reported, although much less frequently (1.4% and 0.3% of reports, respectively). Protamine-heparin complexes produce reversible platelet aggregation with transient thrombocytopenia in animals [9,10] and damage the mitochondria of endothelial cells [ll]. In the latter instance, one can speculate that toxicity affecting the aortic endothelium might be experienced as back pain. Protamine-heparin complexes also occasionally produce acute pulmonary hypertension. This reaction, first described by Lowenstein et al [12], is thought to be due to the nonhistamine-mediated release or generation of pulmonary vasoconstrictive substances, such as thromboxane Bs 1131. The reaction generally occurs in patients undergoing cardiopulmonary bypass who receive large doses of protamine. This adverse response predisposes recipients to a rapidly reversible intrapulmonary shunt, which, if severe, could lead to cyanosis in patients not receiving oxygen supplementation. Given the similarities between known adverse effects of protamine-heparin complexes and toxic reactions associated with certain lots of AlPI, both of which contain polysaccharide moieties, it is reasonable to postulate similar mechanisms. Thus, we suggest that the suspect lots of AlPI contained higher than normal trace concentrations of high-molecular-weight polysaccharides, which directly or indirectly produced pathophysiologic effects similar to those previously described with protamine-heparin complexes. Further research is needed to define the pathophysiology associated with these and other polysaccharide moieties.
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ACKNOWLEDGMENT We thank Ms. Carol Moore from Cutter Biological for providing information on the manufacturing process, distribution, and animal studies. We also thank Bernard Farrell, M.D., and John Fritz, Pharm.D., for their assistance with a case report.
REFERENCES 1. Wewers MD, Casolaro A, Sellers SE, et a/. Replacement therapy for alpha-lantitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316: 1055-62. 2. Package insert for alpha-l-proteinase inhibitor (human), Cutter Biological, Berkeley, California. 3. Hubbard RC. Crystal RG. Alpha-1-antitrypsin augmentation therapyfor alpha1-antitrypsin deficiency. Am J Med 1988; 84 Suppl 6A: 52-62. 4. Faith GA. Adverse-drug-reaction monitoring. N Engl J Med 1986; 314: 1589-92. 5. Sills JM, Faith GA, Milstien JB, eta/. Postmarketing reporting of adverse drug reactions to the FDA: an overview of the 1985 FDA guideline. Drug Info J 1986; 20: 151-6. 6. Eriksson S. Pulmonary emphysema from alpha-1-antitrypsin deficiency. Acta Med Stand 1964; 175: 197-205. 7. Coan MH. Purification of alpha-1-proteinase inhibitor. Am J Med 1988; 84 Suppl6A: 32-6. 8. O’Reilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rail TW, Murad F, editors. The pharmacologic basis of therapeutics. New York: Macmillan, 1985: 1338-59. 9. Kirklin JK, Chenoweth DE, Naftel DC, et a/. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements and the hemodynamic state. Ann Thorac Surg 1986: 41: 193-9. 10.Alvarez J, Alvarez L, Escudero C. Gilsanz F, de Oya S, Castillo-Olivares JL. Hemodynamic and morphologic alterations after experimental administration of protamine sulfate. Am J Surg 1988; 155: 735-40. 11. Wakefield TW, Hinshaw DB, Burger JM, Burke1 WE, Standly JC. Protamineinduced reductions of endothelial cell ATP. Surgery 1989; 106: 37885. 12. Lowenstein E, Johnston WE, Lappas DG, et al. Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology 1983; 59: 470-3. 13. McIntyre RW, Flezzani P, Knopes KD, Reves JG, Watkins WD. Pulmonary hypertension and prostagfandins after protamine. Am J Cardiol 1986; 58: 857-8.
