Analysis of the CilostazolSafety Database

Craig M. Pratt, MD

Cilostazol, a type III phosphodiesterase inhibitor, wasapproved in the United States in 1999 for the reductionof the symptoms of intermittent claudication. This articlesummarizes the safety data from 8 cilostazol phase 3controlled clinical trials, involving 2,702 patients: 1,374receiving cilostazol, 973 assigned to placebo, and 355taking pentoxifylline. The trials ranged from 12 to 24weeks in duration. There were a total of 475 patient-exposure years on cilostazol, 357 patient-exposureyears on placebo, and 135 patient-exposure years onpentoxifylline. Headache, diarrhea, and other gastroin-testinal complaints were seen more often in cilostazol-treated than placebo-treated patients; pharyngitis andnausea were more common in pentoxifylline-treatedthan placebo-treated patients. Headache requiring dis-continuation occurred in 1.3% of patients taking cilosta-zol 50 mg bid and 3.7% of those receiving cilostazol 100mg bid, compared with 0.3% of placebo-treated pa-tients. Discontinuations due to diarrhea, palpitations, ormyocardial infarction were similar in cilostazol-, place-bo-, and pentoxifylline-treated patients. The rate of se-rious cardiovascular events was similar in all 3 treat-

ment groups. Myocardial infarction occurred in 1.0% ofcilostazol-treated, 0.8% of placebo-treated, and 1.1% ofpentoxifylline-treated patients. The incidence of strokewas 0.5% in both cilostazol- and placebo-treated pa-tients and 1.1% in pentoxifylline-treated patients. Totalcardiovascular morbidity and all-cause mortality was6.5% for cilostazol 100 mg bid, 6.3% for cilostazol 50mg bid, and 7.7% for placebo. There were 16 deathsoccurring in 0.6%, 0.5%, and 0.6% of cilostazol-, place-bo-, and pentoxifylline-treated patients, respectively.The evaluations showed no trend toward increased car-diovascular morbidity or mortality risk in patients receiv-ing cilostazol. In addition, postmarketing surveillance inthe United States, representing 70,430 patient-years ofcilostazol exposure, has shown minimal accounts ofmyocardial infarction, stroke, or death. The safety pro-file of cilostazol in doses of 50 mg bid and 100 mg bidappears to offer an acceptable risk-benefit ratio in pa-tients with intermittent claudication. Q2001 by Ex-cerpta Medica, Inc.

Am J Cardiol 2001;87(suppl):28D–33D

C ilostazol, a type III phosphodiesterase inhibitor,was approved in 1999 by the US Food and Drug

Administration (FDA) for use in patients with inter-mittent claudication. The potential mechanisms of ac-tion of cilostazol are not fully understood but arethought to involve the inhibition of cyclic adenosinemonophosphate (cAMP) phosphodiesterase. As a re-sult, the level of cAMP in platelets and blood vesselsis increased, leading to inhibition of platelet aggrega-tion and to vasodilation, respectively.1–4 The datavalidating the efficacy of cilostazol in patients withintermittent claudication are presented elsewhere inthis supplement. The purpose of this article is toreview the data supporting the safety of cilostazol inthese patients. The emphasis of this review will be the8 controlled phase 3 clinical trials used to definecilostazol efficacy and safety. These trials were eval-uated by the FDA, which led to the approval ofcilostazol in the United States. A second line of evi-dence presented is the postmarketing surveillance da-tabase, which represents “real-world” use of the agent.The relevance and limitations of the data presentedwill be discussed.

METHODSCilostazol was launched in the Japanese market in

1988 and is currently marketed in 9 other Asian andLatin American countries to treat ischemic symptomsincluding ulcers, pain, and cold sensation in chronicarterial occlusion.5–7 In Argentina, cilostazol is alsobeing used for the secondary prevention of restenosisafter revascularization procedures. In the UnitedStates, cilostazol is indicated for use in patients withintermittent claudication to relieve their symptoms, asindicated by an increase in walking distance.8 World-wide clinical trial information is available on.10,000patients, and postmarketing experience is available on.1.5 million patients in Asian and Latin Americancountries. However, these databases were not the mostobjective to use for safety assessment.

