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ARTHRITIS & RHEUMATISM Vol. 54, No. 8, August 2006, pp 2550–2557 DOI 10.1002/art.21955 © 2006, American College of Rheumatology

Mortality in Systemic Lupus Erythematosus

S. Bernatsky,1 J.-F. Boivin,2 L. Joseph,3 S. Manzi,4 E. Ginzler,5 D. D. Gladman,6 M. Urowitz,6 P. R. Fortin,6 M. Petri,7 S. Barr,8 C. Gordon,9 S.-C. Bae,10 D. Isenberg,11 A. Zoma,12 C. Aranow,13 M.-A. Dooley,14 O. Nived,15 G. Sturfelt,15 K. Steinsson,16 G. Alarco´n,17 J.-L. Sene´cal,18 M. Zummer,19 J. Hanly,20 S. Ensworth,21 J. Pope,22 S. Edworthy,8 A. Rahman,11 J. Sibley,23 H. El-Gabalawy,24 T. McCarthy,24 Y. St. Pierre,1 A. Clarke,1 and R. Ramsey-Goldman25

Objective. To examine mortality rates in the larg- observed to deaths expected) estimates were calculated est systemic lupus erythematosus (SLE) cohort ever for all deaths and by cause. The effects of sex, age, SLE assembled. duration, race, and calendar-year periods were deter- Methods. Our sample was a multisite interna- mined. tional SLE cohort (23 centers, 9,547 patients). Deaths Results. The overall SMR was 2.4 (95% confi- were ascertained by vital statistics registry linkage. dence interval 2.3–2.5). Particularly high mortality was Standardized mortality ratio (SMR; ratio of deaths seen for circulatory disease, infections, renal disease, non-Hodgkin’s lymphoma, and lung cancer. The highest Supported by the Systemic Lupus International Collaborating SMR estimates were seen in patient groups character- Clinics (SLICC) investigators group, in collaboration with the Cana- dian Network for Improved Outcomes in Systemic Lupus (CaNIOS). Urowitz, MD, P. R. Fortin, MD, MPH: Toronto Western Hospital, Dr. Bernatsky’s work was supported by Lupus Manitoba. Dr. Ber- Toronto, Ontario, Canada; 7M. Petri, MD, MPH: Johns Hopkins natsky is recipient of a Canadian Institutes of Health Research Junior University School of Medicine, Baltimore, Maryland; 8S. Barr, MD, Investigator award, a Lupus Canada Fellowship, and a Canadian MSc, S. Edworthy, MD: University of Calgary, Calgary, Alberta, Arthritis Network Scholar award. Dr. Joseph is recipient of a Canadian Canada; 9C. Gordon, MD, FRCPC: University of Birmingham, Bir- Institutes of Health Research Senior Investigator award. Dr. Fortin’s mingham, UK; 10S.-C. Bae, MD, PhD, MPH: Hospital for Rheumatic work was supported by the Arthritis Centre of Excellence at the Diseases, Hanyang University, Seoul, South Korea; 11D. Isenberg, University of Toronto, Arthritis & Autoimmunity Research Centre, MD, A. Rahman, PhD, MRCP: University College, London, UK; 12A. University Health Network, and Lupus Canada. Dr. Fortin is recipient Zoma, MB, ChB: Hairmyres Hospital, Glasgow, UK; 13C. Aranow, of an Investigator award from The Arthritis Society and the Canadian MD: Albert Einstein College of Medicine, Bronx, New York; 14M.-A. Institutes of Health Research. Dr. Petri’s work was supported by the Dooley, MD, MPH: University of North Carolina at Chapel Hill; 15O. NIH (grant R01-AR-437337) and the CRC (grant M01-RR-00052). Nived, MD, PhD, G. Sturfelt, MD, PhD: University Hospital, Lund, Dr. Gordon’s work was supported by Lupus UK. Drs. Nived and Sweden; 16K. Steinsson, MD, PhD: Landspitalinn University Hospital, Sturfelt’s work was supported by the Swedish Medical Research Reykjavik, Iceland; 17G. Alarco´n, MD, MPH: University of Alabama Council (grant 13489). Dr. Steinsson’s work was supported by The at Birmingham; 18J.-L. Sene´cal, MD: University of Montreal School of Science Fund of Landspitalinn University Hospital. Dr. Sene´cal’s work Medicine, and Hoˆpital Notre-Dame, Montreal, Quebec, Canada; 19M. was supported by the Canadian Institutes of Health Research (grant Zummer, MD: Hoˆpital Maisonneuve-Rosemont, Montreal, Quebec, MOP-62687). Dr. Clarke’s work was supported by the National Cancer Canada; 20J. Hanly, MD: Queen Elizabeth II Health Sciences Centre Institute of Canada (grant 013135), The Arthritis Society (grant and Dalhousie University, Halifax, Nova Scotia, Canada; 21S. Ens- 99105), the Canadian Institutes of Health Research (grant 100005), worth, MD: University of British Columbia, Vancouver, British Co- and the Singer Family Fund for Lupus Research. Dr. Clarke is lumbia, Canada; 22J. Pope, MD, MPH: St. Joseph’s Hospital, Univer- recipient of a Canadian Institutes of Health Research Investigator sity of Western Ontario, London, Ontario, Canada; 23J. Sibley, MD: award. Dr. Ramsey-Goldman’s work was supported by the Arthritis Royal University Hospital, Saskatoon, Saskatchewan, Canada; 24H. Foundation (Clinical Science grant), the Greater Chicago Chapter of El-Gabalawy, MD, T. McCarthy, MD: University of Manitoba, Win- the Arthritis Foundation, the NIH (grants AR-02138 and AR-48098), nipeg, Manitoba, Canada; 25R. Ramsey-Goldman, MD, DrPH: North- and the Lupus Foundation of Illinois (Chapter grant). western University, Chicago, Illinois. 1S. Bernatsky, MD, PhD, Y. St. Pierre, MSc, A. Clarke, MD, Drs. Clarke and Ramsey-Goldman contributed equally to this MSc: Montreal General Hospital, Montreal, Quebec, Canada; 2J.-F. work. Boivin, MD, ScD: McGill University, Montreal, Quebec, Canada; 3L. Address correspondence and reprint requests to S. Bernatsky, Joseph, PhD: Montreal General Hospital, and McGill University, MD, PhD, Division of Clinical Epidemiology, Montreal General Hospital Montreal, Quebec, Canada; 4S. Manzi, MD, MPH: University of Research Institute, 1650 Cedar Avenue, Room L10-424, Montreal, Que- Pittsburgh School of Medicine and Graduate School of Public Health, bec H3G 1A4, Canada. Pittsburgh, Pennsylvania; 5E. Ginzler, MD: State University of New Submitted for publication November 24, 2005; accepted in York–Downstate Medical Center, Brooklyn; 6D. D. Gladman, MD, M. revised form March 30, 2006.

2550 MORTALITY AND LUPUS 2551

ized by female sex, younger age, SLE duration <1 year, patient was considered to have met the clinical criteria if a or black/African American race. There was a dramatic rheumatologist had confirmed that he/she had a definite decrease in total SMR estimates across calendar-year diagnosis of SLE whether or not 4 ACR criteria had been met. However, the vast majority of our patients did in fact meet the periods, which was demonstrable for specific causes ACR criteria. The study base encompassed 23 collaborating including death due to infections and death due to renal lupus centers in 7 countries. These centers, listed in Appendix disorders. However, the SMR due to circulatory dis- A, were located in North America (Canada and the US), the eases tended to increase slightly from the 1970s to the UK (England and Scotland), Iceland, Sweden, and South Korea. Patients have been followed up in outpatient clinics year 2001. and/or in the inpatient hospital setting. Although most inves- Conclusion. Our data from a very large multi- tigators are based at tertiary academic centers, they actively center international cohort emphasize what has been encourage the enrollment of patients from community physi- demonstrated previously in smaller samples. These cian practices, and thus, the patients represent a spectrum of results highlight the increased mortality rate in SLE disease. This cohort has been used to examine cancer inci- dence in SLE (4). patients compared with the general population, and Most of the patients at the participating centers were they suggest particular risk associated with female sex, prospectively enrolled, although some had been retrospectively younger age, shorter SLE duration, and black/African enrolled after being followed up for a period of time in the American race. The risk for certain types of deaths, clinic at the respective center (see Appendix A). At each center, patients lost to followup were not excluded; in general, primarily related to lupus activity (such as renal dis- patients seen more than once at any of the participating study ease), has decreased over time, while the risk for deaths centers were included in the study. due to circulatory disease does not appear to have Data collection. Data were collected on each patient’s diminished. date of birth, sex, dates of SLE diagnosis and cohort entry, and date of death, if applicable. Probabilistic linkage to vital statistics registries was performed for patients deceased or lost Systemic lupus erythematosus (SLE) is a chronic to followup, with the National Death Index in the US cohorts autoimmune disorder that can be severe and life threat- and with regional vital statistics registries for the non-US ening. Death in patients with SLE may be due to lupus cohorts. In probabilistic linkage (the current standard for activity (when vital organs or systems are involved), to linking with administrative databases), registries are provided with key data on patients (name, date of birth, and unique complications of treatment (particularly infections), or numeric identifier), and previously validated algorithms are to long-term sequelae (such as cardiovascular disease). used for selecting matches on the basis of probability of a Although the literature regarding mortality in correct match. For 3 centers (2 in Canada [Winnipeg and SLE has been growing, it is still important to consolidate Vancouver] and 1 in the UK [London]), linkage of lost-to- and confirm what previous findings have suggested. followup patients to vital status registries was not permitted by local ethics approvals; death data at these centers consisted of Through collaborations with the Systemic Lupus Inter- the information recorded in the clinical records. These 3 national Collaborating Clinics (SLICC) (1) and the centers contributed only a small number of patients (513 of the Canadian Network for Improved Outcomes in Systemic sample total of 9,547 patients), very few of whom were lost to Lupus (CaNIOS) investigator groups, we have con- followup. To be conservative, in the primary analysis, we structed a unique multicenter international cohort of assumed that any lost-to-followup patients from these centers remained alive until the end of the observation interval; in unprecedented size. We compared the mortality in this sensitivity analyses, we repeated the standardized mortality SLE cohort with geographically appropriate age-, sex-, ratio (SMR) calculations using the last date seen for all and calendar-year period–matched general population lost-to-followup patients. mortality rates. Because of the exceptionally large num- Analysis. For death overall and for cause of death, we ber of patients and person-years of observation in our determined the ratio of the observed number of deaths to the expected number of deaths (the SMR). We examined the most sample, we provide novel data comparing all-cause and common identified causes of death, calculating event rates and disease-specific relative mortality (in SLE compared cause-specific SMRs. In secondary analyses, SMRs were esti- with the general population) across groups characterized mated for subgroups according to sex, age group, duration of by sex, age, SLE duration, geographic location, race, and SLE, and geographic location (country). We also estimated calendar-year period. SMRs across calendar-year periods (1970–1979, 1980–1989, and 1990–2001). In addition, we generated race-specific SMRs for the US patients only, since the US mortality rates were the PATIENTS AND METHODS only available general population figures that were stratified by race (for whites and blacks/African Americans). Study subjects. All adult (age Ͼ16 years) patients with To calculate SMRs, the expected numbers of deaths definite SLE according to American College of Rheumatology were obtained by multiplying person-years at risk in the cohort (ACR) (2,3) or clinical criteria were eligible for inclusion. A by the geographically appropriate age-, sex-, and calendar-year 2552 BERNATSKY ET AL

