Propafenone Associated Agranuiocytosis LINDA J. MIWA and HEIDI M. JOLSON From the Epidemiology Branch, Division of Epidemiology and Surveillance, Office of Epidemiology and Biostatistics, Food and Drug Administration, Rockville, Maryland
MIWA, L.J.. ET AL.; Propafenone Associated Agranuiocytosis. Propafenone hydrochloride was approved for marketing by the United States (U.S.) Food and Drug Administration (FDA) in November 1989. During V.S. clinical trials of propafenone, one case of agranuiocytosis was seen. Seven addilionai cases have been reported outside the U.S. One German report of profound but reversible granuJocytopenia appeared in 1982. In fanuary 1991, the FDA reviewed adverse events reported with propafenone. Four reports of agranuJocytosis were identified and are described. The reporting rate of approximately one case of agranuiocytosis per 10,000 propafenone prescriptions per year likely underestimates the true incidence of this adverse event. (PACE, Vol. 15, April, Part I 1992} propafenone, agranuiocytosis, case-report, postmarketing surveillance, adverse drug reaction
Introduction
Methods
Propafenone hydrochloride (Rythmol,^ Knoll Pharmaceuticals, Whippany, NJ. USA) is a type Ic antiarrhythmic that was approved for marketing hy the United States (U.S.) Food and Drug Administration (FDA) in November 1989.' During U.S. clinical trials involving 2,127 propafenone treated patients, one case of agranuiocytosis was seen. Seven additional cases of agranuiocytosis associated with propafenone have been reported in over 800,000 patient years of exposure since 1978 outside the U.S.^ One German report of profound but reversible granulocytopenia appeared in 1982.^ We are unaware of any other reports in the medical literature. In January 1991, 1 complete year after the introduction of propafenone to the U.S. market, the FDA reviewed adverse events reported with propafenone to determine whether additional cases of agranuiocytosis had occurred. The details of this review are presented here.
The FDA spontaneous reporting system contains over 560,000 reports of adverse drug associated events submitted by U.S. and foreign health professionals, drug manufacturers, and consumers. A general description of the FDA spontaneous reporting system has been previously published.^ All reports to the spontaneous reporting system are entered into a computerized datahase using GOSTART, a standardized dictionary of adverse drug reactions.^ The COSTART terms used in this search were agranuiocytosis, blood dyscrasia, leukopenia, marrow depression, and myeloid maturation arrest. Data on the number of propafenone prescriptions dispensed during 1990 was obtained from IMS America's National Prescription Audit (NPA).'' The NPA provides information on prescriptions dispensed by chain and independent pharmacies in the contiguous U.S. Other outpatient retail sources, such as mail-order and supermarket pharmacies, are not included. Although the audit is not a true random sample of all pharmacies, the panel of 2,500 computerized pharmacies (from which the national data are extrapolated) is assumed to he representative of pharmacies in the U.S. in terms of geographical region, type of ownership, and size.
Disclaimer; This article was written by Dr. Miwa and Dr. Jolson in their private capacity. No official support or endGrsement by the U,S, Food and Drug Administration is intended or should be inferred. Address for reprints: Linda ], Miwa, Pharm.D., Epidemiology Branch, Division of Epidemiology and Surveillance, U.S. Food and Drug Administration, 5600 P'ishers Lane, HFD-733, Rockville, MD 20857. Fax: (301) 443-9288, Received December 10, 1991; accepted December 19, 1991.
PACE, Vol. 15
The reporting rate for propafenone associated
April 1992, Part I
387
MIWA, ET AL.
agranulocytosis was calculated by dividing the number of cases by the total number of propafenone prescriptions dispensed in 1990.
