Postmarketing Surveillance Study of Permethrin Creme Rinse
s's.e.s-.5........
Elizabeth B. Andrews, PhD, Michael C. Joseph, MD, MPH, Mark J. Magenheun, MD, MPH, Hugh H. Tilson, MD, DrPH, Peggy A. Doi, and Margaret W. Schultz, MPH
,fs
Introducion
10 *:"*
e
~
-
.....
Infestation with head lice continues to be a public health concern in the United States, particularly among schoolchildren. Surveys indicate that approximately 2.6 million households (or 2.8 million individuals) experience an outbreak of head lice each year, and studies by the Centers for Disease Control between 1973 and 1974 found an overall prevalence of head lice of approximately 8% in schoolchildren (grades K to 8).1-3 Permethrin 1% creme rinse, hereafter referred to as permethrin, contains the synthetic pyrethrin permethrin (a pyrethroid). It has been available by prescription for head lice treatments since June 1986. Before its marketing, the only available pediculicides were prescription compounds containing lindane (Kwell and generic products) and over-the-counter (OTC) products, most of which contain pyrethrins (A-200@, RID®, and others). Since completion of this study, permethrin has become available OTC. In clinical studies of over 3500 patients, the only expected adverse drug experience associated with permethrin was local irritative symptoms, which ranged in frequency from 2.1% to 5.9%. Many of these symptoms were thought to be the result of the lice infestation.4-6 This postmarketing safety study provided the principal new data on which the conversion of permethrin from prescription to OTC status was based.7 It used recognized epidemiological methods both to assess the short-term safety of permethrin for general use in the treatment of head lice and to identify, document, and assess rare but medically important events
following treatment. It was not intended to compare effectiveness of the different pediculicides.
Methods In this observational, epidemiological safety study, public health departments dispensed permethrin or another pediculicide, counseled about treatment in the customary methods, and followed each patient between 7 and 14 days after treatment via return visit or telephone call to identify any subsequent adverse clinical events. Health departments developed treatment allocation schemes to ensure that each diagnosed individual had essentially the same chance of being treated with permethrin or another pediculicide. This quasi-randomization system included such measures as assigning treatment according to day of the week patient was diagnosed with head lice infestation (there being no a priori reason to believe that patient mix varied by day of week), and alternating treatment choice by patient or family group. Analyses of baseline characteristics, by site, were conducted to evaluate the adequacy of the allocation
schemes. Tlhe authors are with the Burroughs Weilcome Company at Research Triangle Park in North Carolina and the Sarasota County Health Department in Florida. Requests for reprints should be sent to Elizabeth B. Andrews, PhD, Burroughs Wellcome Company, 3030 Comwallis Road, Research Triangle Park, NC 27709. This paper was submitted to the Journal May 11, 1990, and accepted with revisions July 10, 1991.
American Journal of Public Health 857
Andrews t al.
Health departments enrolled infested school-aged children and their family members ages 2 years or above with head lice infestation. Pregnant women and persons with a history of allergic reactions to pyrethrins were excluded. The existing staff of 37 public health departments in 12 states were collaborative study investigators (see acknowledgement). During the treatment period (September 1, 1986, to January 31, 1988), 38 160 patients were enrolled for 47 578 treatments. Four sites in Michigan enrolled 13% of all patients, 10 other sites in 10 states enrolled 27%, and 23 sites in Florida enrolled the remaining 60%. The median enrollment for individual sites was approximately 650 patients (ranging from 65 to 3293). In July 1986, the State of Florida Institutional Review Board (IRB) of the Department of Health and Rehabilitative Services and an independent, federally qualified IRB of the fourth-largest hospital in Florida (an 862-bed public facility with substantial research activities) reviewed and approved the full research protocol, including methods and detailed provisions for the protection of human subjects, for all participating Florida study sites. All participating health departments were provided permethrin free of charge and were reimbursed for study expenses, including the cost of obtaining other pediculicides, according to negotiated budgets. Further details of the process of designing and implementing a network of collaborating public health clinic sites will be described in another paper.