Therefore, this article will focus on the safety datafrom the phase 3 randomized, placebo-controlled clin-ical trials in the United States.9 These trials involved1,374 patients taking cilostazol, 973 patients assignedto placebo, and 355 patients assigned to the only otherFDA-approved comparator drug, pentoxifylline.10 Ofthe 1,374 patients treated with cilostazol, all but 73were treated with the currently marketed doses of 50mg bid (n5 303) and 100 mg bid (n5 998). In thecomparator clinical trial, the pentoxifylline dose wasthe marketed dose of 400 mg tid. Reports of treat-ment-related adverse events were collected in standardfashion for presentation to the FDA. These will bereported as adverse events, serious adverse events, and

From the Department of Internal Medicine, Baylor College of Medi-cine, Houston, Texas, USA.

Address for reprints: Craig M. Pratt, MD, The Methodist Hospital,6565 Fannin, M.S. F1001, Houston, Texas 77030. E-mail:cpratt@bcm.tmc.edu.

28D ©2001 by Excerpta Medica, Inc. 0002-9149/01/$ – see front matterAll rights reserved. PII S0002-9149(01)01719-2

adverse events leading to study drug discontinuation.Cardiovascular morbidity and mortality from the pla-cebo-controlled trials will be separately presented.

RESULTSThere were 8 placebo-controlled trials in the phase

3 cilostazol safety database. The distribution and dis-position of patients in these trials are presented inTable 1. Table 2 summarizes the demographic distri-bution of the patients in the cilostazol safety database.There was a predominance of white men in the studypopulation and a mean age of'65 years. One quarterof the patients had diabetes, more than half had hy-pertension, and approximately 40% of the group weresmokers at the time of randomization. The demo-graphics of cilostazol-treated patients were compara-ble to those of the patients treated with placebo andpentoxifylline.

The clinical trials ranged from 12 to 24 weeks in

duration, and all studies were placebo controlled. Pen-toxifylline was used in the 2 comparator trials becauseit was the only drug approved for the symptomatictreatment of intermittent claudication in the UnitedStates before the introduction of cilostazol. As a re-sult, there were a total of 475 patient-exposure yearson cilostazol, 357 patient-exposure years on placebo,and 135 patient-exposure years on pentoxifylline.

Commonly reported adverse events occurring dur-ing the controlled clinical trials are summarized inTable 3, listed by the standard coding symbols for athesaurus of adverse reaction terms (COSTART).Headaches, diarrhea, abnormal stools, peripheraledema, and palpitations were more frequently noted incilostazol-treated patients than in those treated withplacebo. Pharyngitis and nausea were more commonin pentoxifylline-treated than in placebo-treated pa-tients. In a separate evaluation, the most frequentserious adverse events reported (myocardial infarc-

TABLE 2 Safety Database: Demographics

Parameter

CLZ Total*(n 5 1,374)

Placebo†

(n 5 973)PEN‡

(n 5 355)

n % n % n %

Male sex 1,043 75.9 745 76.6 270 76.1Age $65 yr 762 55.5 547 56.2 208 58.6White race 1,225 89.2 866 89.0 328 92.4Duration of PAD

#5 yr 832 60.6 612 62.9 242 68.2.5 yr 541 39.4 361 37.1 113 31.8

Diabetes 362 26.3 244 25.1 77 21.7Previous hypertension 816 59.4 585 60.1 210 59.2Previous MI 298 21.7 211 21.7 88 24.8Previous transient ischemic attack 84 6.1 76 7.8 30 8.5Previous stroke 51 3.7 45 4.6 18 5.1Previous arrhythmia 162 11.8 107 11.0 46 13.0Previous stable angina 230 16.7 183 18.8 74 20.8Currently smoking 547 39.8 403 41.4 116 32.7

CLZ 5 cilostazol; MI 5 myocardial infarction; PAD 5 peripheral arterial disease; PEN 5 pentoxifylline.*Mean age 5 65 years (range, 40–91); mean weight 5 80 kg (range, 36–178).†Mean age 5 65 years (range, 40–88); mean weight 5 79 kg (range, 41–149).‡Mean age 5 66 years (range, 40–87); mean weight 5 79 kg (range, 44–131).