PURPOSE ‘Ihe purpose of this study was to investigate adverse reaction reports of pain and/ or cyanosis attributed to al-proteinase inhibitor (AlPI), a plasma a-globulin protein used to treat AlPI deficiency. PATIENTS AND METHODS: The Food and Drug Administration’s (FDA) Spontaneous Reporting System for the collection and analysis of suspected adverse reactions to drugs and biologics was searched for all reports with dates from January 1,1988, through October 31,1989, in which AlPI was named as the suspect biologic. A case of pain and/or cyanosis was defined and characteristics of cases were compared with all other reactions. Information about the production of AlPI and results from animal studies conducted by the manufacturer were also gathered. RESULTS: Fourteen cases of acute chest pain, back pain, and/or cyanosis among patients receiving AlPI infusions were reported to the FDA. The clinical aspects of reported cases were consistent with a rapidly acting, nonallergic mechanism and were easily distinguished from other reactions associated with AlPI. The characteristics of reported cases, the epidemic curve, and lot-specific analyses suggested a point source and strongly implicated two AlPI lots. Information about the production of AlPI and results from animal studies further implicated high-molecular-weight polysaccharides associated with sucrose stabilization of the suspect lots. CONCLUSION: These cases resemble adverse reactions attributed to complexes of protamine and heparin (a mucopolysaccharide). Similar vasoactive mechanisms are suggested. Research is needed to further define the pathophysiology associated with polysaccharide moieties.
From the Office of Epidemiology and Biostatistics, Food and Drug Administration, Rockville. Maryland. The opinions expressed in this article are those of the authors and not necessarily those of the Food and Drug Administration. Requests for reprints should be addressed to Thomas P. Gross, M.D., M.P.H., Food and Drug Administration, Epidemiology Branch HFD-733, 5600 Fishers Lane, Rockville, Maryland 20857. Manuscript submitted April 19, 1991, and accepted in revised form January 27, 1992.
A
lpha-1-proteinase inhibitor (cul-antitrypsin) is a plasma a-globulin protein possessing biologic activity against neutrophil elastase and other proteinases [l]. A commercially available preparation (Prolastin*; Cutter Biological) derived from processed pooled plasma has been marketed as a treatment for al-proteinase inhibitor (AlPI) deficiency since January 1988. Although safety information was collected on AlPI prior to its marketing, knowledge of its adverse reaction profile at the time of approval was limited [Z], as is the case for many newly marketed drugs and biologics. Premarketing studies indicated that adverse reactions occurred at a low rate and were rarely life-threatening [2]. The only major safety concern prior to marketing was the infrequent occurrence of allergic reactions [l-3]. To further monitor the postmarketing safety of drugs and biologics, the Food and Drug Administration (FDA) maintains a computerized Spontaneous Reporting System (SRS) for the collection and analysis of suspected adverse reactions to drugs and biologics [4]. During the first quarter of 1989, 14 patients were reported to the FDA’s SRS to have had chest pain, back pain, and/or cyanosis during infusions of AlPI. The characteristics of reported cases, the epidemic curve, information about the production of AlPI, and ‘results from animal studies conducted by the manufacturer suggested that these reactions were due to biologically active substances, most likely high-molecular-weight polysaccharides, introduced during manufacture of some lots of AlPI.
PATIENTSAND METHODS Since 1969, about 500,000 adverse drug and biologic reaction reports have been received by the FDA’s SRS database. The majority of reports are forwarded by pharmaceutical manufacturers or distributors based on information they have received, while a minority come directly from health care professionals [5]. Each report is coded and entered into the SRS using terms from a computerized drug reaction dictionary. Once coded, a suspect report and its associated data elements can be retrieved for further analysis. The major elements of each report are: the patient’s initials or identification number, age, sex, date of birth, reaction onset date, description of the reaction, the suspect drug or bio*Trade names are provided do not imply any endorsement tion. June
1992
The American
Journal
for product identification only and by the Food and Drug Administraof Medicine
Volume
92
621
AlPI-ASSOCIATED
PAIN AND CYANOSIS
/ CLARK AN6 GROSS
other reactions in the SRS that were not cases and in which AlPI was named as the suspect biologic.