Treatment and Assessment Plan At enrollment, patient initials, birth date, sex, ethnic group, history of allergic problems, name of the pediculicide dispensed, and previous enrollment in the study were recorded. Follow-up information was solicited using a common protocol. If patients did not return to the health department, a telephone callback system was used to gather the information. When an adverse event was reported, symptoms, concurrent medications and illnesses, and course of required treatment, if any, were solicited. An adverse event was classified as "medically important" if medical consultation was actually sought or if the event was likely to require clinical monitoring, whether or not any medical consultation was obtained. Events of unspecified or ambiguous severity were classified as medically important. 858 Amencan Journal of Public Health
Information
was
obtained
on treat-
ments for 38 180
patients. Only those treatments for which follow-up was com-
plete (41 955 treatments of 34 275 patients) were used in the analysis. The proportion of patients available for follow-up did not vary by treatment type, and their
baseline characteristics did not differ from those of patients lacking follow-up. Classified by pediculicide exposure, 18 950 (55.3%) patients received permethrin, 10 155 (29.6%) received lindane products, and 5170 (15.1%) received one of the 28 different OTC products. OTC products included RID (3171 patients), Pyrinyl* (699 patients), and an assortment of similar pediculicides. Lindane and OTC groups were analyzed separately because of differences in their potency and safety
profiles.
Sample Size and Power The sample size was sufficient to detect a threefold increase in the incidence of an adverse event that had an expected frequency of 1 in 1000, with a 95% significance level when comparing the group
treated with permethrin with the group treated with lindane, and 80% power and a 95% significance level when comparing the permethrin group with the group treated with OTC products. Calculations were based on the binomial distnbution.
Resus Participant Characten7stics The distribution of patients by age, sex, ethnic group, and allergy history was similar among the three treatment groups (Table 1). No significant differences were seen across sites (data available upon request). The age distribution of the study participants was bimodal: 57% were between 2 and 15 years of age and 25% were between 21 and 55 years of age. Eight percent of the participants reported a history of allergies or allergic conditions.
Anaysis UsingAl Treatment Data were first analyzed using all treatments for which follow-up information was obtained (n = 41 955). Because the retreatment experience might be dependent on the outcome of the first study treatment, an analysis of data restricted to the first study treatment was also completed (n = 34 275). Of the 41 955 evaluable treatments, there were 103 reported adverse events (2.5 per 1000), 2.2 per 1000 (95% CI: 1.6, 2.9 per 1000) after permethrin treatment,
3.4 per 1000 (95% CI: 2.5, 4.6 per 1000) after lindane treatment, and 1.5 per 1000 (95% CI: 0.7, 2.7 per 1000) after OTC treatment. The risk difference when comparing permethrin with lindane was -1.2 per 1000 (i.e., 1.2 fewer problems per 1000 permethrin treatments; 95% CI: -2.4, -0.05). The risk difference when comparing permethrin with OTC treatments was 0.7 problems per 1000 treatments (i.e., 0.7 more problems per 1000 permethrin treatments; 95% CI: -0.4, 1.8 per 1000). Consistent with results firom cIcal trials in the United States, all three treatment groups reported pnrritus and rash more frequently than they reported other adverse events. Eight events were considered medically important. When the statistical analysis was restricted to those events, or to events for which medical attention was sought, there were no sificant differences between the permethrin group and either of the comparison groups. In the permethrin group, five adverse events, summarized below, were medically important. Two of the patients were not treated with permethrin themselves but came into contact with a treated family member.
Case Pl: A 16-year-old girl with no previous history of allergy experienced breathing difficulty while her sister was being treated with permethrin. The episode subsided after the girl left the treatment room. Case P2: A 34-year-old woman
with a history of drug allergies experienced mild nausea and moderate to severe shortness of breath that lasted about 4 hours. The patient had been taking Inderal® (propranolol) (12 mg daily). Case P3: A 10-year-old girl with a history of asthma and food allergies experienced arm shaking and stuttering that lasted less than a minute and did not recur. The patient did not require a medical visit. She had used the pediculicide A-200 on two occasions, 10 days and 6 days before treatment with permethrin. Case P4: A 35-year-old woman (mother of P3) with a history of food
allergies experienced two incidents
of arm shaking for about 40 seconds and some skin irritation. The patient did not have a medical visit for these events. The Health Department physician stated that the arm shaking was probably due to the patient's steady use of her arms in applying 10-minute massages to three individuals on the same day.