TABLE 1 Safety Database: Patient Disposition and Distribution*

CategoryCLZ

(50 mg bid)†CLZ

(100 mg bid)†CLZ

(150 mg bid)TotalCLZ Placebo

PEN(400 mg tid)

Randomized 303 998 73 1,374 973 355Completed 250 (82.5%) 775 (77.7%) 48 (65.8%) 1,073 (78.1%) 835 (85.8%) 258 (72.7%)Withdrawn 53 (17.5%) 223 (22.3%) 25 (34.2%) 301 (21.9%) 138 (14.2%) 97 (27.3%)Primary withdrawal reason

Failed screening 0 6 (0.6%) 0 6 (0.4%) 1 (0.1%) 0General inability to continue 2 (0.7%) 11 (1.1%) 0 13 (0.9%) 9 (0.9%) 3 (0.8%)Noncompliance 2 (0.7%) 9 (0.9%) 1 (1.4%) 12 (0.9%) 7 (0.7%) 3 (0.8%)Marked deterioration 1 (0.3%) 4 (0.4%) 0 5 (0.4%) 6 (0.6%) 0Lack of response to study drug 2 (0.7%) 2 (0.2%) 0 4 (0.3%) 4 (0.4%) 0Adverse experience 39 (12.9%) 161 (16.1%) 24 (32.9%) 224 (16.3%) 88 (9.0%) 76 (21.4%)Death 2 (0.7%) 6 (0.6%) 0 8 (0.6%) 4 (0.4%) 2 (0.6%)Other 5 (1.7%) 24 (2.4%) 0 29 (2.1%) 19 (2.0%) 13 (3.7%)

CLZ 5 cilostazol; PEN 5 pentoxifylline.*Data are expressed as sample size (and percentage of sample).†Dosage approved for use in the United States.

MANAGEMENT OF CLAUDICATION 29D

tion, chest pain, or angina) were similar in placebo-treated and cilostazol-treated patients.

The reasons for study withdrawal were relatedprimarily to adverse events that occurred in 9% ofplacebo-treated patients and in 12.9% and 16.1% ofcilostazol-treated patients at doses of 50 mg bid and100 mg bid, respectively. In Table 4, which details theadverse events severe enough to require discontinua-tion, it can be seen that 1.3% of patients taking cilosta-zol 50 mg bid and 3.7% of those receiving 100 mg biddropped out due to headache, compared with 0.3% ofplacebo-treated patients and 0.8% of those receivingpentoxifylline. The numbers of patients who discon-tinued the study drug due to diarrhea, palpitations, ormyocardial infarction were similar in cilostazol-, pla-cebo-, and pentoxifylline-treated patients.

A critical consideration in assessing cilostazolsafety is the evaluation of cardiovascular morbidity

and mortality in controlled clinical trials. To enhancethe accuracy of this evaluation, an additional 4 place-bo-controlled clinical trials conducted outside theUnited States were added to the database for a total of1,441 cilostazol-treated patients, 1,032 placebo-treated patients, and 355 pentoxifylline-treated pa-tients evaluated. The development of serious cardio-vascular events was similar in the cilostazol-, place-bo-, and pentoxifylline-treated patients. For instance,the incidence of myocardial infarction was 1.0% incilostazol-treated, 0.8% in placebo-treated, and 1.1%in pentoxifylline-treated patients. The incidence ofstroke was 0.5% in both cilostazol- and placebo-treated patients and 1.1% in pentoxifylline-treated pa-tients. The distribution of total cardiovascular morbid-ity and all-cause mortality in the phase 3 trials wassimilar in the cilostazol and placebo groups. In 2studies, cardiovascular morbidity and all-cause mor-

TABLE 4 Safety Database: Adverse Events Requiring Discontinuation

Adverse Event

CLZ(50 mg bid,n 5 303)*

CLZ(100 mg bid,n 5 944)*

CLZ(150 mg bid,

n 5 73)CLZ Total

(n 5 1,320)Placebo

(n 5 946)

PEN(400 mg tid,

n 5 355)

n % n % n % n % n % n %

Headache 4 1.3 35 3.7 5 6.8 44 3.3 3 0.3 3 0.8Diarrhea 1 0.3 8 0.8 5 6.8 14 1.1 4 0.4 3 0.8Peripheral vascular disorder 5 1.7 8 0.8 0 0.0 13 1.0 8 0.8 7 2.0Palpitations 3 1.0 9 1.0 2 2.7 14 1.1 1 0.1 1 0.3Myocardial infarction 3 1.0 10 1.1 2 2.7 14 1.1 8 0.7 4 1.1

CLZ 5 cilostazol; PEN 5 pentoxifylline.*Dosage approved for use in the United States.