Results Among 61 reports of adverse events associated with propafenone, four reports of agranulocytosis were identified. Three reports were from the U,S., one was from Canada. Descriptions of the four reports follow. Figure 1 illustrates the time course of each patient's recovery after propafenone dechallenge. Case 1
An 85-year-old man who was treated with propafenone 450 mg/day for 52-64 days was admitted with chills, fever, myalgia, and arthralgia. A white blood cell count was 0.8 cells x 10^/L with a differential of 10% neutrophils, 86% lymphocytes, 1% monocytes, 2% eosinophils, and 1% basophils. Blood cultures obtained on admission were negative, A bone marrow biopsy showed normal cellularity for age, relative normoblastic erythroid hyperplasia, and normal marrow iron stores. The myeloid series showed a virtually pure population of young myelocytes, which was suggestive of an early recovery from a relatively myeloid-specific marrow insult. Megakaryocytes and platelets appeared unaffected. There was no bone marrow evidence of a metastatic tumor or a granuloma. The patient had a history of athero-
sclerotic cardiovascular disease, with congestive heart failure, ventricular arrhythmias, and a bradyarrhythmia that required insertion of a pacemaker. Other medical conditions included mild renal insufficiency and calculi, diverticulitis, osteoarthritis, gout, and glaucoma. Concurrent medications included furosemide, methazolamide, potassium citrate/sodium citrate, and an unidentified nonsteroidal antiinflammatory drug. Propafenone was discontinued; further information on the other medications was not provided. Seven days after discontinuation of propafenone, a white blood cell count was 9.8 cells x 10^/L. The patient recovered and is clinically well on alternative antiarrhythmic therapy. Case 2
A 57-year-old man who was treated with propafenone 900 mg/day for 59 days was admitted with fever and fatigue. A white blood cell count wasl.8cells x lO'^/LwithOneutrophils. Examination of the bone marrow revealed isolated suppression of white blood cell precursors with normal red blood cell and platelet precursors. A complete workup for a viral or a neoplastic etiology for agranulocytosis was negative. The past medical history included an inferior wall myocardial infarction, single vessel coronary artery bypass graft surgery, and paroxysmal atrial flutter. Concurrent medications were digoxin, ranitidine, and dipyridamole, but propafenone was the only recently introduced drug, Propafenone was discontinued; further information on the other drugs was not provided. The patient recovered. A white blood cell count reported 1 month later was 11.1 cells X 10^/L. The patient remains off the drug and is clinically well on alternative antiarrhythmic therapy. Case 3
Days
Figure 1. Changes m white blood cell (WBCJ count in four pafj'enfs wilh propafenone associated agranulocytosis reported to Food and Drug Administration in 1990. Propafenone discontinued on Day 0. Prefreatment WBC available/or cases 3 and 4 onJy.
388
An 83-year-old man who was treated with propafenone 450-750 mg/day for 49 days was admitted for an arrhythmic event. He was incidentally found to have a white blood cell count of 1.5 cells X 10"/L with a differential of 3% neutrophils. Propafenone was discontinued. Five days later the patient remained neutropenic with a white blood cell count of 1.1 cells X 10^/L and 0 neutrophils. Agranulocytosis, possibly associated with medul-
April 1992, Part I
PACE, Vol. 15
PROPAFENONE ASSOCIATED AGRANULOCYTOSIS
lary hypoplasia, was suspected based on the results of a bone marrow biopsy. Past medical history included noninsulin dependent diabetes mellitus, hypertension, and coronary artery disease. Concurrent medications included digoxin, glyburide, nifedipine, ferrous sulfate, aspirin, naproxen, and ketoprofen. Naproxen was discontinued shortly after propafenone was started. Propafenone, aspirin, and ketoprofen were discontinued simultaneously. Eleven days after stopping propafenone the patient began to recover, and he had a white blood cell count of 2.4 cells x lO^/L with 16% neutrophils. The patient made an uneventful recovery and is currently clinically well on sotalol therapy. Case 4 A 51-year-old woman treated with propafenone 450 mg/daily for 30 days was admitted with dysuria, dyspnea, diarrhea, chills, weakness, and fever. A white blood cell count was 0.6 cells x 10^/ L with 0 neutrophils on the differential. A blood culture was positive for a Group B streptococcus. Bone marrow examination showed a normocellular to mildly hypercellular