June 1992, Vol. 82, No. 6
Postmarkeig Surveillance Study of Pennethrin Creme Rinse
Case PS: A 23-year-old woman with no previous allergy history experienced a swollen face beginning I day after treatment and lasting 1 week. She required medical treatment. The patient reported that the adverse event could have been caused by a new facial soap and that she did not attnbute it to the permethrin treatment.
Among patients treated with lindane, three adverse events were judged medically important.
Case Ll: A 31-year-old woman with no previous history of allergies experienced "extreme" blurred vision that lasted 7 days and did not recur. The event required a medical visit.
Case L2 A 39-year-old man with an extensive history of allergies and asthma experienced moderate respiratory irritation that lasted 18 hours. No medical visit was required. Case L3: A 28-year-old woman with a history of asdtma, hay fever, and other allergies experienced moderate dffxclty in breathing for 24 hours following treatment. An OTC bronchodflator was used to treat the episode, and no medical visit was required. June 1992, Vol. 82, No. 6
Among patients treated with OTC pediculicides, there were not medically important adverse events.
Analysis Using First Treatment per Patient
Among the 34 275 first study treatments, there were 87 reported adverse events, 2.4 per 1000 (95% CI: 1.8, 3.2 per 1000 patients) after permethrin treatment, 3.5 per 1000 (95% CI: 2.5, 4.9 per 1000 patients) after lindane treatment, and 1.0 per 1000 (95% CI: 0.3, 2.3 per 1000 patients) after OTC treatment. The risk difference when comparing permethrin with lindane was -1.1 per 1000 (i.e., 1.1 fewer problems per 1000 patients treated with permethrin; 95% CI: -2.5, 0.2 per 1000). The risk difference when comparing permethrin with OTC patients was 1.5 events per 1000 patients (i.e., 1.5 more problems per 1000 patients treated with permethrin; 95% CI: 0.4, 2.6 per 1000). When the analyses were restricted to adverse events that appeared to be medically important orforwhich medical consultation was sought, there were no statistically significant differences between the permethrin group and either the lindane or the OTC group. Stratified analyseswere performed to determine if the different reporting rates
for adverse events were caused by small differences between treatment groups in age, sex, ethnicity, or allergy status. The prior findings were not altered substantially when these factors were controlled (data available upon request). Analyses were also performed across all exposure groups to assess the relationship between patient characteristics and the reporting of adverse events following treatment. When all pediculicidal exposure was combined (Table 2), patients with a history of allergy were more than four times as likely (8.4 per 1000) to report an adverse event after treatment than were patients without a prior allergy history (2.0 per 1000). The risk difference was 6.4 per 1000 (95% CI: 2.9,9.8 per 1000). In addition, females were 2.4 times as likely (3.4 per 1000) to report an adverse event than males (1.4 per 1000). The risk difference was small (2.0 per 1000 patients; 95% CI: 0.98, 3.00 per 1000).
Diwussion The overall rate of adverse events re-
ported after treatment in this study was
very low-between 1.0 and 3.5 events per 1000 patients. This rate of events was approximately one tenth that seen in more American Joumal of Public Health 859
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closely monitored experimental trials in the United States. Because this postmarketing epidemiological study sought primarily to discover rare, serious, and unexpected adverse events, data collection was not designed to assess or confirm frequent and less serious events. Therefore, the low reporting rate of common, expected events observed in this study was predictable. Although adverse events might have been underreported, there was no incentive for participants to report preferentially or underreport problems by treatment group. However, it is acknowledged that such bias could not have been strictly controlled in this unblinded, nonrandomized trial. The perceived risk of treatment with each product by patients, parents of patients, and medical staff, or the perception that this was a "permethrin study," could have introduced bias in reporting problems. When the rate of overall reported problems among the permethrin treatments was compared with the rates among the lindane and OTC groups, there was a consistent pattern. The permethrin patients reported a rate of adverse events lower than that of the lindane patients and higher than that of the OTC patients. Observed differences, however, were small. Because the sample size was so large, even small and perhaps unimportant differences would be statistically significant. Moreover, risk differences observed in this study were small, on the order of one per thousand patients or treatments. 860 American Journal of Public Health
There were no significant differences between permethrin and either the lindane or the OTC comparison group when the analysis was restricted to those problems that were medicaly important. The most important adverse event was difficulty in breathing, which was reported in 4 patients (2 of 18 950 permethrin patients and 2 of 10 155 lindane patients), 3 of whom had a previous history of allergies. No serious or unexpected adverse event was detected in association with permethrin despite a sample size adequate to detect such an event at a rate of 1 per 10 000 treatments with 85% probability. Although considerations for patient safety and methodology were paramount in the study design and analysis, attention to feasibility and to patient and provider acceptability were also important practical objectives. Careful attention not to interfere unduly with normal patient care activities imposed several limitations on study design (and on data quality to a minimal degree). Strict randomization of pediculicide treatments was not feasible, and the choice of allocation schemes varied among and within participating local public health agencies. However, once determined, individual allocation schemes were reported to have been followed, and there was no evidence of systematic bias in overall treatment allocation, given that summary analyses indicated comparable allocations among all treatment options. Additional analyses comparing patient characteristics and results by site also showed no differences.