TABLE 3 Safety Database: Most Commonly Reported Adverse Events*

Adverse Event

CLZ(50 mg bid,n 5 303)†

CLZ(100 mg bid,

n 5 998)†

CLZ(150 mg bid,

n 5 73)CLZ Total

(n 5 1,374)Placebo

(n 5 973)

PEN(400 mg tid,

n 5 355)

n % n % n % n % n % n %

Headache 78 25.7 333 33.4 32 43.8 443 32.2 127 13.1 40 11.3Diarrhea 34 11.2 185 18.5 14 19.2 233 17.0 65 6.7 29 8.2Abnormal stools 37 12.2 146 14.6 10 13.7 193 14.0 40 4.1 19 5.4Pain 53 17.5 113 11.3 10 13.7 176 12.8 137 14.1 48 13.5Infection 35 11.6 88 8.8 4 5.5 127 9.2 72 7.4 26 7.3Dizziness 25 8.3 98 9.8 4 5.5 127 9.2 60 6.2 29 8.2Palpitation 15 5.0 96 9.6 7 9.6 118 8.6 10 1.0 8 2.3Pharyngitis 21 6.9 84 8.4 7 9.6 112 8.2 60 6.2 46 13.0Rhinitis 32 10.6 67 6.7 2 2.7 101 7.4 45 4.6 2 0.6Peripheral edema 23 7.6 66 6.6 8 11.0 97 7.1 37 3.8 14 3.9Nausea 16 5.3 64 6.4 9 12.3 89 6.5 56 5.8 41 11.5Dyspepsia 18 5.9 55 5.5 4 5.5 77 5.6 40 4.1 33 9.3Back pain 15 5.0 60 6.0 2 2.7 77 5.6 52 5.3 10 2.8Chest pain 18 5.9 53 5.3 5 6.8 76 5.5 53 5.4 19 5.4Peripheral vascular disorder 17 5.6 43 4.3 1 1.4 61 4.4 75 7.7 34 9.6Tachycardia 11 3.6 43 4.3 7 9.6 61 4.4 7 0.7 2 0.6Abdominal pain 11 3.6 45 4.5 4 5.5 60 4.4 27 2.8 15 4.2Accidental injury 16 5.3 34 3.4 5 6.8 55 4.0 46 4.7 13 3.7Asthenia 9 3.0 33 3.3 5 6.8 47 3.4 31 3.2 10 2.8Cough increased 9 3.0 37 3.7 1 1.4 47 3.4 27 2.8 10 2.8Flu syndrome 21 6.9 26 2.6 0 0 47 3.4 41 4.2 11 3.1Dyspnea 6 2.0 34 3.4 1 1.4 41 3.0 36 3.7 13 3.7

CLZ 5 cilostazol; PEN 5 pentoxifylline.*Incidence $2% in any treatment group.†Dosage approved for use in the United States.

30D THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 87 (12A) JUNE 28, 2001

tality were specified as secondary endpoints, and theseevents were adjudicated by an independent panel ofexperts. The distribution of adjudicated total cardio-vascular morbidity and mortality was also comparableamong the 3 treatment groups: 20 of 308 (6.5%) forcilostazol 100 mg bid, 19 of 303 (6.3%) for cilostazol50 mg bid, and 23 of 299 (7.7%) for placebo. Therewere 16 cardiovascular deaths, occurring in 0.6%,0.5%, and 0.6% of cilostazol-, placebo-, and pentoxi-fylline-treated patients, respectively. Table 5 summa-rizes the specific causes of death in the patients whodied within 30 days of study drug cessation.

The evaluation of the 12-lead electrocardiographicchanges is presented in Table 6. Although QTc inter-val by Bazett’s formula appeared increased on cilosta-zol treatment, this is a heart-rate effect, as evidencedby calculation of QTc by Fredericia and linear regres-sion, which revealed no change compared with pla-cebo. The most consistent electrocardiographic obser-vation was an increase in heart rate of 5 and 7 beatsper minute on cilostazol 50 mg bid and 100 mg bid,respectively.