period–matched mortality rates. The person-years for each disease, and cerebrovascular events (strokes). Other patient were determined by subtracting the later of 2 entry common types of deaths resulted from neoplasms dates (the beginning of the vital statistics registry observation (ICD-9 codes 140–239), nephritis (ICD-9 codes 580– interval or the first visit to the respective lupus clinic) from the earlier of 2 exit dates (end date of vital statistics registry data 589), and infections (ICD-9 codes 001–139; these codes or death). The SMRs were calculated by dividing the observed do not include pneumonia [ICD-9 codes 480–486] or the number of deaths by the expected number, and 95% confi- term bacteremia [ICD-9 code 790.7], although they do dence intervals (95% CIs) were calculated using methods include the term septicemia [ICD-9 code 038]). Circu- described elsewhere (5) for Poisson parameters. Information latory disease was the identified cause of 313 deaths, for on deaths by cause was grouped according to International a rate of 4.1 events per 1,000 person-years; cancer was Classification of Diseases, Ninth Revision (ICD-9) codes. In additional secondary analyses, we used the entire the cause ascribed to 114 deaths, for a rate of 1.5 events sample to perform a multivariate hierarchical regression to per 1,000 person-years; and infection (not including determine independent effects of the factors examined (sex, pneumonia) was identified as the cause of 45 deaths, for age group, SLE duration, calendar-year period, country) on a rate of 0.6 events per 1,000 person-years. the SMRs among the patients in the SLE cohort. The hierar- The overall (all-cause) SMR estimate was 2.4 chical model allowed for differences in effects from one (95% CI 2.3–2.5). For death due to circulatory disease, country to the next. Poisson regression methods were used, with the logarithm of the expected number of deaths serving as the SMR was 1.7 (95% CI 1.5–1.9). For the ICD the offset variable. The model included an extra variance term category of infectious causes of death, the SMR was 5.0 to handle slight overdispersion in the data. For each variable in (95% CI 3.7–6.7); for pneumonia (which in the ICD the model, one of the categories was chosen as a reference, and codes is classified under respiratory diseases), the SMR the estimate for each of the other categories is thus interpret- was 2.6 (95% CI 1.6–4.1). For cancer overall, the SMR able as the relative risk compared with the reference, adjusted was 0.8 (95% CI 0.6–1.0); in terms of cancer types, for for the other factors in the model. Finally, we undertook secondary analyses of the 291 deaths for which lupus was the assigned cause, evaluating stratified rates of lupus-related death for groups characterized by demographics, SLE dura- Table 1. Unadjusted SMR estimates for all-cause mortality and for tion, and calendar-year period. death by cause* SMR Cause of death (ICD-9 code) Observed Expected (95% CI) RESULTS All deaths 1,255 526 2.4 (2.3–2.5) The 9,547 patients were observed for a total of Disease of the circulatory system† 76,948 person-years (average followup 8.1 years). The All disease (390–459) 313 184.3 1.7 (1.5–1.9) Heart disease (390–429)‡ 126 73.8 1.7 (1.4–2.0) calendar-year period of observation was 1958–2001, Stroke (430–459)‡ 21 19.3 1.1 (0.7–1.7) although the majority of the observation interval oc- Malignancy† curred between 1970 and 2001. Most of the patients All neoplasms (140–239) 114 138 0.8 (0.6–1.0) All hematologic cancer 15 7.2 2.1 (1.2–3.4) (71%) entered into the observation interval within the (200–208)‡ first 2 years of their SLE diagnosis. As expected, given NHL (200, 201)‡ 8 2.8 2.8 (1.2–5.6) Lung cancer (162)‡ 44 19.4 2.3 (1.6–3.0) that SLE is a disease primarily of women, 90% of the Infections† patients were female (n ϭ 8,607). The number of Infections (001–139) 45 9.0 5.0 (3.7–6.7) person-years of observation was divided among the age Pneumonia (480–486)‡ 19 7.2 2.6 (1.6–4.1) Ͻ Other† groups 40 years (33,001 person-years), 40–59 years Respiratory, excluding 14 10.4 1.3 (0.8–1.6) (30,976 person-years), and Ն60 years (12,971 person- pneumonia (460–479, years). Regarding SLE duration, the person-years of 487–519) Renal (580–589) 34 4.3 7.9 (5.5–11.0) observation were fairly equally divided among the dura- tion groups of 0–4 years (27,037 person-years), 5–9 years * Data shown are for 23 participating sites in North America, Europe, Ն Iceland, and Asia, for a total 9,547 patients (76,948 person-years), and (21,931 person-years), and 10 years (27,980 person- for the calendar-year period 1958–2001. SMR ϭ standardized mortal- years). ity ratio; ICD-9 ϭ International Classification of Diseases, Ninth Within the observation interval, 1,255 deaths Revision; 95% CI ϭ 95% confidence interval; NHL ϭ non-Hodgkin’s lymphoma. occurred; lupus was the assigned cause of death in 291 † Cause-specific death data on this level of detail were available from cases (3.8 events per 1,000 person-years). The most all centers except for Iceland (n ϭ 221), Sweden (n ϭ 114), Saskatche- common types of deaths not directly attributed to SLE wan (n ϭ 306), and Manitoba (n ϭ 158). ‡ Cause-specific death data on this level of detail were available from were deaths due to circulatory disease (ICD-9 codes all centers except for Iceland (n ϭ 221), Sweden (n ϭ 114), Saskatche- 390–459); this includes all types of heart disease, arterial wan (n ϭ 306), Manitoba (n ϭ 158), and Scotland (n ϭ 1,937). MORTALITY AND LUPUS 2553

Table 2. Unadjusted SMR estimates, stratified by sex, age, and SLE duration* SMR (95% CI) Sex Female 2.5 (2.3–2.7) Male 1.9 (1.7–2.2) Age, years Ͻ40† 10.7 (9.5–11.9) 40–59 3.7 (3.3–4) Ն60 1.4 (1.3–1.5) Figure 2. Unadjusted standardized mortality ratio (SMR) estimates, SLE duration, years stratified by country. Korea represents South Korea. Ͻ1 5.4 (4.7–6.3) 1–4 2.5 (2.2–2.8) 5–9 2.1 (1.9–2.4) the SMR due to circulatory diseases tended to increase 10–19 2.0 (1.8–2.3) Ն20 2.0 (1.7–2.4) slightly from the 1970s to the year 2001. Unadjusted SMR estimates stratified according * SMR ϭ standardized mortality ratio; SLE ϭ systemic lupus erythem- atosus; 95% CI ϭ 95% confidence interval. to geographic location are shown in Figure 2. Although † Within the age group Ͻ40 years, the SMR for very young adults slight differences may be present, overall the evidence (ages 16–24 years) was particularly high, at 19.2 (95% CI 14.7–24.7). suggests a relatively consistent increased risk of death The SMR for adults ages 25–39 years was 8.0 (95% CI 7.0–9.1). (ϳ2-fold) in SLE patients compared with the general population. However, although Figure 2 indicates that the unadjusted country-specific estimates are largely non-Hodgkin’s lymphoma (NHL), the SMR was 2.8 overlapping, it appears that the magnitude of effect may (95% CI 1.2–5.6), and, for lung cancer, the SMR was 2.3 be somewhat less for certain groups, notably the Swed- (95% CI 1.6–3.0) (Table 1). ish. This may in part relate to various factors, including Patient groups characterized by any of the follow- differences in demographic makeup or clinical charac- ing: female sex, younger age, or SLE duration Ͻ1 year, teristics of the cohort members; an important factor may all had particularly high SMR estimates (Table 2). This also relate to site-specific variations in the enrollment phenomenon was evident not only for all-cause mortal- criteria and methods (as outlined in Appendix A). ity, but also for cause-specific mortality estimates, in- Race-specific SMR estimates for the US patients were cluding death due to circulatory diseases, infections, and as follows: whites 1.4 (95% CI 1.2–1.7), blacks/African renal disorders. Within the age group Ͻ40 years, the Americans 2.6 (95% CI 2.3–2.9). The overall race- SMR for very young adults (ages 16–24 years) was adjusted SMR for the US sites was 2.2 (95% CI 2.0–2.4). particularly high, at 19.2 (95% CI 14.7–24.7). Figure 1 In sensitivity analyses, when we repeated the SMR presents the unadjusted SMR estimates by calendar-year calculations using the last date seen for all lost-to- period. Across calendar-year periods, there was a dra- followup patients, the results were essentially un- matic decrease in total SMR estimates, which was changed. demonstrable for specific causes, including death due to Table 3 presents the results of the multivariate infections and death due to renal disorders. However, hierarchical regression to determine independent effects of the factors examined (sex, age group, SLE duration, calendar-year period of SLE diagnosis, country) on the relative SMR estimates among SLE patients. These adjusted estimates were consistent with the unadjusted results in terms of suggesting independent effects for each variable of interest (female sex, younger age, SLE duration Ͻ1 year, calendar-year period) on the risk of death among the SLE patients (relative to the general population). However, the 95% CIs were wider, and in the case of the effects of different calendar-year periods, the estimates did overlap and include the null value. Figure 1. Unadjusted standardized mortality ratio (SMR) estimates, Regarding secondary stratified analyses for rates by calendar-year period. of death due to SLE, we found that lupus-related death 2554 BERNATSKY ET AL