fif}S:
Although complete follow-up was not attainable for 10% of enrolled patients, there is no a priori reason to believe that the patients lackdng follow-up information experienced different outcomes from those experienced by patients who provided such information. Analyses of baseline characteristics showed that the two groups were not different. Furthermore, because the local health department is often an important source of medical care in the community, it is likely that significant problems among patients without explicit follow-up information would have come to the attention of the responsible health department. This public-private collaborative study approach demonstrates the ability to gather relatively basic, yet clinically important safety information on an extremely large and diverse study population through a public health field research stratagem without unduly compromising safety or data quality. E]
Acknowledgments This study was funded by research grants from the Burroughs Wellcome Company. The authors wish to thank the participating health departments as well as Kathy Schoeffler, Linda Wastila, and Anita Blanchard for their assistance in data management and quality assurance. The participating health departments: La Paz County, Arizona; Dougherty County, California; San Bernardino County, California; these Florida counties: Alachua, Collier, Gadsden, Hardee, Highlands, Hilisborough, Jackson, Lake, Lee, Pasco, Pinellas, Polk, Sarasota, Sumter, Putnam, Calhoun, DeSoto, Escambia, Brevard, Nassua, St. Johns, Okaloosa, Holmes; Winnebago County, Illinois; Marion County, Indiana; Branch-Hillsdale-St. Joseph District, Michigan; Midland, Michigan; Muskegon County, Michigan; Ottawa County, Michigan; CUHCC, Minnesota; Moore County, North Carolina; Nashua, New Hampshire; Warren City, Ohio; BremertonKitsap County, Washington.
References 1. Slonka GF, McKinley TW, McCroan JE, et al. Epidemiology of an outbreak of head lice in Georgia.AmJTropMedHyg. 1976;25(5): 739-743. 2. Juranek DD. Epidemiologic investigations of pediculosis capitis in school children. In: Orkin M, ed. Scabies and Pediculosis. Philadelphia, Pa, and Toronto, Canada: JR Lip-
pincott Co; 1977:168-173. 3. Slonka GF, Fleissner ML, Berlin J, Puleo J, Harrod EK, Schultz MG. An epidemic of pediculosis capitis. J ParasitoL 1977;63(2):
377-383.
4. Taplin D, Meinking TL, Castillero PM, Sanchez R. Permethrin 1% creme rinse for the treatment of Pediculus hwmanus var. capitis infestation. Pediatr Dermatol.
1986;3(4):344-348.
5. Brandenburg K, Deinard AS, DiNapoli J, Englender SJ, Orthoefer J, Wagner D. One
June 1992, Vol. 82, No. 6
P
percent pennethrin creme rinse vs 1% lindane shampoo in treating pediculosis capitis. Am J Dis Ch/dd 1986;140:894-896. 6. Bowerman JG, Gomez MP, Austin RD,
Wold DE. Comparative study of permethrin 1% creme rinse and lindane shampoo for the treatment of head lice. Pediatr Infect Dis J. 1987;6:252-255.
CaliforPpenfor~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~y m n ~~~~~~~~~~~~~~~~~~m na43~~~~~~~~~~~~~~* posiw A
Peuvkum Cowdituents~~~~~~~~UIT311
Surveillance Study of Pernetrin Creme Rinse 7. Strom BL. Position paper on the use of purported post-marketing drug surveillance studies for promotional purposes. Phamnacol Ther. 1990;48(5):598.