Of the 42 placebo-treated and 55 cilostazol-treatedpatients with a previous history of congestive heartfailure, 4.8% and 5.5%, respectively, developed wors-ening congestive heart failure during the phase 3 pro-

gram. New onset of congestive heart failure occurredin very few placebo-assigned or cilostazol-assignedpatients (7 of 973 [0.72%] and 12 of 1,374 [0.87%],respectively). Overall, there was no indication of anyincreased cardiovascular risk due to cilostazol in thephase 3 safety database.

In the evaluation of laboratory measurements, theonly consistent relevant changes were beneficial alter-ations in lipid levels.

Postmarketing safety surveillance: The postmarket-ing patient exposure to cilostazol since it has beenavailable in the United States totals 70,430 patient-years. During that time, there were 461 reported ad-verse events, of which 34 were considered serious and427 nonserious. These events are presented in Table 7,expressed as the incidence of each event per 1,000patient-exposure years of cilostazol exposure. Therehave been minimal reports of heart failure, myocardialinfarction, stroke, or death in this spontaneous report-ing system. About 1.5 million patients have receivedcilostazol worldwide.

DISCUSSIONThe value of analyzing the safety database of a

recently released drug is that the entire controlled-trialexperience is represented, including several individual

TABLE 6 12-Lead Electrocardiogram (ECG) Changes

ECG Parameter

CLZ(50 mg bid,n 5 303)*

CLZ(100 mg bid,n 5 998)*

CLZ(150 mg bid,

n 5 73)CLZ Total

(n 5 1,374)Placebo

(n 5 973)

PEN(400 mg tid,

n 5 355)

PR (msec) 21.10 22.76 25.65 22.51 0.20 22.29QRS (msec) 20.79 20.80 20.85 20.80 22.10 20.12QT (msec) 210.79 214.93 220.77 214.20 20.40 1.83HR (bpm) 5.10 7.43 10.47 7.03 20.07 21.03QTc (msec) by:

Bazett’s 3.05 5.70 8.21 5.20 0.12 0.85Fredericia’s 22.01 21.69 22.22 21.79 20.45 1.68Linear regression 20.50 0.31 0.93 0.14 20.38 1.15

bpm 5 beats per minute; CLZ 5 cilostazol; HR 5 heart rate; PEN 5 pentoxifylline.*Dosage approved for use in the United States.

TABLE 5 Number of Deaths in the Safety Database*

COSTART Term

CLZ(50 mg bid,n 5 303)†

CLZ(100 mg bid,n 5 1,048)†

CLZ(150 mg bid,

n 5 90)CLZ Total

(n 5 1,441)Placebo

(n 5 973)

PEN(400 mg tid,

n 5 355)

CardiovascularAngina pectoris 2 2Myocardial infarct 1 3 4 1Ventricular fibrillation 1 1Heart arrest 1Vascular anomaly 1 1Sudden death 3 1Kidney failure‡ 1

Death (not classified)§ 1 1Other 2 1 3 2

CLZ 5 cilostazol; COSTART 5 coding symbols for a thesaurus of adverse reaction terms; PEN 5 pentoxifylline.*Deaths occurring #30 days after administration of study drug.†Dosage approved for use in the United States.‡Patient died of ventricular fibrillation (status post coronary artery bypass graft) and resultant complications.§Autopsy revealed that death was attributed to myocardial infarction.

MANAGEMENT OF CLAUDICATION 31D

trials that are not published.8 The efficacy of cilostazolin improving walking distance is reviewed elsewherein this supplement. This consistent improvement inwalking distance is very promising, provided that drugsafety is also reassuring.

In reviewing the safety of a drug used to treatintermittent claudication, it is important to considerthat these patients are at high risk for cardiovascularsequelae due to the very nature of their disease. Forexample, patients with peripheral arterial disease,whether or not they have symptomatic intermittentclaudication, have an approximately 2 to 3 timeshigher risk of mortality associated with cardiovasculardiseases than healthy persons.11,12In those with large-vessel peripheral arterial disease, the relative increasein cardiovascular mortality may be as high as 15-fold.13 In addition, the great majority of patients ex-posed to cilostazol in these clinical trials had other riskfactors and comorbidities, including older age ($65years), multiple cardiovascular diseases (atherosclero-sis, previous myocardial infarction, hypertension), di-abetes, and hyperlipidemia. In light of these inherentrisks for morbidity and mortality, the placebo-con-trolled database is remarkably free of cardiovascularevents.