Table 3. Results of adjusted multivariate regression to determine some years. However, our results do emphasize what has independent effect of variables on SMR estimates* been demonstrated previously in smaller samples. In Adjusted SMR addition, because of the large numbers of patients and (95% CI)† person-years of observation in the multicenter cohort, Female sex 1.2 (1.0–1.4) we were able to provide data comparing all-cause and Age, years disease-specific relative mortality (in SLE patients com- Ͻ 40 6.4 (5.5–7.5) pared with the general population) across groups char- 40–59 2.6 (2.3–3.0) Ն60 1.0 (reference group) acterized by age, sex, SLE duration, calendar-year pe- SLE duration, years riod, geographic location, and race. Ͻ 1 7.7 (5.9–10.2) In terms of the slightly higher total SMR esti- 1–4 3.2 (2.5–4.1) 5–9 2.4 (1.8–3.0) mates suggested for females, some prior work by others 10–19 1.8 (1.4–2.2) has suggested greater mortality in male than in female Ն 20 1.0 (reference group) SLE patients (6,7). However, this previous work did not Calendar-year period of SLE diagnosis 1970–1979 1.3 (1.0–1.5) calculate mortality rates relative to the general popula- 1980–1989 1.2 (1.0–1.4) tion. The longevity of males is generally lower than that 1990–2001 1.0 (reference group) of females; thus, when comparing the effect of sex on Country Canada 1.8 (1.6–2.1) mortality in SLE patients, it is preferable to use a England 1.6 (1.2–2.2) parameter such as the SMR. Similarly, the SMR pro- Scotland 1.3 (1.1–1.5) vides a clearer understanding of which age group of SLE Iceland 1.2 (0.9–1.6) US 1.0 (reference group) patients has the greatest increased risk (compared with Sweden 0.8 (0.5–1.4) the general population counterparts), since mortality South Korea 0.7 (0.3–2.0) rates in the general population increase with age. * SMR ϭ standardized mortality ratio; 95% CI ϭ 95% confidence Although the highest SMR estimates for our interval. SLE ϭ systemic lupus erythematosus. sample were seen within the first year, there was evi- † Variables adjusted concomitantly for all others (sex, age, SLE duration, calendar-year period, and country). dence that death rates in SLE patients are much higher than those in the general population throughout the course of SLE, even up to 20 years of SLE duration. rates were a little higher for men (3.6 deaths per 1,000 Overall, across countries, we noted a relatively consis- person-years) than for women (2.7 deaths per 1,000 tent increased risk of death in SLE patients compared person-years), although the 95% CIs for these estimates with the general population. Slight regional differences overlapped. With respect to age, very young individuals were present (Figure 2); adjusting for sex, age, SLE (ages Ͻ25 years) had the highest rate of deaths due to duration, and calendar-year period appeared to remove SLE (5.3 deaths per 1,000 person-years, 95% CI 3.7–7.5) most of this variation (Table 3). Small residual regional compared with other age groups; the estimates across differences may be due in part to differences in cohort other age groups (for those ages Ն25 years) were all very assembly (see details in Appendix A) and may reflect similar, with an average of 2.5 deaths due to SLE per variations in other factors, including disease character- 1,000 person-years (95% CI 2.2–3.5). There were gener- istics (and severity), medication exposures, comorbidity, ally very few differences regarding lupus-related death and racial mix. We note that the cohorts from countries rates for groups characterized by SLE duration, and no with the lowest SMR point estimates (Sweden, Iceland, trend over calendar time was observed for deaths due to and Scotland) were population based. This may indicate lupus. the potential role of sample recruitment in the findings. Among SLE patients in the US, the question of why blacks/African Americans have a higher SMR than DISCUSSION whites is an interesting one; previous work has also The primary value of this work is that it formally shown this phenomenon (8,9). Since the results of other presents the increased risk of mortality in SLE com- studies have suggested worse renal involvement and pared with that in the general population, and it exam- outcomes in black/African American (and also black ines the particular risk in groups of patients character- Caribbean) patients (10–13), a reasonable hypothesis is ized by demographic and other factors. The increased that the higher SMR estimate in blacks is driven in part risk of mortality in SLE is by no means a new phenom- by SLE severity and comorbidity. Another related factor enon; on the contrary, it has been a point of concern for may be economic status, since poverty has been sug- MORTALITY AND LUPUS 2555

gested to contribute to increased mortality in SLE example, by limiting cumulative exposure). An alterna- (6,14). Previous work has suggested high mortality in tive explanation is that in more recent eras, there is more Asian SLE patients as well (15), but estimates relative to effective recognition and treatment of infectious compli- the general population are lacking. We are unable to cations. comment about racial groups other than white and It seems clear that certain types of deaths, pri- black/African American patients in the US. marily related to lupus activity (such as renal disease), Early work by Urowitz et al (16,17) first drew have decreased over time. However, the trend for circu- attention to the importance of mortality due to circula- latory disease shows no such decline, a finding suggested tory disease in SLE, particularly late in the disease as well by Bjornadal et al (19). This may reflect in part course. As their work and that of others has suggested, the complex nature of cardiovascular disease in SLE. circulatory disease (related to the heart, arteries, and Classic atherosclerosis risk factors, such as hypertension cerebrovascular events) is a common cause of death in and hypercholesterolemia, do play a role, although SLE (9,18,19). Previous work by Manzi et al (20) has recent work has suggested that additional risk is con- shown a very high incidence of cardiac events (specifi- ferred by some disease-related characteristics, such as cally, myocardial infarction and angina) in SLE patients SLE duration and, perhaps, severity (26). However, compared with the general population. Our data sub- other elements, such as medication exposures, may also stantiate an increased risk of death due to circulatory alter atherosclerosis risk in SLE. causes in SLE patients compared with the general Limitations of our study should be considered. population. We cannot be certain that the causes of death in our We identified an increased risk of death due to SLE patients were identified correctly, since we relied specific cancers, including hematologic malignancies primarily on death registry linkage results. However, (particularly NHL) and lung cancer. This is of interest important biases in our estimates would only arise if given recent data showing a heightened incidence of misclassification occurred differentially between SLE these types of cancer in SLE (4), and it is not concordant patients versus the general population. A fairly large with surveillance bias as the explanation for the observed number of deaths were ascribed to SLE itself; it is association between cancer and SLE. An increased risk possible that the primary cause of death was actually of death was also estimated for infections and renal another condition (e.g., cardiovascular disease or infec- disease. It is well known that infections, often attributed tion), but the patient’s preexisting diagnosis of SLE may to the use of immunosuppressant medications, are a have led to this being listed as the cause of death. This frequent cause of death in SLE (9,18,21). An increase in might lead to an underestimation of some of the cause- the rate of death due to renal disease reflects the specific SMR estimates; however, the data on causes of potential seriousness of nephritis in SLE (9,22). death recorded for SLE patients do not suggest that this Our work shows a dramatic 60% decrease over effect is likely (27). time in the standardized all-cause mortality rates, from Although we believe that our cohort is probably 1970–1979 (SMR 4.9) to 1990–2001 (SMR 2.0). Work in representative of the general population of lupus pa- several SLE cohorts over the last 3 decades has sug- tients, it is not a random sample. Therefore, claims of gested an improvement in survival, at least early in the representativeness must be made very cautiously, since course of SLE (17,23–25). Results of our work are unobserved selection biases may certainly operate. Most consistent with increased survival over time, in keeping investigators involved in our multicenter cohort are with previous findings, although we note that the use of based at tertiary academic centers, although they ac- different methodologies may produce somewhat differ- tively encourage the enrollment of patients from com- ent estimates from one study to the next. It is important munity physician practices. The patients enrolled do to keep in mind that, since the SMR estimate compares represent a spectrum of disease severity, but sicker the observed number of deaths in SLE patients with the patients may indeed be overrepresented. We do note expected number of deaths in the general population, that our findings are consistent with the results reported the decrease over the last 2 decades probably reflects by Bjornadal et al (19) in their assessment of a improvements specific to the excess mortality in SLE population-based cohort, which was assembled using rather than a general increase in population longevity. A administrative databases (which are not without their decrease in deaths due to infections over time may be own sources of bias and error). due to the evolution of strategies to limit the incidence In conclusion, the data from our very large of infections when immunomodulators are used (for multicenter international cohort emphasize what has 2556 BERNATSKY ET AL