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American Journal of Public Health.....861........
--------
........
s's.e.s-.5........
Elizabeth B. Andrews, PhD, Michael C. Joseph, MD, MPH, Mark J. Magenheun, MD, MPH, Hugh H. Tilson, MD, DrPH, Peggy A. Doi, and Margaret W. Schultz, MPH
,fs
Introducion
10 *:"*
e
~
-
.....
Infestation with head lice continues to be a public health concern in the United States, particularly among schoolchildren. Surveys indicate that approximately 2.6 million households (or 2.8 million individuals) experience an outbreak of head lice each year, and studies by the Centers for Disease Control between 1973 and 1974 found an overall prevalence of head lice of approximately 8% in schoolchildren (grades K to 8).1-3 Permethrin 1% creme rinse, hereafter referred to as permethrin, contains the synthetic pyrethrin permethrin (a pyrethroid). It has been available by prescription for head lice treatments since June 1986. Before its marketing, the only available pediculicides were prescription compounds containing lindane (Kwell and generic products) and over-the-counter (OTC) products, most of which contain pyrethrins (A-200@, RID®, and others). Since completion of this study, permethrin has become available OTC. In clinical studies of over 3500 patients, the only expected adverse drug experience associated with permethrin was local irritative symptoms, which ranged in frequency from 2.1% to 5.9%. Many of these symptoms were thought to be the result of the lice infestation.4-6 This postmarketing safety study provided the principal new data on which the conversion of permethrin from prescription to OTC status was based.7 It used recognized epidemiological methods both to assess the short-term safety of permethrin for general use in the treatment of head lice and to identify, document, and assess rare but medically important events
following treatment. It was not intended to compare effectiveness of the different pediculicides.
Methods In this observational, epidemiological safety study, public health departments dispensed permethrin or another pediculicide, counseled about treatment in the customary methods, and followed each patient between 7 and 14 days after treatment via return visit or telephone call to identify any subsequent adverse clinical events. Health departments developed treatment allocation schemes to ensure that each diagnosed individual had essentially the same chance of being treated with permethrin or another pediculicide. This quasi-randomization system included such measures as assigning treatment according to day of the week patient was diagnosed with head lice infestation (there being no a priori reason to believe that patient mix varied by day of week), and alternating treatment choice by patient or family group. Analyses of baseline characteristics, by site, were conducted to evaluate the adequacy of the allocation
schemes. Tlhe authors are with the Burroughs Weilcome Company at Research Triangle Park in North Carolina and the Sarasota County Health Department in Florida. Requests for reprints should be sent to Elizabeth B. Andrews, PhD, Burroughs Wellcome Company, 3030 Comwallis Road, Research Triangle Park, NC 27709. This paper was submitted to the Journal May 11, 1990, and accepted with revisions July 10, 1991.
American Journal of Public Health 857
Andrews t al.
Health departments enrolled infested school-aged children and their family members ages 2 years or above with head lice infestation. Pregnant women and persons with a history of allergic reactions to pyrethrins were excluded. The existing staff of 37 public health departments in 12 states were collaborative study investigators (see acknowledgement). During the treatment period (September 1, 1986, to January 31, 1988), 38 160 patients were enrolled for 47 578 treatments. Four sites in Michigan enrolled 13% of all patients, 10 other sites in 10 states enrolled 27%, and 23 sites in Florida enrolled the remaining 60%. The median enrollment for individual sites was approximately 650 patients (ranging from 65 to 3293). In July 1986, the State of Florida Institutional Review Board (IRB) of the Department of Health and Rehabilitative Services and an independent, federally qualified IRB of the fourth-largest hospital in Florida (an 862-bed public facility with substantial research activities) reviewed and approved the full research protocol, including methods and detailed provisions for the protection of human subjects, for all participating Florida study sites. All participating health departments were provided permethrin free of charge and were reimbursed for study expenses, including the cost of obtaining other pediculicides, according to negotiated budgets. Further details of the process of designing and implementing a network of collaborating public health clinic sites will be described in another paper.