marrow for age, with severe relative myeloid hypoplasia. Megakaryocytes appeared normal in number. There was no evidence of granulomas, obvious fibrosis, or malignancy. The patient's medical history included chronic atrial fibrillation, supraventricular tachycardia, noninsulin dependent diabetes melUtus, sarcoidosis, obesity, deep vein thrombosis, pulmonary embolus, sleep apnea, and severe restrictive lung disease. The patient had a history of adverse events with quinidine and procainamide (diarrhea and rash), and an allergy to sulfa. Concurrent medications were digoxin, verapamil, insulin, coumadin, furosemide, potassium chloride, ibuprofen, and estrogen; propafenone was the only recently introduced drug. Propafenone was discontinued; no information was provided on the other drugs. After discontinuation of propafenone the patient recovered. She remains off the drug and is doing clinically well on alternative antiarrhythmic therapy. Data from the NPA estimates that 45,000 prescriptions were dispensed for propafenone in the U.S. in 1990, thus yielding a reporting rate of pro-
PACE, Vol. 15
pafenone associated agranulocytosis of nearly one report per 10,000 prescriptions per year.
Discussion The FDA has received four reports of agranulocytosis associated with propafenone in its first year of marketing. While a definitive causal association between propafenone and agranulocytosis in these patients cannot be proven, these cases are compelling because of their similarities: (1) all occurred within 2 months of initiating propafenone therapy; [2} the bone marrow presentation was similar in all, showing an isolated insult to myeloid precursors; (3) a positive dechallenge, i.e., the bone marrow recovered after discontinuation of propafenone in all cases; and (4) the time course to recovery was similar, occurring within 2 weeks after discontinuation of propafenone. Other medications reported in these cases, which have been rarely associated with leukopenia or agranulocytosis, include digoxin, furosemide, methazolamide, glyburide, ranitidine. and nonsteroidal antiinflammatory drugs.^-^"^^ Although the possible contribution of these medications cannot be excluded, two reports noted that there had been no recent change in medications other than the addition of propafenone. Agranulocytosis is a rare disease with an estimated incidence from population based studies of 2.5 to 10 cases per million persons per year.^ While a variety of drugs have been associated with agranulocytosis, a causal association has been established for only a few.^"^^ The reporting rate of approximately one case per 10.000 propafenone prescriptions per year likely underestimates the true incidence of propafenone associated agranulocytosis since all adverse events are not reported and a single patient may receive more than one prescription per year. If the reporting rate approximates the true incidence of propafenone associated agranulocytosis, patients taking propafenone have a tenfold to fortyfold greater risk for developing agranulocytosis than the general population. The cases presented here are highly suggestive of an association between propafenone and agranulocytosis. Although not reported in these cases, more definitive evidence of a drug etiology for agranulocytosis (either immune mediated or
April 1992, Part I
389
MIWA, ET AL.
direct toxicity) can be obtained from in vitro tests, such as marrow culture, agglutination, and competitive enzyme linked immunoassay. These techniques are complex, extensive use of positive and negative controls is mandatory, and acute phase sera must be sampled immediately on diagnosis since drug dependent antibodies and drug antibody complexes disappear rapidly after drug dechallenge. The application of these methods is, therefore, probably limited to clinical research institutions.^*"'^ Physicians need to be aware of the association of agranulocytosis with propafenone so they may caution propafenone treated patients to seek medi-
cal attention if they develop a fever or other signs of infection. Since agranulocytosis following propafenone appears to be readily reversible, this medication should be stopped at the first suspicion of white blood cell marrow suppression. Furthermore, the alert clinician can help increase the current understanding of drug induced agranulocytosis by: (1) complete and accurate reporting of cases; and (2) awareness of the availability of in vitro techniques for investigation of a suspected drug etiology for agranulocytosis. Acknotvledgmenf: We thank Lilia Talarico, M.D.. for her review and comments.