been demonstrated previously in smaller samples. The of 338 patients with systemic lupus erythematosus. Ann Rheum results highlight the increased mortality rate in SLE Dis 2002;61:1065–70. 8. Reveille JD, Bartolucci A, Alarcon GS. Prognosis in systemic patients compared with the general population. This lupus erythematosus: negative impact of increasing age at onset, increased mortality is highest in patient groups charac- black race, and thrombocytopenia, as well as causes of death. terized by female sex, younger age, or SLE duration Ͻ1 Arthritis Rheum 1990;33:37–48. 9. Mody G, Parag K, Nathoo B, Pudifin D, Duursma J, Seedat Y. year, although an increased risk of mortality in SLE High mortality with systemic lupus erythematosus in hospitalized patients compared with the general population was African blacks. Br J Rheumatol 1994;33:1151–3. generally seen across all demographic groups. The 10. Ginzler EM, Diamond HS, Weiner M, Schlesinger M, Fries JF, Wasner C, et al. A multicenter study of outcome in systemic lupus country-specific estimates also showed a relatively con- erythematosus. I. Entry variables as predictors of prognosis. sistent increased risk of death in SLE patients compared Arthritis Rheum 1982;25:601–11. with the general population. There was evidence of a 11. Hopkinson N, Jenkinson C, Muir K, Doherty M, Powell R. Racial group, socioeconomic status, and the development of persistent striking increase in mortality among black/African proteinuria in systemic lupus erythematosus. Ann Rheum Dis American SLE patients in the US, although a smaller 2000;59:116–9. increase in mortality was also present for white SLE 12. Walsh SJ, Algert C, Rothfield NF. Racial aspects of comorbidity in systemic lupus erythematosus. Arthritis Care Res 1996;9:509–16. patients in the US. The decrease in SMR estimates over 13. Bastian H, Roseman J, McGwin G, Alarcon G, Friedman A, time for our lupus cohort is encouraging, but the resid- Fessler B, et al. Systemic lupus erythematosus in three ethnic ual increased risk of death in SLE suggests that contin- groups. XII. Risk factors for lupus nephritis after diagnosis. Lupus 2002;11:152–60. ued efforts should focus on developing better means of 14. Alarcon GS, McGwin GJ Jr, Bastian HM, Roseman J, Lisse J, preventing and treating the sequelae of SLE as well as Fessler BJ, et al, and the LUMINA Study Group. Systemic lupus other comorbidity, particularly cardiovascular disease. erythematosus in three ethnic groups. VIII. Predictors of early mortality in the LUMINA cohort. Arthritis Rheum 2001;45: 191–202. ACKNOWLEDGMENTS 15. Samanta A, Feehally J, Roy S, Nichol F, Sheldon P, Walls J. High prevalence of systemic disease and mortality in Asian subjects with Angela Allen, Natalie Gonzalez, and Katie Arrigo systemic lupus erythematosus. Ann Rheum Dis 1991;50:490–2. functioned as research co-coordinators responsible for all US 16. Urowitz M, Bookman A, Koehler B, Gordon D, Smythe H, Ogryzlo M. The bimodal mortality pattern of systemic lupus sites. We wish to thank the following physicians for their erythematosus. Am J Med 1976;60:221–5. significant assistance in providing access to patients and col- 17. Urowitz M, Gladman D, Abu-shakra M, Farewell V. Mortality lecting data: Simon Bowman, Linda Lee, Moon-Ho Leung, studies in systemic lupus erythematosus. Results from a single Ibraheem Nahr, and Martha Sanchez. Stephanie Heaton, RN, center. III. Improved survival over 24 years. J Rheumatol 1997;24: assisted with data collection for the Birmingham, UK, lupus 1061–5. cohort. The National Death Index and regional or national 18. Abu-shakra M, Urowitz M, Gladman D, Gough J. Mortality vital statistics registries provided vital status information on studies in systemic lupus erythematosus. Results from a single center. I. Causes of death. J Rheumatol 1995;22:1259–64. deceased and lost-to-followup patients. 19. Bjornadal L, Yin L, Granath F, Klareskog L, Ekbom A. Cardio- vascular disease a hazard despite improved prognosis in patients with systemic lupus erythematosus: results from a Swedish popu- REFERENCES lation based study. J Rheumatol 2004;31:713–19. 20. Manzi S, Meilahn E, Rairie J, Conte C, Medsger T, Jansen- 1. Isenberg D, Gladman D. The Systemic Lupus International Col- McWilliams L, et al. Age-specific incidence rates of myocardial laborating Clinics Group: origins and outcomes. Lupus 2001;10: infarction and angina in women with systemic lupus erythemato- 375–7. sus: comparison with the Framingham Study. Am J Epidemiol 2. Hochberg MC. Updating the American College of Rheumatology 1997;145:408–15. revised criteria for the classification of systemic lupus erythema- 21. Cervera R, Khamashta M, Font J, Sebastiani G, Gil A, Lavilla P, tosus [letter]. Arthritis Rheum 1997;40:1725. et al, the European Working Party on Systemic Lupus Erythem- 3. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield atosus. Morbidity and mortality in systemic lupus erythematosus NF. The 1982 revised criteria for the classification of systemic during a 5-year period: a multicenter prospective study of 1,000 lupus erythematosus. Arthritis Rheum 1982;25:1271–7. patients. Medicine (Baltimore) 1999;78:167–75. 4. Bernatsky S, Boivin JF, Joseph L, Rajan R, Zoma A, Manzi S, et 22. Moss K, Ioannou Y, Sultan S, Haq I, Isenberg D. Outcome of a al. An international cohort study of cancer in systemic lupus cohort of 300 patients with systemic lupus erythematosus attend- erythematosus. Arthritis Rheum 2005;52:1481–90. ing a dedicated clinic for over two decades. Ann Rheum Dis 5. Breslow ND. Statistical methods in cancer research. The design 2002;61:409–413. and analysis of cohort studies. Lyon: WHO International Agency 23. Bongu A, Chang E, Ramsey-Goldman R. Can morbidity and for Research on Cancer; 1987. p. 302–4. mortality of SLE be improved? Best Pract Res Clin Rheumatol 6. Ward MM, Pyun E, Studenski S. Long-term survival in systemic 2002;16:313–32. lupus erythematosus: patient characteristics associated with 24. Stahl-Hallengren C, Jonsen A, Nived O, Sturfelt G. Incidence poorer outcomes. Arthritis Rheum 1995;38:274–83. studies of systemic lupus erythematosus in Southern Sweden: 7. Manger K, Manger B, Repp R, Geisselbrecht M, Geiger A, increasing age, decreasing frequency of renal manifestations and Pfahlberg A, et al. Definition of risk factors for death, end stage good prognosis. J Rheumatol 2000;27:685–91. renal disease, and thromboembolic events in a monocentric cohort 25. Uramoto KM, Michet CJ Jr, Thumboo J, Sunku J, O’Fallon WM, MORTALITY AND LUPUS 2557

Gabriel SE. Trends in the incidence and mortality of systemic APPENDIX A: INTERNATIONAL SYSTEMIC LUPUS lupus erythematosus, 1950–1992. Arthritis Rheum 1999;42:46–50. ERYTHEMATOSUS COHORT, PARTICIPATING CENTERS 26. Roman MJ, Shanker BA, Davis A, Lockshin MD, Sammaritano L, Simantov R, et al. Prevalence and correlates of accelerated Country atherosclerosis in systemic lupus erythematosus. N Engl J Med (no. of patients)* Centers 2003;349:2399–406. North America 27. Ward MM. Education level and mortality in systemic lupus Canada (2,688)† Calgary, Alberta‡; Halifax, Nova Scotia‡; erythematosus (SLE): evidence of underascertainment of deaths London, Ontario§; Montreal, Quebec due to SLE in ethnic minorities with low education levels. Arthritis (Hoˆpital Maisonneuve-Rosemont§, Rheum 2004;51:616–24. Montreal General Hospital‡, Hoˆpital Notre-Dame¶); Saskatoon, Saskatchewan‡; Toronto, Ontario‡; Vancouver, British Columbia§; Winnipeg, Manitoba (Health Science Centre and Manitoba Clinic)§ US (3,558)† Baltimore, Maryland¶; Birmingham, Alabama‡; Chapel Hill, North Carolina¶; Chicago, Illinois¶; New York, New York (Albert Einstein College of Medicine, Bronx§; State University of New York–Downstate Medical Center, Brooklyn‡); Pittsburgh, Pennsylvania¶ UK England (712)† Birmingham‡; London‡ Scotland (1,937)# Lanarkshire§ Other Sweden (114)† Lund‡ Iceland (221)† Reykjavik¶ South Korea (317)† Seoul¶ Total ϭ 9,547 * The number of patients at each center corresponds to the number of patients present during the time that vital status registry data were available. † At least 95% of cohort members met 4 of the American College of Rheumatology (ACR) diagnostic criteria for systemic lupus erythem- atosus (SLE) (2,3); patients diagnosed clinically as having SLE but meeting fewer than 4 ACR criteria are not excluded. ‡ Prospective assembly. § Retrospective assembly. ¶ Retrospective and prospective assembly. # Any hospital discharge diagnosis of SLE, primary or nonprimary. Cohort entry date is first discharge date with SLE as a diagnosis. Downloaded from ard.bmj.com on June 10, 2013 - Published by group.bmj.com

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CONCISE REPORT Suicide attempts in patients with systemic lupus erythematosus F B Karassa, M Magliano, D A Isenberg ......

Ann Rheum Dis 2003;62:58–60

RESULTS Background: Suicide and suicide attempts, although well Since 1979 five patients with SLE (2%), four women and one recognised in patients with systemic lupus erythematosus man, made seven suicide attempts, although only one was (SLE), have been commented on relatively little. fatal. The mean age of the patients at the time of the suicide Objective: To obtain a better understanding of the attempt was 41 (SD 8.69) years and median disease duration reasons for suicidal behaviour in patients with SLE. 2.5 years (range 1–11 years). All patients had a history of Methods: The records of 300 patients with SLE were depression at the time of the suicide attempt. None of them reviewed to identify completed or attempted suicides. were inpatients at the time of the attempt. Only one patient Results: Five patients made seven attempts at suicide over had expressed prior suicidal intent and was found to have left a 20 year follow up period; one of them was fatal. All of a suicide note (patient 1); none of the others had, as far as we those attempting suicide had a history of neuropsychiatric could ascertain, expressed suicidal thoughts or gave warnings. SLE (NPSLE) presenting with depression and they made the After two attempts patients were unable to describe clearly attempts soon after the onset of NPSLE (median time how they became vulnerable to suicidal impulses; however, 12.5 months). Two patients had appreciable disease four patients expressed difficulties in coming to terms with activity at the time of the suicide attempt. Lymphopenia the diagnosis of SLE. One patient (patient 3) reported sleeping was present in five suicide attempts. Anti-SSA/Ro antibod- difficulties and irritability in the year before the attempt at ies were detected in three patients, none of whom had suicide. Psychological factors such as unemployment, being anti-SSB/La. All patients apart from one responded to separated, and being isolated in the community due to the treatment for depression; the remaining female patient chronic illness were present in all patients. Ingestion was the made two subsequent suicide attempts, with a fatal only form of suicidal behaviour and involved analgesic drugs outcome despite intensive treatment. regularly used by patients in six cases; the other ingestion was Conclusion: Greater awareness of the risk of suicide in of turpentine fluid. All patients were reviewed by a patients with psychiatric manifestations of SLE may help to psychiatrist and received treatment for depression. reduce the incidence of this potentially fatal phenomenon. All of the patients had evidence of NPSLE before the time of attempted suicide. Patients 2–5 all had depression with or without an anxiety state at the time of the attempt. Patient 1 had a complicated history and two psychiatrists who were suicide attempt is an act of self inflicted harm accom- seeing her gave divergent opinions. On balance we thought it panied by explicit or implicit intent to cause death. reasonable to regard her as being depressed at the time of her A Although only one in eight to 10 people attempting first suicide attempt but this was not as clear cut at the time of suicide succeed, suicide remains a major cause of death. More the second attempt. She had progressive cognitive dysfunction than 90% of suicide victims are psychiatrically ill and 45–77% 1 as manifested by a decline in verbal IQ and memory of them have a mood disorder at the time of death. Chronic impairment, with a profound effect on the patient’s mood and physical illness is an important risk factor for suicide. feeling of hopelessness. Systemic lupus erythematosus is one with a risk quoted to be Median time from the onset of involvement of the central fivefold higher than expected.2 Many factors may contribute to nervous system (CNS) to the attempt at suicide was 12.5 this occurrence: pathophysiological changes in the brain months (range 3–27 months). In two out of three patients resulting from the underlying disease (NPSLE), depression who were evaluated with brain MRI multiple white matter related to the variable course and the unpredictable nature of lesions were found. the disease, and may rarely induce mental dis- Two patients had appreciable disease activity at the time of turbance. the attempt. Lymphopenia was present in six instances, in two × 9 METHODS the lymphocyte count was less than 0.7 10 /l. Anti SSA/Ro We reviewed the medical records of the first 300 patients with antibodies were detected in three patients whereas none of SLE attending our lupus clinic over a 20 year period to identify them had anti-SSB/La. After the suicide attempt patient 1 was attempted and completed suicides. Our aim was to identify treated with pulses of cyclophosphamide and methylpred- any potential risk factors for the suicide in these patients nisolone (the first cycle was followed by the suicide attempt), related to their underlying condition. patient 4 received three pulses of methylprednisolone and oral All patients fulfilled the American College of Rheumatology prednisolone was increased in patients 2, 3, and 5 (by a mean of (ACR) 1982 revised criteria for the classification of SLE.3 Demographic, clinical, and laboratory data as well as current and previous treatments were recorded from patients’ charts...... Disease activity was evaluated using the British Isles Lupus 4 Abbreviations: ACR, American College of Rheumatology; BILAG, British Assessment Group (BILAG) index (version 3). Neuropsychi- Isles Lupus Assessment Group; CNS, central nervous system; NPSLE, atric lupus (NPSLE) was defined according to the ACR neuropsychiatric systemic lupus erythematosus; SLE, systemic lupus definitions.5 Table 1 lists the details. erythematosus