Treatment and Assessment Plan At enrollment, patient initials, birth date, sex, ethnic group, history of allergic problems, name of the pediculicide dispensed, and previous enrollment in the study were recorded. Follow-up information was solicited using a common protocol. If patients did not return to the health department, a telephone callback system was used to gather the information. When an adverse event was reported, symptoms, concurrent medications and illnesses, and course of required treatment, if any, were solicited. An adverse event was classified as "medically important" if medical consultation was actually sought or if the event was likely to require clinical monitoring, whether or not any medical consultation was obtained. Events of unspecified or ambiguous severity were classified as medically important. 858 Amencan Journal of Public Health
Information
was
obtained
on treat-
ments for 38 180
patients. Only those treatments for which follow-up was com-
plete (41 955 treatments of 34 275 patients) were used in the analysis. The proportion of patients available for follow-up did not vary by treatment type, and their
baseline characteristics did not differ from those of patients lacking follow-up. Classified by pediculicide exposure, 18 950 (55.3%) patients received permethrin, 10 155 (29.6%) received lindane products, and 5170 (15.1%) received one of the 28 different OTC products. OTC products included RID (3171 patients), Pyrinyl* (699 patients), and an assortment of similar pediculicides. Lindane and OTC groups were analyzed separately because of differences in their potency and safety
profiles.
Sample Size and Power The sample size was sufficient to detect a threefold increase in the incidence of an adverse event that had an expected frequency of 1 in 1000, with a 95% significance level when comparing the group
treated with permethrin with the group treated with lindane, and 80% power and a 95% significance level when comparing the permethrin group with the group treated with OTC products. Calculations were based on the binomial distnbution.
Resus Participant Characten7stics The distribution of patients by age, sex, ethnic group, and allergy history was similar among the three treatment groups (Table 1). No significant differences were seen across sites (data available upon request). The age distribution of the study participants was bimodal: 57% were between 2 and 15 years of age and 25% were between 21 and 55 years of age. Eight percent of the participants reported a history of allergies or allergic conditions.
Anaysis UsingAl Treatment Data were first analyzed using all treatments for which follow-up information was obtained (n = 41 955). Because the retreatment experience might be dependent on the outcome of the first study treatment, an analysis of data restricted to the first study treatment was also completed (n = 34 275). Of the 41 955 evaluable treatments, there were 103 reported adverse events (2.5 per 1000), 2.2 per 1000 (95% CI: 1.6, 2.9 per 1000) after permethrin treatment,
3.4 per 1000 (95% CI: 2.5, 4.6 per 1000) after lindane treatment, and 1.5 per 1000 (95% CI: 0.7, 2.7 per 1000) after OTC treatment. The risk difference when comparing permethrin with lindane was -1.2 per 1000 (i.e., 1.2 fewer problems per 1000 permethrin treatments; 95% CI: -2.4, -0.05). The risk difference when comparing permethrin with OTC treatments was 0.7 problems per 1000 treatments (i.e., 0.7 more problems per 1000 permethrin treatments; 95% CI: -0.4, 1.8 per 1000). Consistent with results firom cIcal trials in the United States, all three treatment groups reported pnrritus and rash more frequently than they reported other adverse events. Eight events were considered medically important. When the statistical analysis was restricted to those events, or to events for which medical attention was sought, there were no sificant differences between the permethrin group and either of the comparison groups. In the permethrin group, five adverse events, summarized below, were medically important. Two of the patients were not treated with permethrin themselves but came into contact with a treated family member.
Case Pl: A 16-year-old girl with no previous history of allergy experienced breathing difficulty while her sister was being treated with permethrin. The episode subsided after the girl left the treatment room. Case P2: A 34-year-old woman
with a history of drug allergies experienced mild nausea and moderate to severe shortness of breath that lasted about 4 hours. The patient had been taking Inderal® (propranolol) (12 mg daily). Case P3: A 10-year-old girl with a history of asthma and food allergies experienced arm shaking and stuttering that lasted less than a minute and did not recur. The patient did not require a medical visit. She had used the pediculicide A-200 on two occasions, 10 days and 6 days before treatment with permethrin. Case P4: A 35-year-old woman (mother of P3) with a history of food
allergies experienced two incidents
of arm shaking for about 40 seconds and some skin irritation. The patient did not have a medical visit for these events. The Health Department physician stated that the arm shaking was probably due to the patient's steady use of her arms in applying 10-minute massages to three individuals on the same day.