TABLE I Incidence of CommonlyReported Symptomsin Casesand Noncases
RESULTS
No. (%I Cases (n = 14) Pain Chest pain&back pain Chest pain & dyspnea Back pain & dyspnea
2 (14) 2 (14)
Cyanosis Cyanosis & dyspnea Cyanosis alone
1 (7)
Pain &cyanosis Back pain & cyanosis & dyspnea
1 (7) 1 (7)
Noncases
(n = 29)
Constitutional Fever &/or chills Faintness &/or dizziness Nausea &/or vomiting
8 (28) 4 (14)
Urticaria Alone Urticaria & hypotension
7 (24) 6(21) 1 (3)
Pain Chest pain & dyspnea Flank pain &cyanosis & dyspnea Arm pain & dyspnea Chest pain & back pain &cyanosis dyspnea Flu-like reaction with myalgias
7 (24)
Respiratory Dyspnea Respiratory failure Dyspnea & pallor
i I:; &
i Iii 3 (10) 5 (17) 3 (10)
. i I;;
Other Tinnitus Circumoral paresthesia
:1371 1 (3)
logic, date(s) of administration, pertinent laboratory values, and relevant past medical history. The, name of the suspect drug or biologic’s manufacturer and lot number(s) may also be provided. The SRS was searched for all reports with dates from January 1,1988, through October 31,1989, in which AlPI was named as the suspect biologic. A case of pain and/or cyanosis was defined as: (1) the sudden occurrence of chest pain, back pain, and/or cyanosis during infusion of AlPI; (2) the absence of indicators of bronchospasm such as wheezing; (3) the absence of signs suggestive of histamine release such as urticaria, angioedema, laryngeal edema, or hypotension; and (4) the resolution of signs and symptoms upon withdrawal of the infusion. Although a common symptom among cases, dyspnea was not included in the case definition in order to increase its specificity. Therefore, reports of individuals without pain and/or cyanosis but with dyspnea, which might well be explained as an exacerbation of their underlying emphysema, were not counted as cases. Noncases were defined as all 622
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Adverse Reaction Reports Of the 43 reports forwarded to the SRS during the study interval, 14 met the case definition. Pain (chest pain, back pain, or a combination) was reported in nine of 14 patients (64%), cyanosis in four (29%), and a combination of both pain and cyanosis in one (7%) (Table I). Dyspnea was mentioned in eight patients (57%). Other less commonly reported signs and symptoms included pallor (three patients), dizziness/faintness/lightheadedness (three), and one each of chills, cold sensation, diaphoresis, dysgeusia, fever, throbbing headache, hot sensation, hypertension, leukocytosis, pressure sensation in the ears, and tachycardia. Of the six case reports that mentioned vital signs, four noted increased respiratory rates, all in patients with cyanosis and/or dyspnea. Due to the acute nature of the reaction, blood gas values were not obtained prior to oxygen therapy in these or other cases with cyanosis and/or dyspnea. The most commonly reported adverse reactions among the 29 noncases were constitutional signs and symptoms (28%), such as fever or nausea, or reactions characteristic of histamine release, such as urticaria (24%) (Table I). Of the seven reports that described pain, four resembled, but did not satisfy, the case definition. One was an instance of chest pain and dyspnea and another of flank pain, cyanosis, and dyspnea. Both were excluded as cases because of concomitant bronchospastic signs. A third patient experienced arm pain, dyspnea, and chest tightness. A fourth patient had chest pain, back pain, cyanosis, and dyspnea, but symptoms did not improve with cessation of exposure. Five noncase reports described reactions presumed to be of respiratory origin, four of which listed dyspnea. The overall prevalence of dyspnea among noncases (eight of 29, or 28%) was not significantly different from that of cases (p = 0.06). Other reported signs and symptoms included single reports of blurry vision, circumoral paresthesia, coldness, convulsion, dry mouth, infection, nervousness, pain in the apical lung area, palpitations, petechiae, sensation of heat, sensation of lip swelling, tinnitis, and transient paralysis. The month of occurrence and associated AlPI retail lot for cases and noncases are presented in Figure 1. All cases occurred during the first quarter of 1989 and the majority (13 of 14) were associated with lots i or j. These lots were released from the manufacturer for distribution on January 17,1989,, and January 19, 1989, respectively (lots h and k were released on October 27, 1988, and December