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Suicide attempts in patients with systemic lupus erythematosus 59

20 mg/day). Patient 1 continued to deteriorate cognitively despite the treatment with cyclophosphamide and anti-CD20 monoclonal antibody directed at NPSLE manifestations. This patient made two subsequent attempts of suicide, the last one being fatal. /l) 9

Lymphocytes (10 DISCUSSION Patients with SLE are at almost five times greater risk for suicide than expected.2 In our cohort of patients 2% had a documented history of attempted suicide. Could we have missed more suicide attempts? We cannot completely exclude this possibility but consider it unlikely as the BILAG form that we complete at § ESR

3 every patient assessment specifically records depression and any worsening of this feature would have led to further enquir- ies about suicide attempts. As a control we reviewed the notes of 140 patients with primary Sjogren’s syndrome followed up by us from 1988 to 2001. To date none have attempted suicide. All our patients who made attempts at suicide had been diagnosed with depression at some time before the attempt. Psychiatric dysfunction represents a common NPSLE mani- Total score DNA‡ C festation and may range from mild affective disorders to severe psychosis.67 Our patients with NPSLE made suicide attempts within two years of the onset of involvement of the CNS; all but one had favourable outcomes with more intense treatment. Similarly, five out of seven previously reported sui- cidal patients with SLE presented either with depression or ved; †no data available on patient 1 at the time of the last suicide attempt; ‡DNA: schizophrenia; all three survivors had a favourable response to increased dose of or immunosupressant drugs.8 To our knowledge none of our 300 patients have attempted suicide after treatment with large amounts of corticosteroids. Insom- nia was a feature in all patients before the suicide attempts, and the presence of hypocomplementaemia and reducing dose of steroids possibly resulting in suboptimal control of the dis- ease activity were implied as important suicidal risk factors.8 Futrell et al described six suicide attempts in 31 patients with NPSLE with major behavioural changes.9 Suicidal patients with SLE coupled with depression and aggressive 10 11 CVS/ respiratory Vasculitis Renal Haematological behaviour have also been reported. Although a link between lupus psychosis and antiribosomal P antibodies has been claimed,12 assays to detect these antibodies are not readily available for identifying patients at risk in routine clinical practice. Interestingly anti-SSA/Ro was detected in three of our patients; this is twice the 30% preva- lence of these antibodies in our patients with SLE overall (relative risk=3.66; D A Isenberg, unpublished observations). None of them had concomitant anti-SSB/La antibodies. The relevance of this finding is unknown. Patients with SLE are at greater risk of suicide, and vigilance to identify and treat symptoms and signs of depres- sion is crucial. Although involvement of the CNS creates an additional risk we should not underestimate the importance of the psychosocial factors that coping with life threatening and unpredictable illness creates.

...... Authors’ affiliations F B Karassa, M Magliano, D A Isenberg, Centre for Rheumatology, The Middlesex Hospital, University College London, UK BILAG index for each organ system General manifestations Mucocutaneous CNS Musculoskeletal Correspondence to: Professor D A Isenberg, The Middlesex Hospital : normal values 0.75–1.75 mg/ml; B, black; I, Indian; W, white; M, male; F, female; CNS, central nervous system; CVS, cardiovascular system. 3 University College, London, Arthur Stanley House, 40–50 Tottenham Street, London W1T 4NJ, UK; [email protected]

Date of suicide Accepted 7 June 2002 REFERENCES

BILAG index (version 3) for each organ system on suicidal attempts* 1 Ghosh TB, Victor BS. Suicide. In: Hales RE, Yudofsky SC, Talbott JA,

Age/sex/ ethnic group eds. Textbook of Psychiatry. 3rd ed. Washington, DC: The American Psychiatric Press, 1999:1383–400. 2 Harris EC, Barraclough BM. Suicide as an outcome for medical disorders. Medicine 1994;73:281–96. Tan EM Patient No 1112 39/F/W34 5/995 53/F/I 29/F/W B*The BILAG 40/F/B index is 10/95antimalarial scored 8/89 drugs, as 44/M/W or follows: 9/00 low A,normal dose disease range steroids; of 12/99 <50 C, sufficient 4/01† units/ml; stable activity §C C mild to B 7/99 disease; warrant D, disease B system modifying was treatment – previously with C affected high but dose currently steroids C inactive; or E, immunosupression; system B, C was disease never of invol less activity than in A, requiring only symptomatic treatment, D D C3 – C D B, Cohen D D B DAS, A – BFries C B D C – JF, B Masi D AT, McShane B C D D C – E DJ, Rothfield E D C E D – E NF, et D D E Eal E. – E C B C C – C 8 3 13 260 6 13 – 0.87 7 1800 68 262 170 3 0.93 1.16 0.9 1.2 10 – 14 2.2 43 1.2 – 5 – 0.3 1.2 9 1.1 1.2 – 0.6 – Table 1 The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.

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60 Karassa, Magliano, Isenberg

4 Hay EM, Bacon PA, Gordon C, Isenberg DA, Maddison P, Snaith ML, et 8 Matsukawa Y, Sawada S, Hayama T, Usui H, Horie T. Suicide in al. The BILAG index: a reliable and valid instrument for measuring patients with systemic lupus erythematosus: a clinical analysis of seven clinical disease activity in systemic lupus erythematosus. Q J Med suicidal patients. Lupus 1994;3:31–35. 1993;86:447–58. 9 Futrell N, Schultz LR, Millikan C. Central nervous system disease in 5 ACR Ad Hoc committee on neuropsychiatric lupus nomenclature case patients with systemic lupus erythematosus. Neurology definitions for neuropsychiatric syndrome in systemic lupus 1992;42:1649–57. erythematosus. Arthritis Rheum 1999;42:559–608. Goodwin JM 6 West SG. Neuropsychiatric lupus. Rheum Dis Clin North Am 10 , Goodwin JS, Kellner R. Psychiatric symptoms in disliked 1994;20:129–58. medical patients. JAMA 1979;241:1117–20. 7 Karassa FB, Ioannidis JP, Boki KA, Touloumi G, Argyropoulou MI, 11 MacNeil A, Grennan DM, Ward D, Dick WC. Psychiatric problems in Strigaris KA, et al. Predictors of clinical outcome and radiologic systemic lupus erythematosus. Br J Psychiatry 1976;128:442–5. progression in patients with neuropsychiatric manifestations of systemic 12 Sterling G, West MD. Neuropsychiatric lupus. Rheum Dis Clin North Am lupus erythematosus. Am J Med 2000;109:628–34. 1994;20:129–56.

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Suicide attempts in patients with systemic lupus erythematosus

F B Karassa, M Magliano and D A Isenberg

Ann Rheum Dis 2003 62: 58-60 doi: 10.1136/ard.62.1.58

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Topic Articles on similar topics can be found in the following collections Collections Connective tissue disease (3176 articles) Immunology (including allergy) (3756 articles) Systemic lupus erythematosus (446 articles)

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° See FDA’s website (www.fda.gov/ tigate and, when warranted, take steps ucts on the market to identify those weightlossfraud) to help recognize to have the product removed from the that contain potentially harmful hid- fraudulent weight-loss products market. However, it is much easier for den ingredients. Consumers must also and claims. a firm to get a product on the market be aware of these dangerous products than it is for FDA to take a product off and learn how to identify and avoid If you suspect a dietary supplement the market. them using the warning signs described sold online may be illegal, FDA urges FDA has worked with industry to above. you to report that information online recall numerous products with poten- (www.fda.gov/Safety/ReportaProblem/ tially harmful ingredients including ucm059315.htm). In addition, you or • more than 40 products marketed for Find this and other Consumer your health care professional can also weight loss Updates at www.fda.gov/ report an illness or injury you believe to • more than 70 products marketed for ForConsumers/ConsumerUpdates be related to the use of a dietary supple- sexual enhancement ment by phone at 1-800-FDA-1088 or • more than 80 products marketed for Sign up for free e-mail online (www.fda.gov/Safety/ReportaProb- body building subscriptions at www.fda.gov/ lem/ucm053074.htm). consumer/consumerenews.html FDA last alerted the public to tainted Dietary Supplements and FDA products in December 2010, and will Dietary supplements, in general, are continue to issue consumer alerts and not FDA-approved. Under the law press announcements about these prod- (Dietary Supplement Health and Edu- ucts. The agency has issued warning let- cation Act of 1994), dietary supple- ters, seized products, and conducted ment firms do not need FDA approval criminal prosecutions. In December prior to marketing their products. It is 2010, a woman pleaded guilty to an the company’s responsibility to make 18-count indictment charging her with sure its products are safe and that any the illegal importation and distribu- claims are true. tion of more than four million diet pills Just because you see a supplement that contained a controlled substance, product on a store shelf does NOT unapproved drugs, and a possible can- mean it is safe or effective. When safety cer-causing agent. issues are suspected, FDA must inves- Remember, FDA cannot test all prod-

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ARTHRITIS & RHEUMATISM Vol. 46, No. 11, November 2002, pp 2924–2927 DOI 10.1002/art.10615 © 2002, American College of Rheumatology

Dehydroepiandrosterone Treatment of Women With Mild-to-Moderate Systemic Lupus Erythematosus