June 1992, Vol. 82, No. 6
Postmarkeig Surveillance Study of Pennethrin Creme Rinse
Case PS: A 23-year-old woman with no previous allergy history experienced a swollen face beginning I day after treatment and lasting 1 week. She required medical treatment. The patient reported that the adverse event could have been caused by a new facial soap and that she did not attnbute it to the permethrin treatment.
Among patients treated with lindane, three adverse events were judged medically important.
Case Ll: A 31-year-old woman with no previous history of allergies experienced "extreme" blurred vision that lasted 7 days and did not recur. The event required a medical visit.
Case L2 A 39-year-old man with an extensive history of allergies and asthma experienced moderate respiratory irritation that lasted 18 hours. No medical visit was required. Case L3: A 28-year-old woman with a history of asdtma, hay fever, and other allergies experienced moderate dffxclty in breathing for 24 hours following treatment. An OTC bronchodflator was used to treat the episode, and no medical visit was required. June 1992, Vol. 82, No. 6
Among patients treated with OTC pediculicides, there were not medically important adverse events.
Analysis Using First Treatment per Patient
Among the 34 275 first study treatments, there were 87 reported adverse events, 2.4 per 1000 (95% CI: 1.8, 3.2 per 1000 patients) after permethrin treatment, 3.5 per 1000 (95% CI: 2.5, 4.9 per 1000 patients) after lindane treatment, and 1.0 per 1000 (95% CI: 0.3, 2.3 per 1000 patients) after OTC treatment. The risk difference when comparing permethrin with lindane was -1.1 per 1000 (i.e., 1.1 fewer problems per 1000 patients treated with permethrin; 95% CI: -2.5, 0.2 per 1000). The risk difference when comparing permethrin with OTC patients was 1.5 events per 1000 patients (i.e., 1.5 more problems per 1000 patients treated with permethrin; 95% CI: 0.4, 2.6 per 1000). When the analyses were restricted to adverse events that appeared to be medically important orforwhich medical consultation was sought, there were no statistically significant differences between the permethrin group and either the lindane or the OTC group. Stratified analyseswere performed to determine if the different reporting rates
for adverse events were caused by small differences between treatment groups in age, sex, ethnicity, or allergy status. The prior findings were not altered substantially when these factors were controlled (data available upon request). Analyses were also performed across all exposure groups to assess the relationship between patient characteristics and the reporting of adverse events following treatment. When all pediculicidal exposure was combined (Table 2), patients with a history of allergy were more than four times as likely (8.4 per 1000) to report an adverse event after treatment than were patients without a prior allergy history (2.0 per 1000). The risk difference was 6.4 per 1000 (95% CI: 2.9,9.8 per 1000). In addition, females were 2.4 times as likely (3.4 per 1000) to report an adverse event than males (1.4 per 1000). The risk difference was small (2.0 per 1000 patients; 95% CI: 0.98, 3.00 per 1000).
Diwussion The overall rate of adverse events re-
ported after treatment in this study was
very low-between 1.0 and 3.5 events per 1000 patients. This rate of events was approximately one tenth that seen in more American Joumal of Public Health 859
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closely monitored experimental trials in the United States. Because this postmarketing epidemiological study sought primarily to discover rare, serious, and unexpected adverse events, data collection was not designed to assess or confirm frequent and less serious events. Therefore, the low reporting rate of common, expected events observed in this study was predictable. Although adverse events might have been underreported, there was no incentive for participants to report preferentially or underreport problems by treatment group. However, it is acknowledged that such bias could not have been strictly controlled in this unblinded, nonrandomized trial. The perceived risk of treatment with each product by patients, parents of patients, and medical staff, or the perception that this was a "permethrin study," could have introduced bias in reporting problems. When the rate of overall reported problems among the permethrin treatments was compared with the rates among the lindane and OTC groups, there was a consistent pattern. The permethrin patients reported a rate of adverse events lower than that of the lindane patients and higher than that of the OTC patients. Observed differences, however, were small. Because the sample size was so large, even small and perhaps unimportant differences would be statistically significant. Moreover, risk differences observed in this study were small, on the order of one per thousand patients or treatments. 860 American Journal of Public Health
There were no significant differences between permethrin and either the lindane or the OTC comparison group when the analysis was restricted to those problems that were medicaly important. The most important adverse event was difficulty in breathing, which was reported in 4 patients (2 of 18 950 permethrin patients and 2 of 10 155 lindane patients), 3 of whom had a previous history of allergies. No serious or unexpected adverse event was detected in association with permethrin despite a sample size adequate to detect such an event at a rate of 1 per 10 000 treatments with 85% probability. Although considerations for patient safety and methodology were paramount in the study design and analysis, attention to feasibility and to patient and provider acceptability were also important practical objectives. Careful attention not to interfere unduly with normal patient care activities imposed several limitations on study design (and on data quality to a minimal degree). Strict randomization of pediculicide treatments was not feasible, and the choice of allocation schemes varied among and within participating local public health agencies. However, once determined, individual allocation schemes were reported to have been followed, and there was no evidence of systematic bias in overall treatment allocation, given that summary analyses indicated comparable allocations among all treatment options. Additional analyses comparing patient characteristics and results by site also showed no differences.