I
I
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JAN
I
MAR
I
I
I
MAY
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JUL
I
I
SEPT
I
I
I
NOV
I,
I
JAN
MAR
I
I
I
MAY
I
I
JUL
I
SEPT
l-lj i
u I JAN
1. Cases and noncases by month of onset and lot, January 1988 through October 1989.
b/c I I
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MAR
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MAY
d I JUL
Figure
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f I SEPT
g/h f b
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i I MAR
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1988 - 1989 *u-unknown
13, 1988, respectively). Lots i and j were later recalled on March 22,1989 (personal communication, Cutter Biological). Cases originated in 11 states, three of which reported two. In all three states, the two reports were forwarded by different individuals and institutions. In contrast to cases, noncases were first reported to have occurred in January 1988, shortly after initial marketing of AlPI (Figure 1). An increase in noncase reports was noted in March 1989, followed by a single report in April, during which AlPI was not being distributed. Reporting of noncases resumed after remarketing of AlPI in June 1989. Compared with cases, noncases were significantly less likely to have been exposed to lots i or j (p = 0.00004, Table
II
e b/c
II).
Further characteristics of reported case- and noncase-patients are noted in Table II. Their average age was comparable, reflecting the age at onset of significant respiratory impairment from AlPI deficiency [6]. Compared with noncase-patients, case-patients were as likely to be male, to have started infusions with doses consistent with the 60
mg/kg weekly regimen recommended in the package insert (the total dose administered prior to reaction onset was not available), and to have had rates of infusion consistent with package insert recommendations (0.08 mL/kg/min or 60 mg/kg administered over approximately 30 minutes). Case-patients compared with noncase-patients reported a sixfold greater median number of treatments prior to the adverse reaction, although the difference was not statistically significant. The lack of statistical significance may have been influenced by the limited number of case reports with this information (n = 5). Median time to onset of reaction was significantly different in cases (9 minutes) and in noncases (2 hours). Although a greater proportion of case-patients (43% versus 24%) had a medical intervention for their symptoms, the difference was not statistically significant. Although, by definition, all case-patients indicated resolution of their symptoms following interruption of the AlPI infusion, the time to resolution was generally not reported. Eight reports noted an “unJune
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TABLE II
Characteristicsof Repotted Casesand Noncases Characteristic Aget (Y)
CaseRate(%) 50.5
Mean Range
41-66
Sex Male Female AlPl Treatments Standard doset: Standard ratet No. prior to onset5 Median Range
Noncase Rate(%)
p Value*
49.0
NS
32-71
9114 (64)
13/28 (46)
NS
5114 (36)
15/28 (54)
NS
13/14 (93) 12/14 (86)
26129 (89) 9112 (75)
Ii:
2j33
1%
NS
Time to onset (min)
1 min120 to 10 d
2T20 Patient treatment Hospitalized Prescription drug None Associated lot Lot i
Lotj Lotiorj All others Unknown
1114 (7) 4114 (29) 8/14 (57) 6114 (43) 7i14 i5Oj 13/14 (93)
0.009
l/29 (3)
NS
6/29 (21) 22/29 (76)
rig
3129 3/29 6129 21/29 7129
(10) iloi (21) (72) (24)
0.04 0.0007 0.00004 0.005 NS I
IS = nonsignificant if p value >0.05. Tests used: Student’s t-test for differences in means; ?dian test for differences in medians, chi-square with Yates’ _. correction for differences in ropottions If expected values for all cells were 2 5, the two-tailed Fisher exact test It not. Ages 40 to 59 years: case-patients 12/14, noncase-patients 24/29. %tandard dose = 60 mgikg. Standard rate = 0.08 mL/kg/min or 60 mgikg administered over approximately 30 minutes (nonstandard definedas over 40 minutes). SEasedon five case reports, 22 noncase reports. l!Basedon six case reports, 11 noncase reports.