A Multicenter Randomized, Double-Blind, Placebo-Controlled Trial

Deh-Ming Chang,1 Joung-Liang Lan,2 Hsiao-Yi Lin,3 and Shue-Fen Luo4

-Objective. To evaluate the efficacy and tolerability cant between the two groups (DHEA ؊5.5 versus pla The number of patients with .(0.005 ؍ of dehydroepiandrosterone (DHEA) at a dosage of 200 cebo 5.4; P mg/day in adult women with active systemic lupus serious adverse events, most of which were related to erythematosus (SLE). SLE flare, was significantly lower in DHEA-treated ؍ Methods. In a multicenter randomized, double- patients compared with placebo-treated patients (P blind, placebo-controlled trial, 120 adult women with 0.010). Expected hormonal effects, including increased or levels and increased incidence of acne, were (61 ؍ active SLE received oral DHEA (200 mg/day; n for 24 weeks. The primary end point observed. No life-threatening reactions or serious safety (59 ؍ placebo (n was the mean change from baseline in the Systemic issues were identified during this study. Lupus Activity Measure (SLAM) score at 24 weeks of Conclusion. The overall results confirm that therapy. Secondary end points included time to first DHEA treatment was well-tolerated, significantly re- flare, change in SLE Disease Activity Index (SLEDAI) duced the number of SLE flares, and improved patient’s score, and physician’s and patient’s global assessment global assessment of disease activity. scores at week 24. Results. The two groups were well balanced for Systemic lupus erythematosus (SLE) is a multi- baseline characteristics. Mean reductions in SLAM system autoimmune inflammatory disease with diverse scores from baseline were similar and were not statisti- clinical and laboratory manifestations and with a vari- cally significantly different between treatment groups able course and prognosis. Although the etiology of SLE ؎ ؎ ؊ ؎ ؊ (DHEA 2.6 3.4 versus placebo 2.0 3.8, mean is unknown, hormonal influences may play a key role in SD). The number of patients with flares was decreased disease development and progression. by 16% in the DHEA group (18.3% of DHEA-treated The adrenal dehydroepiandrosterone ؍ patients versus 33.9% of placebo-treated patients; P (DHEA) is secreted primarily as its sulfated metabolite 0.044, based on time to first flare). The mean change in DHEAS. Although the biologic function of DHEA in the patient’s global assessment was statistically signifi- humans has not been ascertained, it has mild intrinsic androgenic properties, and in peripheral tissues, both Supported in part by Genelabs Biotechnology Company, Ltd., and by a grant from the National Science Council (NSC90-2314-B- DHEA and DHEAS can be converted to various other 016-069). as well as aromatized to estrogenic steroids 1Deh-Ming Chang, MD: Tri-Service General Hospital, Na- (1). The potential for using DHEA in the treatment of tional Defense Medical Center, Taipei, Taiwan, Republic of China; 2Joung-Liang Lan, MD: Veteran’s General Hospital, Taichung, Tai- SLE was suggested by such observations as the female wan, Republic of China; 3Hsiao-Yi Lin, MD: Veteran’s General predominance of SLE, the low circulating levels of Hospital, Taipei, Taiwan, Republic of China; 4Shue-Fen Luo, MD: DHEA and DHEAS in patients with active disease (2), Chang-Gung Memorial Hospital, Taipei, Taiwan, Republic of China. Address correspondence and reprint requests to Deh-Ming the immunomodulatory effects of DHEA (3), and the Chang, MD, Deputy Director, Tri-Service General Hospital, 325 delayed onset of and reduced mortality from SLE in Cheng-Kung Road, Section 2, Neihu 114, Taipei, Taiwan, Republic of NZB ϫ NZW mice that were fed DHEA (4). China. E-mail: [email protected]. Submitted for publication February 6, 2002; accepted in The present study was designed to evaluate the revised form July 26, 2002. safety and efficacy of DHEA treatment in female pa-

2924 DHEA TREATMENT IN WOMEN WITH SLE 2925

tients with mild-to-moderate SLE disease activity. Our Table 1. Efficacy variables in the study patients, by treatment group* findings are presented herein. DHEA-treated Placebo-treated patients patients (n ϭ 61) (n ϭ 59) P† PATIENTS AND METHODS SLAM score Study design. This study was a randomized, double- Baseline 10.3 Ϯ 2.8 10.4 Ϯ 2.6 blind, placebo-controlled trial conducted at 4 medical centers Mean change Ϫ2.6 Ϯ 3.4 Ϫ2.0 Ϯ 3.8 0.355 in Taiwan using the same protocol. Adult Chinese women with SLEDAI score Baseline 8.2 Ϯ 4.9 6.6 Ϯ 3.4 SLE according to the American College of Rheumatology Mean change Ϫ1.2 Ϯ 5.4 Ϫ1.4 Ϯ 4.6 0.742 criteria (5) who were receiving a dosage of 0–10 mg/day of Patient’s VAS score prednisone (or its equivalent) at study entry were enrolled. Baseline 37.0 Ϯ 18.8 33.7 Ϯ 17.9 Patients had active SLE, which was originally defined as a Mean change Ϫ5.5 Ϯ 20.0 5.4 Ϯ 26.6 0.005 Systemic Lupus Activity Measure (SLAM) score Ն7 (6). This Physician’s VAS score Ϯ Ϯ was subsequently amended to also require a baseline SLE Baseline 31.0 11.3 31.4 14.0 Mean change Ϫ9.2 Ϯ 13.9 Ϫ6.3 Ϯ 16.9 0.104 Disease Activity Index (SLEDAI) score Ͼ2 (7). In patients treated with hydroxychloroquine, azathioprine, methotrexate, * Values are the mean Ϯ SD baseline scores and the mean Ϯ SD or cyclophosphamide, either alone or in combination, the change in scores at the last visit in the intent-to-treat population. DHEA ϭ dehydroepiandrosterone; SLAM ϭ Systemic Lupus Activity regimen had to have been stable, with no changes in the dosage ϭ or drug combination, for at least 6 weeks prior to study entry. Measure; SLEDAI Systemic Lupus Erythematosus Disease Activity Index; VAS ϭ visual analog scale. This regimen was to remain unchanged throughout the study. † P values were determined by analysis of variance, with treatment, Patients who were receiving androgens, immunoglobulins, center, and treatment by center interaction as factors. cyclosporin A, or immunosuppressive agents other than those noted above were excluded. After a 10-day screening and qualifying baseline pe- riod, patients were assigned by predetermined randomization code to receive DHEA at a dosage of 200 mg/day or placebo RESULTS for 24 weeks. Scheduled evaluations at baseline and at weeks 4, 12, and 24 included a physical examination, routine laboratory Characteristics of the study patients. A total of determinations, the SLAM score, and patient’s and physician’s 120 patients were randomized into the study and re- global assessments (using a 100-mm visual analog scale ceived treatment as follows: 61 patients received DHEA [VAS]). The SLEDAI score was measured at baseline and at 200 mg/day and 59 patients received placebo. The two weeks 12 and 24 only. Serum levels of sex hormones and treatment groups were well balanced with regard to DHEAS were measured at baseline and at the last visit. baseline characteristics. The patients were of similar age The protocol was approved by the Institutional Review Board at each center. All patients gave their written informed and menopause status, and their prednisone dosage/use, consent. use of cytotoxic agents, use of antimalarials, and scores Efficacy end point. The primary end point was the on the SLE activity instruments were similar at baseline. mean change in the SLAM score at 24 weeks of therapy Patients were evaluated for 24 weeks or until compared with baseline. Secondary end points included SLE early termination of the study drug. Fifty-eight patients flare, change in SLEDAI score, and physician’s and patient’s in the DHEA group (95.1%) and 55 patients in the VAS scores at 24 weeks. Our definition of disease flare was similar to that of the ongoing SELENA (Safety of in placebo group (93.2%) completed the study. The mean Lupus Erythematosus: National Assessment) study (8), except duration of exposure was approximately the same in that we included an increase in dosage of Ն2.5 both treatment groups (164 Ϯ 26.6 days in DHEA group mg for at least 7 days for SLE-related reasons as a component. and 163.7 Ϯ 23.5 in placebo group; P ϭ 0.986); the Safety variables. Adverse events were coded according median duration of exposure was identical (169.0 days). to the COSTART system. The variables were summarized by Efficacy of DHEA. The primary end point was the treatment group and body system. Laboratory measurements. Laboratory assessments in- change in SLAM scores from baseline. No significant cluded a urinalysis, a Westergren erythrocyte sedimentation difference in SLAM scores between the two treatment rate (ESR), and routine serum biochemistries. Anti–double- groups was detected (P ϭ 0.355) (Table 1). As shown in stranded DNA (anti-dsDNA) antibody, C3 and C4 comple- Table 2 and Figure 1, significantly fewer patients in the ␤ ment, serum 17 -, total testosterone, and DHEAS DHEA group had disease flares. levels were also measured. The DHEA group showed significantly greater Statistical analysis. All statistical tests were 2-sided and evaluated at the 0.05 level of significance. Continuous improvement in patient’s VAS scores compared with the variables were analyzed using an analysis of variance model. placebo group. Patient’s VAS scores decreased by 5.5 Categorical variables were analyzed using chi-square test. from a baseline score of 37.0 in the DHEA group and 2926 CHANG ET AL

Table 2. Frequency of disease flares in the study patients, by treat- appeared to be well matched at baseline. There were no ment group* overall trends in the results of hematologic, biochemical, DHEA-treated Placebo-treated or lipid tests that would be suggestive of an adverse patients patients effect of DHEA treatment. Levels of triglycerides de- ϭ ϭ (n 60) (n 59) creased in the DHEA group compared with the placebo First disease flare group (P Ͻ 0.05). No. of patients 11 20 Estradiol levels decreased in both groups. The % of patients 18.3 33.9 median decrease was slightly larger for the DHEA group * There was a statistically significant difference between groups for the (39.3 pg/ml versus 31.5 pg/ml in the placebo group). time to first disease flare (P ϭ 0.044). DHEA ϭ dehydroepiandros- terone. Mean and median testosterone levels increased in the DHEA group and decreased in the placebo group (46.6 and 39.5 pg/ml versus Ϫ6.6 and Ϫ6.5 pg/ml, respectively; increased by 5.4 from a baseline score of 33.7 in the P Ͻ 0.05). placebo group (P ϭ 0.005) (Table 1). The mean and median levels of C3 and C4 serum Safety of DHEA. DHEA was well tolerated in complement decreased in patients in the DHEA group, these study patients. Expected androgenic effects, in- whereas a small increase or no change was noted in cluding increased testosterone levels and increased inci- patients in the placebo group (P Ͻ 0.05). Anti-dsDNA dence of acne, were observed. No life-threatening reac- antibody titers decreased in both treatment groups, but tions or serious safety issues were identified during this the mean and median decreases were greater in the study. placebo group. In both treatment groups, the majority of Adverse events. Adverse events that were as- patients had abnormally high anti-dsDNA titers at the sessed by the investigators as being serious were re- baseline visit and at the final visit. The ESR was ported in a significantly higher proportion of patients in comparable in the two treatment groups at baseline. the placebo group than in the DHEA group. One or Small decreases in the median ESR values at each visit more serious adverse events were reported for 7 of 61 were observed in both treatment groups. patients treated with DHEA (11.5%) and for 18 of 59 Most patients in both treatment groups had patients treated with placebo (30.5%); the difference DHEAS levels of 0–200 ␮g/dl at baseline. At the assess- was statistically significant (P ϭ 0.010 by chi-square ments after baseline, ϳ60% of patients in the DHEA test). In most cases, the types of serious adverse events group had DHEAS levels Ͼ1,000 ␮g/dl. The levels in the reported were consistent with SLE flares or hospitaliza- remaining patients were distributed over each of the tion for manifestations of SLE, rather than being ad- lower 200-␮g/dl incremental ranges. There was no evi- verse effects of the study drug. dence of elevated DHEAS levels in the placebo group at Findings of clinical laboratory evaluations. For baseline or at subsequent visits. all standard laboratory tests of safety, the two groups DISCUSSION In this double-blind study evaluating the efficacy and safety of DHEA for the treatment of mild-to- moderate SLE in women, we found significant reduc- tions in the time to disease flare and serious lupus- related adverse events, as well as improvement in patient’s global assessment in the DHEA-treated group compared with the placebo-treated group. This is of particular interest since almost all patients were already receiving treatment with standard medications, includ- ing and other immunosuppressive agents. While the planned primary analysis, change in SLAM score from baseline to last visit, did not demon- Figure 1. Time to first flare in Chinese women with mild-to-moderate strate significant differences between the two treatment systemic lupus erythematosus treated with dehydroepiandrosterone groups, it is important to recognize that this study was of (DHEA) versus placebo (P ϭ 0.044). relatively short duration (6 months), and there are as yet DHEA TREATMENT IN WOMEN WITH SLE 2927