fif}S:
Although complete follow-up was not attainable for 10% of enrolled patients, there is no a priori reason to believe that the patients lackdng follow-up information experienced different outcomes from those experienced by patients who provided such information. Analyses of baseline characteristics showed that the two groups were not different. Furthermore, because the local health department is often an important source of medical care in the community, it is likely that significant problems among patients without explicit follow-up information would have come to the attention of the responsible health department. This public-private collaborative study approach demonstrates the ability to gather relatively basic, yet clinically important safety information on an extremely large and diverse study population through a public health field research stratagem without unduly compromising safety or data quality. E]
Acknowledgments This study was funded by research grants from the Burroughs Wellcome Company. The authors wish to thank the participating health departments as well as Kathy Schoeffler, Linda Wastila, and Anita Blanchard for their assistance in data management and quality assurance. The participating health departments: La Paz County, Arizona; Dougherty County, California; San Bernardino County, California; these Florida counties: Alachua, Collier, Gadsden, Hardee, Highlands, Hilisborough, Jackson, Lake, Lee, Pasco, Pinellas, Polk, Sarasota, Sumter, Putnam, Calhoun, DeSoto, Escambia, Brevard, Nassua, St. Johns, Okaloosa, Holmes; Winnebago County, Illinois; Marion County, Indiana; Branch-Hillsdale-St. Joseph District, Michigan; Midland, Michigan; Muskegon County, Michigan; Ottawa County, Michigan; CUHCC, Minnesota; Moore County, North Carolina; Nashua, New Hampshire; Warren City, Ohio; BremertonKitsap County, Washington.
References 1. Slonka GF, McKinley TW, McCroan JE, et al. Epidemiology of an outbreak of head lice in Georgia.AmJTropMedHyg. 1976;25(5): 739-743. 2. Juranek DD. Epidemiologic investigations of pediculosis capitis in school children. In: Orkin M, ed. Scabies and Pediculosis. Philadelphia, Pa, and Toronto, Canada: JR Lip-
pincott Co; 1977:168-173. 3. Slonka GF, Fleissner ML, Berlin J, Puleo J, Harrod EK, Schultz MG. An epidemic of pediculosis capitis. J ParasitoL 1977;63(2):
377-383.
4. Taplin D, Meinking TL, Castillero PM, Sanchez R. Permethrin 1% creme rinse for the treatment of Pediculus hwmanus var. capitis infestation. Pediatr Dermatol.
1986;3(4):344-348.
5. Brandenburg K, Deinard AS, DiNapoli J, Englender SJ, Orthoefer J, Wagner D. One
June 1992, Vol. 82, No. 6
P
percent pennethrin creme rinse vs 1% lindane shampoo in treating pediculosis capitis. Am J Dis Ch/dd 1986;140:894-896. 6. Bowerman JG, Gomez MP, Austin RD,
Wold DE. Comparative study of permethrin 1% creme rinse and lindane shampoo for the treatment of head lice. Pediatr Infect Dis J. 1987;6:252-255.
CaliforPpenfor~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~y m n ~~~~~~~~~~~~~~~~~~m na43~~~~~~~~~~~~~~* posiw A
Peuvkum Cowdituents~~~~~~~~UIT311
Surveillance Study of Pernetrin Creme Rinse 7. Strom BL. Position paper on the use of purported post-marketing drug surveillance studies for promotional purposes. Phamnacol Ther. 1990;48(5):598.
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