P
eventful recovery,” five noted that “symptoms cleared,” and one noted resolution of symptoms in 28 minutes. Of the five case-patients in whom administration of the same lot of AlPI was known to have been resumed during the same treatment session, two reported recurrence of symptoms. The infusion rate for the three who did not report recurrence had been decreased. Six other case-patients were reexposed to the same lot of AlPI 1 week later; four reported recurrence of symptoms (one of whom discontinued treatment). Of the two who did not, one had received a lower dose and the other’s dose and rate of infusion were unknown. Three of the remaining case-patients were not reexposed to the same lot, and, as was true for all case-patients, did not have recurrence of symptoms upon exposure to nonsuspect lots. Manufacturing Process, Distribution, and Results of Animal Studies AlPI is produced by a complex, multistep process that begins with plasmapheresis of screened do624
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nors. The pooled plasma then undergoes fractionation (mainly precipitation and ion-exchange chromatography) designed to separate the AlPI component from other plasma constituents [7]. After an adequate concentration of the active protein is achieved, the solution undergoes heat treatment to decrease the risk of parenterally transmitted viral infections. In preparation for this step, two stabilizing agents, sodium citrate and sucrose, are added to protect against deterioration of AlPI protein [7]. After removal of the stabilizers, the solution is adjusted to bulk form, lyophilized, assigned a lot number, and tested prior to release. At administration, AlPI is reconstituted using sterile water, generally to a concentration of 25 mg/mL. The final product volume of about 150 to 250 mL is infused over about 30 minutes [2]. This quantity corresponds to 3.75 to 6.25 g per treatment. During 1989, the manufacturer distributed 75,729 l-g equivalents in one-half and l-g vials (personal communication, Cutter Biological). Assuming a treatment dose of 5 g, the quantity distributed in 1989 corresponds to about 291 persons treated weekly for 1 year. The two suspect lots, namely i and j, comprised a combined total of 8,267 l-g equivalents, of which 2,371(29%) were returned upon recall of the lots. The remaining 5,896 l-g equivalents comprised 1,179 5-g doses. Assuming that 1,179 individuals received these 5-g doses, an estimated miltimal attack rate would be 13 of 1,179 or 1.1 of 100. Adjusting for overestimation of persons exposed (some may have received multiple doses or doses less than 5 g) and underreporting, both of which are likely, would result in a higher attack rate. In response to these unusual adverse reaction reports, the manufacturer tested suspect retain material set aside at various steps of the manufacturing sequence and performed a series of animal studies. High-pressure liquid chromatography (HPLC) columns were used for size exclusion separation of the sucrose additive used in lots i and j and in control lots. The resulting chromatograms showed detectable levels of unidentified high-molecular-weight polysaccharides (molecular weight greater than 500,000) in the suspect lots, but chromatograms of control lots showed significantly lower or no detectable levels (personal communication, Cutter Biological). The manufacturer also used a rabbit bioassay, which showed a significant increase in platelet reactivity over controls in rabbits given material from lots i and j. This effect was accompanied by a rapid, transient thrombocytopenia as evidenced by the reduction in platelet count as great as 60% to 70% in the suspect lots and no greater than 10% to 20% in
AlPI-ASSOCIATED
clinically well-tolerated lots (personal communication, Cutter Biological). HPLC of the sucrose additive was not able to consistently predict which lots would elicit an adverse response in the animal model. Only the animal model was able to consistently distinguish the suspect lots.