no fully validated end points for therapeutic interven- ACKNOWLEDGEMENT tions in lupus trials. Given the multiple end points of this We deeply appreciate Dr. Peter H. Schur for his advice study, its findings should be confirmed in a trial of longer and revision of the manuscript. duration. Multiple mechanisms could be mediating these effects, including favorable changes in inflammatory REFERENCES cytokines such as interleukin-6 (IL-6), which is increased 1. Schmidt M, Kreutz M, Loffler G, Scholmerich J, Straub RH. in patients with active SLE (9). DHEA has been re- Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages. J Endocrinol 2000;164:161–9. ported to reduce the release of IL-6 from human 2. Lahita RG, Bradlow HL, Ginzler E, Pang S, New M. Low plasma mononuclear cells in vitro (3,10). Decreases in comple- androgens in women with systemic lupus erythematosus. Arthritis ment levels without SLE flare during DHEA treatment Rheum 1987;30:241–8. were observed in this study as well as in two other 3. Straub RH, Scholmerich J, Zietz B. Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory clinical studies (11,12). A presumed reduction in IL-6 diseases: substitutes of adrenal and sex hormones. Z Rheumatol production during DHEA administration might be asso- 2000;59 Suppl 2:II/108–18. ciated with a reduction in the levels of C3, which is an 4. Lucas JA, Ahmed SA, Casey ML, MacDonald PC. Prevention of autoantibody formation and prolonged survival in New Zealand acute-phase reactant (13). black/New Zealand white F1 mice fed dehydroisoandrosterone. DHEA was well tolerated by the patients in this J Clin Invest 1985;75:2091–93. study, with no evidence of unexpected or serious adverse 5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic effects of the drug. Most of the serious adverse events lupus erythematosus. Arthritis Rheum 1982;25:1271–7. reported in this study appeared to be related to SLE 6. Liang MH, Socher SA, Larson MG, Schur PH. Reliability and flares or to hospitalization for manifestations of SLE, validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989;32: rather than to adverse study drug effects. The propor- 1107–18. tion of patients experiencing serious adverse events was 7. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang DH, statistically significantly higher in the placebo group. and the Committee on Prognosis Studies in SLE. Derivation of the SLEDAI: a disease activity index for lupus patients. Arthritis This finding is consistent with the reduction in SLE Rheum 1992;35:630–40. flares observed in the efficacy analysis of this study. 8. Petri M, Buyon J, Kim M. Classification and definition of major A double-blind study conducted at Stanford Uni- flares in SLE clinical trials. Lupus 1999;8:685–91. 9. Linker-Israeli M, Deans RJ, Wallace DJ, Prehn J, Ozeri-Chen T, versity suggested that DHEA at a dosage of 200 mg/day Klinenberg JR. Elevated levels of endogenous IL-6 in systemic was well tolerated and may have steroid-sparing effects lupus erythematosus: a putative role in pathogenesis. J Immunol and reduce the number of flares in patients with mild- 1991;147:117–23. 10. Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich to-moderate SLE (14). Furthermore, in two subsequent J, et al. Serum dehydroepiandrosterone (DHEA) and DHEA multicenter studies, DHEA treatment at a dosage of 200 sulfate are negatively correlated with serum interleukin-6 (IL-6), mg/day allowed for a reduction in the prednisone dosage and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immu- to near-physiologic levels in a significantly greater pro- nosenescence. J Clin Endocrinol Metab 1998;83:2012–17. portion of patients than did placebo (11), and it stabi- 11. Petri MA, Lahita RG, Van Vollenhoven RF, Merrill JT, Schiff M, lized or improved the SLE activity and its symptoms and Ginzler EM, et al. Effects of on require- ments of women with systemic lupus erythematosus: a double- prevented bone loss (12). blind, randomized, placebo-controlled trial. Arthritis Rheum 2002; In summary, in this 24-week study of adult Chi- 46:1820–9. nese women with mild-to-moderate SLE, treatment with 12. Mease PJ, Merrill JT, Lahita RG, Petri MA, Ginzler EM, Katz RS, et al. GL701 (prasterone, dehydroepiandrosterone) improves sys- DHEA at a dosage of 200 mg once a day resulted in a temic lupus erythematosus [abstract]. Arthritis Rheum 2000;43 stabilization of the overall lupus activity, with fewer Suppl 9:S271. flares and fewer hospitalizations and without serious or 13. Zhao YX, Andoh A, Shimada M, Takaya H, Hata K, Fujiyama Y, et al. Secretion of complement components of the alternative unexpected adverse effects. Concurrent use of DHEA pathway (C3 and factor B) by the human alveolar type II epithelial will offer meaningful benefit, especially for steroid- cell line A549. Int J Mol Med 2000;5:415–9. dependent lupus patients. Confirmation in a larger study 14. Van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepi- in systemic lupus erythematosus: results of a double- of longer duration will be necessary to further define the blind, placebo-controlled, randomized clinical trial. Arthritis role of DHEA in SLE. Rheum 1995;38:1826–31. ARTHRITIS & RHEUMATISM Vol. 50, No. 9, September 2004, pp 2858–2868 DOI 10.1002/art.20427 © 2004, American College of Rheumatology

Effects of Prasterone on Disease Activity and Symptoms in Women With Active Systemic Lupus Erythematosus

Results of a Multicenter Randomized, Double-Blind, Placebo-Controlled Trial

Michelle A. Petri,1 Philip J. Mease,2 Joan T. Merrill,3 Robert G. Lahita,4 Mark J. Iannini,5 David E. Yocum,6 Ellen M. Ginzler,7 Robert S. Katz,8 Oscar S. Gluck,† Mark C. Genovese,9 Ronald Van Vollenhoven,10 Kenneth C. Kalunian,11 Susan Manzi,12 Maria W. Greenwald,13 Jill P. Buyon,14 Nancy J. Olsen,15 Michael H. Schiff,16 Arthur F. Kavanaugh,11 Jacques R. Caldwell,17 Rosalind Ramsey-Goldman,18 E. William St.Clair,19 Allan L. Goldman,20 Rita M. Egan,21 Richard P. Polisson,22 Kevin G. Moder,23 Naomi F. Rothfield,24 Robert T. Spencer,25 Kathryn Hobbs,16 Barri J. Fessler,26 Leonard H. Calabrese,27 Larry W. Moreland,26 Stanley B. Cohen,28 Betty J. Quarles,29 Vibeke Strand,9 Marc Gurwith,29 and Kenneth E. Schwartz29

Objective. To determine whether prasterone ad- systemic lupus erythematosus (SLE) disease activity ministration results in improvement or stabilization of and its symptoms. Methods. Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treat- Presented in part at the 64th Annual Scientific Meeting of the American College of Rheumatology, Philadelphia, PA, November ments or with placebo plus standard SLE treatments for 2000, and at the Annual Meeting of the British Society for Rheuma- up to 12 months in this randomized, double-blind tology, Manchester, UK, April 2003. investigation conducted at 27 centers. Standard SLE Supported by Genelabs Technologies, Inc., Redwood City, CA. < 1Michelle A. Petri, MD, MPH: Johns Hopkins University treatments included prednisone ( 10 mg/day), antima- Medical Center, Baltimore, Maryland; 2Philip J. Mease, MD: Seattle larials, and immunosuppressive agents; dosages were Rheumatology Associates, Seattle, Washington; 3Joan T. Merrill, MD: required to be stable for >6 weeks prior to enrollment Oklahoma Medical Research Foundation, Oklahoma City; 4Robert G. Lahita, MD, PhD: Liberty Health, Jersey City, New Jersey; 5Mark J. and remain unchanged during protocol treatment. Re- Iannini, MD, MPH: Carondelet Medical Group, Tucson, Arizona; 6David E. Yocum, MD: University of Arizona Health Sciences Center, Kentucky; 22Richard P. Polisson, MD, MHS: Massachusetts General Tucson; 7Ellen M. Ginzler, MD, MPH: SUNY Health Science Center Hospital, Boston; 23Kevin G. Moder, MD: Mayo Clinic Foundation, at Brooklyn, Brooklyn, New York; 8Robert S. Katz, MD: Rheumatol- Rochester, Minnesota; 24Naomi F. Rothfield, MD: University of ogy Associates, Chicago, Illinois; 9Mark C. Genovese, MD, Vibeke Connecticut Medical Center, Farmington; 25Robert T. Spencer, MD: Strand, MD: Stanford University School of Medicine, Stanford, Cali- Colorado Arthritis Center, Englewood; 26Barri J. Fessler, MD, Larry fornia; 10Ronald Van Vollenhoven, MD, PhD: Karolinska Hospital, W. Moreland, MD: University of Alabama School of Medicine at Stockholm, Sweden; 11Kenneth C. Kalunian, MD, Arthur F. Ka- Birmingham; 27Leonard H. Calabrese, DO: Cleveland Clinic Founda- vanaugh, MD: University of California, San Diego School of Medicine, tion, Cleveland, Ohio; 28Stanley B. Cohen, MD: St. Paul Medical San Diego; 12Susan Manzi, MD, MPH: University of Pittsburgh School Center, Dallas, Texas; 29Betty J. Quarles, BS, Marc Gurwith, MD, JD of Medicine, Pittsburgh, Pennsylvania; 13Maria W. Greenwald, MD: (current address: Vaxgen, Inc., San Bruno, California), Kenneth E. Advances in Medicine, Rancho Mirage, California; 14Jill P. Buyon, Schwartz, MD: Genelabs Technologies, Inc., Redwood City, California. MD: New York University School of Medicine, New York; 15Nancy J. †Dr. Gluck is deceased. Olsen, MD: Vanderbilt University School of Medicine, Nashville, Drs. Petri, Kalunian, Ramsey-Goldman, and Strand have Tennessee; 16Michael H. Schiff, MD, Kathryn Hobbs, MD: Denver served as consultants to Genelabs Technologies, Inc. Arthritis Clinic, Denver, Colorado; 17Jacques R. Caldwell, MD: Hali- Address correspondence and reprint requests to Michelle A. fax Clinical Research Institute, Daytona Beach, Florida; 18Rosalind Petri, MD, MPH, Professor of Medicine, Division of Rheumatology, Ramsey-Goldman, MD, DrPH: Northwestern University Feinberg Department of Medicine, Johns Hopkins University Medical Center, School of Medicine, Chicago, Illinois; 19E. William St.Clair, MD: Duke 1830 East Monument Street, Suite 7500, Baltimore, MD 21205. University Medical Center, Durham, North Carolina; 20Allan L. E-mail: [email protected]. Goldman, MD: Rheumatic Disease Center, Milwaukee, Wisconsin; Submitted for publication August 15, 2003; accepted in 21Rita M. Egan, MD: Arthritis Center of Lexington, Lexington, revised form April 29, 2004.