References 1. Burke LB, Baum C, Jolson HM, et al. Eleventh Annual Review of Drug Utilization in the United States. Rockville, Maryland, Department of Health and Human Services, 1991, p.10. 2. Physicians' Desk Reference, 45th Ed. Oradell, N], Medical Economics Company, Inc., 1991, pp.1153-1156 3. Harron DWG. Brogden RN. Propafenone—A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 1987; 34:617-647. 4. Faich CA. Adverse drug reaction monitoring, N Engl J Med 1986; 314:1589-1592. 5. U.S. Food and Drug Administration. 'COSTART' Coding Symbols for Thesaurus of Adverse Reaction Terms, 3rd Ed. Rockville, Maryland, Food and Drug Administration, 1989. 6. IMS America. National Prescription Audit, Therapeutic Category Report, Plymouth Meeting, PA, IMS America. Ltd., December 1990, p.4O3.
390
7. Heimpel H. Drug-induced agranulocytosis. Med Toxicol 1988; 3:449-462. 8. Vincent PC, Drug-induced aplastic anemia and agranulocytosis—Incidence and mechanisms. Drugs 1986; 31:52-63. 9. Wintrobe MM, Lee CR, Boggs DR, et al. Clinical Hematology, 8th Ed. Philadelphia, PA, Lea & Febiger, 1981, pp. 1305-1309. 10. Davies DM, Ed. Textbook of Adverse Drug Reactions 3rd Ed, New York, NY, Oxford University Press, 1987, pp. 578-594, 11. Kelly JP, Kaufman DW, Shapiro S. Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study. Clin Pharmacol Ther 1991; 49:330-341, 12. Salama A, Schutz B. Kiefel V, et al. Immune-mediated agranulocytosis related to drugs and their metabolites: Mode of sensitization and heterogeneity of antibodies. Br J Haematol 1989; 72:127-132.
April 1992, Part I
PACE, Vol. 15
MIWA, L.J.. ET AL.; Propafenone Associated Agranuiocytosis. Propafenone hydrochloride was approved for marketing by the United States (U.S.) Food and Drug Administration (FDA) in November 1989. During V.S. clinical trials of propafenone, one case of agranuiocytosis was seen. Seven addilionai cases have been reported outside the U.S. One German report of profound but reversible granuJocytopenia appeared in 1982. In fanuary 1991, the FDA reviewed adverse events reported with propafenone. Four reports of agranuJocytosis were identified and are described. The reporting rate of approximately one case of agranuiocytosis per 10,000 propafenone prescriptions per year likely underestimates the true incidence of this adverse event. (PACE, Vol. 15, April, Part I 1992} propafenone, agranuiocytosis, case-report, postmarketing surveillance, adverse drug reaction
Introduction
Methods
Propafenone hydrochloride (Rythmol,^ Knoll Pharmaceuticals, Whippany, NJ. USA) is a type Ic antiarrhythmic that was approved for marketing hy the United States (U.S.) Food and Drug Administration (FDA) in November 1989.' During U.S. clinical trials involving 2,127 propafenone treated patients, one case of agranuiocytosis was seen. Seven additional cases of agranuiocytosis associated with propafenone have been reported in over 800,000 patient years of exposure since 1978 outside the U.S.^ One German report of profound but reversible granulocytopenia appeared in 1982.^ We are unaware of any other reports in the medical literature. In January 1991, 1 complete year after the introduction of propafenone to the U.S. market, the FDA reviewed adverse events reported with propafenone to determine whether additional cases of agranuiocytosis had occurred. The details of this review are presented here.