COMMENTS Although inferences drawn from comparisons of case- and noncase-patients in a spontaneous reporting system are potentially biased, such effects are reduced in this analysis due to the manner in which patients become selected for treatment. AlPI is unusual in that it is administered for a single disease entity, and then only in a subset where a known pulmonary complication (i.e., emphysema) has supervened. Furthermore, the age range of the treatment population is comparatively narrow, since the emphysema of AlPI deficiency usually occurs when patients reach their 40s or 50s [6]. Therefore, both case and noncase reports are likely to be representative of the underlying treatment population in terms of two important characteristics that could produce confounding bias, i.e., the disease for which treatment is indicated and age (a crude surrogate measure for disease severity). Indeed, the mean age for both case- and noncase-patients was about 50 years, and over 80% of all reported patients were aged 40 through 59 years. Furthermore, there is no evidence that the bias of most concern, i.e., that cases were more likely to be reported in association with the two suspect lots than noncases, was operative. Support for this statement comes from lack of similar case reports following recall of the suspect lots (but continued noncase reporting), despite increased awareness of the problem among health care professionals administering AlPI. The unique clinical presentation of cases, i.e., moderate to severe pain, cyanosis out of proportion to the respiratory status, and occasional indicators of vasomotor activity, such as pallor or throbbing headache, was easily distinguished from that of noncases. Furthermore, the case reports suggested that the reactions were not due to exacerbation of underlying pulmonary disease by either allergic or nonallergic mechanisms, but rather were more consistent with a vascular, rather than a respiratory, mechanism. The rapid reaction onset among cases could be consistent with exposure to an allergen. However, cases tended to occur only after several exposures, which is more compatible with a toxin-like substance (delivered at rates or doses sufficient to induce an adverse reaction). Both clinical presentation and reaction time course suggest that the case-patients experienced a
PAIN AND CYANOSIS
/ CLARK AND GROSS
nonallergic, toxin-like, reaction. Furthermore, the appearance of such a unique reaction well after initial marketing suggests that the illness could have been related to a contaminant in the product, introduced either at the time of manufacture or during reconstitution. If the latter were true, the expected geographic case-distribution would be that of reports from one or a few sites, not one or two reports each from a variety of geographic locations as was the case. The epidemic curve provides further support for a source contamination at the time of manufacture. Although cases had not previously been reported either during clinical trials or after one full postmarketing year, they were reported within 1 month of distribution of lots i and j, lots that were significantly more associated with cases than with noncases, but were no longer reported after lots i and j were withdrawn. The sudden increase in March in noncase reports can be explained either as misclassification of some cases as noncases or as “stimulated” reporting of noncases after case-finding inquiries had been made by the manufacturer. Further support for a lot-specific problem is noted in the recurrence of symptoms in the majority of casepatients reexposed to the suspect lots (reduced infusion rates or doses may explain lack of recurrence in the minority) and the lack of symptoms in all case-patients upon exposure to lots other than i or j. Potential case misclassification might explain why one case was associated with another lot. Findings by the manufacturer of an altered HPLC pattern in the sucrose additive used in suspect lots, and lot-related transient thrombocytopenia in animals, suggested the presence of biologically active substances (i.e., high-molecular-weight polysaccharides) in higher than normal concentrations. That the animal model could consistently distinguish the suspect lots is likely due to its sensitivity in detecting trace amounts of these agents remaining following removal of the sodium citrate and sucrose stabilizers after heat treatment of AlPI. HPLC was used to test the bulk sucrose additives and not the final product and therefore could not consistently predict responses in the animal model. The subsequent use of sucrose-stabilized product screened for more than trace amounts of suspect high-molecular-weight polysaccharides has not yet been associated with additional case reports to the FDA’s SRS. Although new to AlPI, reports of cyanosis, chest pain, and back pain have been associated with another therapeutic agent, protamine sulfate. This highly basic protein reverses the anticoagulant effects of heparin, an acidic mucopolysaccharide [8]. In the FDA’s SRS, the adverse reaction most comJune