In addition, based on the analyses presented here,the minor adverse events that occur more often oncilostazol than placebo include headache, diarrhea,and other gastrointestinal complaints. The severity hasusually been minor, as judged by the small dropoutrate from the placebo-controlled trials (headache 1%to 3%, diarrhea#1% vs placebo). Cilostazol also hada beneficial effect on the lipid profiles of the studypatients, a finding consistent with the results of Elamet al.13 In this multicenter, randomized, placebo-con-trolled trial involving a group of patients with inter-mittent claudication, cilostazol (100 mg bid) reducedplasma triglycerides by 15%, increased high-densitylipoprotein cholesterol by 10%, and increased apoli-poprotein A1 by 5.7% when compared with placebo.Furthermore, the effect on triglycerides was greater inpatients with elevated baseline levels and lower inthose with normal baseline values.

Because cilostazol is a type III phosphodiesteraseinhibitor, there are merited concerns about cardiovas-cular safety on the basis of increased mortality inprevious trials of compounds sharing similar mecha-nisms of action.14–18 A consistent observationthroughout the cilostazol database is an increase inheart rate (5 and 7 beats per minute on cilostazol 50mg bid and 100 mg bid, respectively). Because of themechanism of action of this compound and the ob-served chronotropic effects, scrutinization of cardio-vascular adverse events is critical.

The phase 3 trials of cilostazol show no trendtoward increased cardiovascular morbidity or mortal-ity risk. Chest pain, angina, myocardial infarction,congestive heart failure, stroke, sudden death, andtotal mortality were numerically similar in cilostazol-and placebo-treated patients. In fact, a recently pub-lished long-term, placebo-controlled, double-blindstudy performed in Japan showed that cilostazol sig-nificantly reduced the risk of recurrent cerebral infarc-tion, with a relative-risk reduction rate of 42%, com-pared with placebo.19 The major limitation in assess-ing the cardiovascular safety of cilostazol is the smallnumber of cardiovascular events in the database, sodefinitive statements on cardiovascular safety are notpossible.

Because of the adverse events documented withother phosphodiesterase inhibitors in patients withclass III–IV congestive heart failure, FDA labelingcontraindicates the use of cilostazol in patients withcongestive heart failure of any severity.8 It is impor-tant to emphasize that this restriction is not based onevidence of cilostazol toxicity but is driven by theo-retical concerns related to its therapeutic class. Theclinical experience with cilostazol in the heart-failurepopulation is sparse, with only 55 of 1,374 cilostazol-treated patients designated as having a history of heartfailure. In the phase 3 controlled trials, 12 (0.87%)cilostazol-assigned patients developed evidence ofnew congestive heart failure compared with 7 (0.72%)placebo-assigned patients. The cardiovascular mortal-ity in the phase 3 database was very small (16 deaths),occurring in 0.6% of cilostazol-, 0.5% of placebo-,and 0.6% of pentoxifylline-treated patients. All-causemortality was not significantly different for cilostazol(0.8%) and placebo (0.7%). Although there are wideconfidence limits to this point estimate of mortality(95% confidence interval, 0.5–3.1), it can be con-cluded that there is no cause for concern based on theavailable data.

CONCLUSIONCilostazol consistently improves both the maximal

and pain-free walking distance of patients with inter-mittent claudication. Noncardiac side effects are usu-ally mild, consisting primarily of headache and diar-rhea. In doses of 50 mg bid and 100 mg bid, the safetyprofile of cilostazol has been reviewed and appears tooffer an acceptable risk-benefit ratio in patients withintermittent claudication.

TABLE 7 Cilostazol Spontaneous Cardiovascular AdverseEvents in the United States*

Adverse EventEvents

Reported (n)Incidence/1,000 PEY

Hypertension 11 0.156Hypotension (mild) 3 0.043Atrial fibrillation 1 0.014Atrial flutter 1 0.014Palpitation 23 0.327Tachycardia 24 0.327Angina pectoris 1 0.014Myocardial infarction 1 0.014Transient ischemic attack 0 0Stroke 0 0Death 1 0.014

*Postmarketing surveillance data in the United States, covers reports be-tween May 10, 1999, and January 15, 2001.

PEY 5 patient-exposure years.

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