The FDA spontaneous reporting system contains over 560,000 reports of adverse drug associated events submitted by U.S. and foreign health professionals, drug manufacturers, and consumers. A general description of the FDA spontaneous reporting system has been previously published.^ All reports to the spontaneous reporting system are entered into a computerized datahase using GOSTART, a standardized dictionary of adverse drug reactions.^ The COSTART terms used in this search were agranuiocytosis, blood dyscrasia, leukopenia, marrow depression, and myeloid maturation arrest. Data on the number of propafenone prescriptions dispensed during 1990 was obtained from IMS America's National Prescription Audit (NPA).'' The NPA provides information on prescriptions dispensed by chain and independent pharmacies in the contiguous U.S. Other outpatient retail sources, such as mail-order and supermarket pharmacies, are not included. Although the audit is not a true random sample of all pharmacies, the panel of 2,500 computerized pharmacies (from which the national data are extrapolated) is assumed to he representative of pharmacies in the U.S. in terms of geographical region, type of ownership, and size.
Disclaimer; This article was written by Dr. Miwa and Dr. Jolson in their private capacity. No official support or endGrsement by the U,S, Food and Drug Administration is intended or should be inferred. Address for reprints: Linda ], Miwa, Pharm.D., Epidemiology Branch, Division of Epidemiology and Surveillance, U.S. Food and Drug Administration, 5600 P'ishers Lane, HFD-733, Rockville, MD 20857. Fax: (301) 443-9288, Received December 10, 1991; accepted December 19, 1991.
PACE, Vol. 15
The reporting rate for propafenone associated
April 1992, Part I
387
MIWA, ET AL.
agranulocytosis was calculated by dividing the number of cases by the total number of propafenone prescriptions dispensed in 1990.
Results Among 61 reports of adverse events associated with propafenone, four reports of agranulocytosis were identified. Three reports were from the U,S., one was from Canada. Descriptions of the four reports follow. Figure 1 illustrates the time course of each patient's recovery after propafenone dechallenge. Case 1
An 85-year-old man who was treated with propafenone 450 mg/day for 52-64 days was admitted with chills, fever, myalgia, and arthralgia. A white blood cell count was 0.8 cells x 10^/L with a differential of 10% neutrophils, 86% lymphocytes, 1% monocytes, 2% eosinophils, and 1% basophils. Blood cultures obtained on admission were negative, A bone marrow biopsy showed normal cellularity for age, relative normoblastic erythroid hyperplasia, and normal marrow iron stores. The myeloid series showed a virtually pure population of young myelocytes, which was suggestive of an early recovery from a relatively myeloid-specific marrow insult. Megakaryocytes and platelets appeared unaffected. There was no bone marrow evidence of a metastatic tumor or a granuloma. The patient had a history of athero-
sclerotic cardiovascular disease, with congestive heart failure, ventricular arrhythmias, and a bradyarrhythmia that required insertion of a pacemaker. Other medical conditions included mild renal insufficiency and calculi, diverticulitis, osteoarthritis, gout, and glaucoma. Concurrent medications included furosemide, methazolamide, potassium citrate/sodium citrate, and an unidentified nonsteroidal antiinflammatory drug. Propafenone was discontinued; further information on the other medications was not provided. Seven days after discontinuation of propafenone, a white blood cell count was 9.8 cells x 10^/L. The patient recovered and is clinically well on alternative antiarrhythmic therapy. Case 2
A 57-year-old man who was treated with propafenone 900 mg/day for 59 days was admitted with fever and fatigue. A white blood cell count wasl.8cells x lO'^/LwithOneutrophils. Examination of the bone marrow revealed isolated suppression of white blood cell precursors with normal red blood cell and platelet precursors. A complete workup for a viral or a neoplastic etiology for agranulocytosis was negative. The past medical history included an inferior wall myocardial infarction, single vessel coronary artery bypass graft surgery, and paroxysmal atrial flutter. Concurrent medications were digoxin, ranitidine, and dipyridamole, but propafenone was the only recently introduced drug, Propafenone was discontinued; further information on the other drugs was not provided. The patient recovered. A white blood cell count reported 1 month later was 11.1 cells X 10^/L. The patient remains off the drug and is clinically well on alternative antiarrhythmic therapy. Case 3
Days
Figure 1. Changes m white blood cell (WBCJ count in four pafj'enfs wilh propafenone associated agranulocytosis reported to Food and Drug Administration in 1990. Propafenone discontinued on Day 0. Prefreatment WBC available/or cases 3 and 4 onJy.