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monly reported with protamine use is back pain (10.4% of reports), which can be obviated by lowering protamine’s rate of administration. Both chest pain and cyanosis have also been reported, although much less frequently (1.4% and 0.3% of reports, respectively). Protamine-heparin complexes produce reversible platelet aggregation with transient thrombocytopenia in animals [9,10] and damage the mitochondria of endothelial cells [ll]. In the latter instance, one can speculate that toxicity affecting the aortic endothelium might be experienced as back pain. Protamine-heparin complexes also occasionally produce acute pulmonary hypertension. This reaction, first described by Lowenstein et al [12], is thought to be due to the nonhistamine-mediated release or generation of pulmonary vasoconstrictive substances, such as thromboxane Bs 1131. The reaction generally occurs in patients undergoing cardiopulmonary bypass who receive large doses of protamine. This adverse response predisposes recipients to a rapidly reversible intrapulmonary shunt, which, if severe, could lead to cyanosis in patients not receiving oxygen supplementation. Given the similarities between known adverse effects of protamine-heparin complexes and toxic reactions associated with certain lots of AlPI, both of which contain polysaccharide moieties, it is reasonable to postulate similar mechanisms. Thus, we suggest that the suspect lots of AlPI contained higher than normal trace concentrations of high-molecular-weight polysaccharides, which directly or indirectly produced pathophysiologic effects similar to those previously described with protamine-heparin complexes. Further research is needed to define the pathophysiology associated with these and other polysaccharide moieties.
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ACKNOWLEDGMENT We thank Ms. Carol Moore from Cutter Biological for providing information on the manufacturing process, distribution, and animal studies. We also thank Bernard Farrell, M.D., and John Fritz, Pharm.D., for their assistance with a case report.
REFERENCES 1. Wewers MD, Casolaro A, Sellers SE, et a/. Replacement therapy for alpha-lantitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316: 1055-62. 2. Package insert for alpha-l-proteinase inhibitor (human), Cutter Biological, Berkeley, California. 3. Hubbard RC. Crystal RG. Alpha-1-antitrypsin augmentation therapyfor alpha1-antitrypsin deficiency. Am J Med 1988; 84 Suppl 6A: 52-62. 4. Faith GA. Adverse-drug-reaction monitoring. N Engl J Med 1986; 314: 1589-92. 5. Sills JM, Faith GA, Milstien JB, eta/. Postmarketing reporting of adverse drug reactions to the FDA: an overview of the 1985 FDA guideline. Drug Info J 1986; 20: 151-6. 6. Eriksson S. Pulmonary emphysema from alpha-1-antitrypsin deficiency. Acta Med Stand 1964; 175: 197-205. 7. Coan MH. Purification of alpha-1-proteinase inhibitor. Am J Med 1988; 84 Suppl6A: 32-6. 8. O’Reilly RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rail TW, Murad F, editors. The pharmacologic basis of therapeutics. New York: Macmillan, 1985: 1338-59. 9. Kirklin JK, Chenoweth DE, Naftel DC, et a/. Effects of protamine administration after cardiopulmonary bypass on complement, blood elements and the hemodynamic state. Ann Thorac Surg 1986: 41: 193-9. 10.Alvarez J, Alvarez L, Escudero C. Gilsanz F, de Oya S, Castillo-Olivares JL. Hemodynamic and morphologic alterations after experimental administration of protamine sulfate. Am J Surg 1988; 155: 735-40. 11. Wakefield TW, Hinshaw DB, Burger JM, Burke1 WE, Standly JC. Protamineinduced reductions of endothelial cell ATP. Surgery 1989; 106: 37885. 12. Lowenstein E, Johnston WE, Lappas DG, et al. Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology 1983; 59: 470-3. 13. McIntyre RW, Flezzani P, Knopes KD, Reves JG, Watkins WD. Pulmonary hypertension and prostagfandins after protamine. Am J Cardiol 1986; 58: 857-8.