388
An 83-year-old man who was treated with propafenone 450-750 mg/day for 49 days was admitted for an arrhythmic event. He was incidentally found to have a white blood cell count of 1.5 cells X 10"/L with a differential of 3% neutrophils. Propafenone was discontinued. Five days later the patient remained neutropenic with a white blood cell count of 1.1 cells X 10^/L and 0 neutrophils. Agranulocytosis, possibly associated with medul-
April 1992, Part I
PACE, Vol. 15
PROPAFENONE ASSOCIATED AGRANULOCYTOSIS
lary hypoplasia, was suspected based on the results of a bone marrow biopsy. Past medical history included noninsulin dependent diabetes mellitus, hypertension, and coronary artery disease. Concurrent medications included digoxin, glyburide, nifedipine, ferrous sulfate, aspirin, naproxen, and ketoprofen. Naproxen was discontinued shortly after propafenone was started. Propafenone, aspirin, and ketoprofen were discontinued simultaneously. Eleven days after stopping propafenone the patient began to recover, and he had a white blood cell count of 2.4 cells x lO^/L with 16% neutrophils. The patient made an uneventful recovery and is currently clinically well on sotalol therapy. Case 4 A 51-year-old woman treated with propafenone 450 mg/daily for 30 days was admitted with dysuria, dyspnea, diarrhea, chills, weakness, and fever. A white blood cell count was 0.6 cells x 10^/ L with 0 neutrophils on the differential. A blood culture was positive for a Group B streptococcus. Bone marrow examination showed a normocellular to mildly hypercellular marrow for age, with severe relative myeloid hypoplasia. Megakaryocytes appeared normal in number. There was no evidence of granulomas, obvious fibrosis, or malignancy. The patient's medical history included chronic atrial fibrillation, supraventricular tachycardia, noninsulin dependent diabetes melUtus, sarcoidosis, obesity, deep vein thrombosis, pulmonary embolus, sleep apnea, and severe restrictive lung disease. The patient had a history of adverse events with quinidine and procainamide (diarrhea and rash), and an allergy to sulfa. Concurrent medications were digoxin, verapamil, insulin, coumadin, furosemide, potassium chloride, ibuprofen, and estrogen; propafenone was the only recently introduced drug. Propafenone was discontinued; no information was provided on the other drugs. After discontinuation of propafenone the patient recovered. She remains off the drug and is doing clinically well on alternative antiarrhythmic therapy. Data from the NPA estimates that 45,000 prescriptions were dispensed for propafenone in the U.S. in 1990, thus yielding a reporting rate of pro-
PACE, Vol. 15
pafenone associated agranulocytosis of nearly one report per 10,000 prescriptions per year.
Discussion The FDA has received four reports of agranulocytosis associated with propafenone in its first year of marketing. While a definitive causal association between propafenone and agranulocytosis in these patients cannot be proven, these cases are compelling because of their similarities: (1) all occurred within 2 months of initiating propafenone therapy; [2} the bone marrow presentation was similar in all, showing an isolated insult to myeloid precursors; (3) a positive dechallenge, i.e., the bone marrow recovered after discontinuation of propafenone in all cases; and (4) the time course to recovery was similar, occurring within 2 weeks after discontinuation of propafenone. Other medications reported in these cases, which have been rarely associated with leukopenia or agranulocytosis, include digoxin, furosemide, methazolamide, glyburide, ranitidine. and nonsteroidal antiinflammatory drugs.^-^"^^ Although the possible contribution of these medications cannot be excluded, two reports noted that there had been no recent change in medications other than the addition of propafenone. Agranulocytosis is a rare disease with an estimated incidence from population based studies of 2.5 to 10 cases per million persons per year.^ While a variety of drugs have been associated with agranulocytosis, a causal association has been established for only a few.^"^^ The reporting rate of approximately one case per 10.000 propafenone prescriptions per year likely underestimates the true incidence of propafenone associated agranulocytosis since all adverse events are not reported and a single patient may receive more than one prescription per year. If the reporting rate approximates the true incidence of propafenone associated agranulocytosis, patients taking propafenone have a tenfold to fortyfold greater risk for developing agranulocytosis than the general population. The cases presented here are highly suggestive of an association between propafenone and agranulocytosis. Although not reported in these cases, more definitive evidence of a drug etiology for agranulocytosis (either immune mediated or
April 1992, Part I
389
MIWA, ET AL.
direct toxicity) can be obtained from in vitro tests, such as marrow culture, agglutination, and competitive enzyme linked immunoassay. These techniques are complex, extensive use of positive and negative controls is mandatory, and acute phase sera must be sampled immediately on diagnosis since drug dependent antibodies and drug antibody complexes disappear rapidly after drug dechallenge. The application of these methods is, therefore, probably limited to clinical research institutions.^*"'^ Physicians need to be aware of the association of agranulocytosis with propafenone so they may caution propafenone treated patients to seek medi-
cal attention if they develop a fever or other signs of infection. Since agranulocytosis following propafenone appears to be readily reversible, this medication should be stopped at the first suspicion of white blood cell marrow suppression. Furthermore, the alert clinician can help increase the current understanding of drug induced agranulocytosis by: (1) complete and accurate reporting of cases; and (2) awareness of the availability of in vitro techniques for investigation of a suspected drug etiology for agranulocytosis. Acknotvledgmenf: We thank Lilia Talarico, M.D.. for her review and comments.
References 1. Burke LB, Baum C, Jolson HM, et al. Eleventh Annual Review of Drug Utilization in the United States. Rockville, Maryland, Department of Health and Human Services, 1991, p.10. 2. Physicians' Desk Reference, 45th Ed. Oradell, N], Medical Economics Company, Inc., 1991, pp.1153-1156 3. Harron DWG. Brogden RN. Propafenone—A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias. Drugs 1987; 34:617-647. 4. Faich CA. Adverse drug reaction monitoring, N Engl J Med 1986; 314:1589-1592. 5. U.S. Food and Drug Administration. 'COSTART' Coding Symbols for Thesaurus of Adverse Reaction Terms, 3rd Ed. Rockville, Maryland, Food and Drug Administration, 1989. 6. IMS America. National Prescription Audit, Therapeutic Category Report, Plymouth Meeting, PA, IMS America. Ltd., December 1990, p.4O3.
390
7. Heimpel H. Drug-induced agranulocytosis. Med Toxicol 1988; 3:449-462. 8. Vincent PC, Drug-induced aplastic anemia and agranulocytosis—Incidence and mechanisms. Drugs 1986; 31:52-63. 9. Wintrobe MM, Lee CR, Boggs DR, et al. Clinical Hematology, 8th Ed. Philadelphia, PA, Lea & Febiger, 1981, pp. 1305-1309. 10. Davies DM, Ed. Textbook of Adverse Drug Reactions 3rd Ed, New York, NY, Oxford University Press, 1987, pp. 578-594, 11. Kelly JP, Kaufman DW, Shapiro S. Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study. Clin Pharmacol Ther 1991; 49:330-341, 12. Salama A, Schutz B. Kiefel V, et al. Immune-mediated agranulocytosis related to drugs and their metabolites: Mode of sensitization and heterogeneity of antibodies. Br J Haematol 1989; 72:127-132.
April 1992, Part I
PACE, Vol. 15