2858 PRASTERONE TREATMENT IN SLE 2859

sponders were patients who experienced no clinical DHEA has an immunomodulatory role, including up- deterioration and had improvement or stabilization regulation of interleukin-2 (IL-2) and down-regulation over the duration of the study in 2 disease activity of IL-6 expression (9,15–17), both of which have been measures (the SLE Disease Activity Index [SLEDAI] reported to be abnormal in SLE (18–20). and the Systemic Lupus Activity Measure) and 2 quality Prasterone is the United States Adopted Names of life measures (patient’s global assessment and the generic designation for dehydroepiandrosterone. In Krupp Fatigue Severity Scale). open-label and placebo-controlled studies, Van Vollen- Results. A total of 381 women with SLE were hoven et al (21,22) reported that SLE patients receiving enrolled. Among patients with clinically active disease oral prasterone 200 mg/day had improvement in a at baseline (SLEDAI score >2), 86 of 147 in the number of outcome variables, including reduction of prasterone group (58.5%) demonstrated improvement steroid dosages, the number of disease flares, and global or stabilization without clinical deterioration, as com- assessments of disease activity (21,22). In an initial phase II/III trial comparing placebo with 100 and 200 ؍ pared with 65 of 146 in the placebo group (44.5%) (P 0.017). Acne and hirsutism were reported in 33% and mg/day of prasterone, it was demonstrated that 200 16%, respectively, of the prasterone group and in 14% mg/day of prasterone allowed a sustained reduction in and 2%, respectively, of the placebo group (P < 0.05 for the glucocorticoid dosage (23). In addition, delay in time both comparisons). However, most cases of acne and to SLE flare has been reported for women treated with hirsutism were mild and did not require withdrawal prasterone (24). from therapy. Myalgias and oral stomatitis were re- The present study was conducted to determine ported less frequently in the prasterone group (22% and whether prasterone administration results in improve- 15%, respectively) than in the placebo group (36% and ment or stabilization in SLE disease activity and its 23%, respectively) (P < 0.05 for both comparisons). symptoms. Serum levels of high-density lipoprotein , triglycerides, and C3 complement significantly de- creased, while levels of testosterone and, to a lesser PATIENTS AND METHODS extent, estradiol increased in the prasterone group. Study participants. This prospective randomized, Conclusion. In adult women with active SLE, double-blind, placebo-controlled trial conducted at 27 study administration of prasterone at a dosage of 200 mg/day sites evaluated female patients with active SLE. Patients were required to meet the American College of Rheumatology 1982 improved or stabilized signs and symptoms of disease criteria for a diagnosis of SLE (25) and have active disease, as and was generally well tolerated. determined by 2 disease activity indices. Initially, active disease was defined as a Systemic Lupus Activity Measure (SLAM) Systemic lupus erythematosus (SLE) is a chronic, score Ն7 at baseline (26). While the study was ongoing and potentially fatal autoimmune disease that occurs 9 times blinded, this was amended to also require a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score Ͼ2at more frequently in women than in men (1). Although baseline (27). Eligibility was determined at screening and the multifactorial etiology of this disease is poorly qualifying visits, which occurred no more than 10 days apart. understood, abnormalities of both and andro- Patients in both treatment groups were allowed to gen metabolism in SLE patients have been reported continue taking standard SLE medications. Baseline medica- Յ (2,3). tions that were allowed included oral glucocorticoids ( 10 mg/day of prednisone or equivalent), hydroxychloroquine, Dehydroepiandrosterone (DHEA) is a naturally and/or immunosuppressive agents, including methotrexate, occurring steroid produced by the adrenal glands. It is azathioprine, cyclophosphamide, and mycophenolate mofetil. secreted primarily as its metabolite, DHEA sulfate Interventions. Patients were assigned by predeter- (DHEAS), which is the most abundant circulating adre- mined randomization codes to receive either prasterone 200 nal steroid in humans (4). Both DHEA and DHEAS are mg/day or placebo as once-daily morning doses for up to 52 weeks. Capsules containing placebo were identical to those subsequently converted into androgenic and estrogenic containing prasterone. Physicians and patients were instructed steroids in peripheral tissues (5,6). Decreases of ϳ50% to maintain the dosages of prednisone and other baseline SLE in circulating levels of DHEA and DHEAS have been medications at the baseline dosages during protocol participa- observed in patients with SLE (7,8). Previous studies in tion. animal models of SLE have demonstrated improvement Outcomes. The primary end point was the proportion of patients who were “responders.” Responders were patients with administration, including DHEA (9–14). who showed improvement or stabilization in SLE disease In addition to serving as a precursor for other andro- activity and constitutional symptoms without clinical deterio- genic and estrogenic steroids (5), there is evidence that ration over the duration of the study. 2860 PETRI ET AL

Responder status was designed prospectively, in con- Cardiovascular conditions were pericarditis that was refractory junction with lupus experts and with significant input by the US to treatment for Ͼ3 months or that required pericardiectomy, Food and Drug Administration, to be a single composite end cardiomyopathy that was refractory to therapy for Ͼ3 months point that integrated 3 domains of SLE: disease activity, organ with hemodynamic compromise (decreased cardiac index, left damage, and health-related quality of life (28). Responders ventricular ejection fraction, and/or dyspnea at rest), or refrac- were those who demonstrated improvement or stabilization in tory arrhythmia. Gastrointestinal conditions were ischemic mean on-treatment scores for 2 disease activity measures (the bowel disease that required bowel resection. Vasculitic condi- SLEDAI and the SLAM) and 2 health-related quality of life tions were vasculitis that resulted in infarction (excluding assessments (patient’s global assessment and the Krupp Fa- vasculitis described under any other organ systems). Hemato- tigue Severity Score [KFSS]) (29) without evidence of clinical logic conditions were thrombocytopenia that resulted in clini- deterioration (reflecting organ damage). A patient was cally significant hemorrhage with sequelae that did not resolve deemed to have improved or stabilized in terms of each of the for at least 3 months or persistent leukopenia (white blood cell disease activity and health-related quality of life measures if count Ͻ1,500/mm3) that resulted in recurrent infections with- the time-weighted mean of all on-treatment visit measure- out improvement in the incidence of recurrent infections for at ments for each of the instruments for that patient was less than least 3 months. the mean of 2 pretreatment values for each of the 4 para- The following qualified as unacceptable increases in meters. “No change” was defined prospectively, while the immunosuppressive or cytotoxic therapy for lupus: any SLE- study was ongoing and blinded. The definition of “no change” related increase in dosages of concomitant methotrexate or allowed for test–retest variability in these scoring instruments, azathioprine, or institution of new therapy with cytotoxic or which was defined as Ϯ0.5 for the SLEDAI and KFSS, Ϯ1.0 immunosuppressive agents (methotrexate, azathioprine, cyclo- for the SLAM, and Ϯ10 mm for the patient’s global assessment phosphamide, or cyclosporine), at any time during treatment (30,31). with the study drug or within 6 weeks after discontinuation of The clinical deterioration component of the responder study drug; and except for stress doses, prescribed prednisone end point was prospectively defined to include serious drug dosage increase to Ͼ10 mg/day over the baseline dosage within toxicity attributable to the study drug or other lupus therapy if the first 2 months of participation or, through the remainder of it occurred during treatment with the study drug or within 6 the study, prednisone dosage increase to Ͼ5 mg/day over the weeks after discontinuation of the study drug, serious new or daily baseline dose for Ͼ2 consecutive months. progressive lupus-related conditions, or requirement for in- Secondary analyses. Prospectively defined secondary creased dosage or institution of new therapy with immunosup- analyses included time to lupus flare and mean changes in pressive or cytotoxic agents for treatment of lupus. The individual scores on the SLEDAI, SLAM, KFSS, and patient’s occurrence of clinical deterioration and its onset date was global assessment instruments. Time to lupus flare was not part determined by Genelabs’ study monitors before the blinding of the initial protocol design. However, given the interest in was broken. lupus flares as a potential study outcome for future lupus The following conditions qualified as serious drug protocols, it was proposed as a secondary outcome in this toxicity: new-onset diabetes mellitus, defined as diabetes requir- study. ing drug therapy for Ն 3 months; new gastric or duodenal ulcer Time to first lupus flare was analyzed from data not due to Helicobacter pylori and requiring hospitalization or derived from chart reviews of all enrolled patients and was transfusion; new-onset hypertension requiring drug therapy for determined while the study was ongoing and blinded. SLE Ն3 months; new myocardial infarction, as demonstrated by flare was defined according to the following 5 criteria: 1) new electrocardiographic or enzymatic criteria; new steroid myop- or worse central nervous system lupus, vasculitis, or myositis athy; new elevation in serum transaminase levels (increases in requiring scoring on the SLEDAI and not present at a previous aspartate aminotransferase or alanine aminotransferase levels visit; 2) thrombocytopenia (Ͻ60,000 platelets/mm3), a hemo- to Ն8 times the upper limit of normal or a single measurement globin value Ͻ7 gm/dl, or a decrease in the hemoglobin level of showing levels Ն3 times the upper limit of normal at multiple at least 3 gm/dl; 3) proteinuria with pyuria and/or hematuria measurements over 3 months); or new fracture and/or verte- treated with new use or increased dosage of glucocorticoids or bral collapse due to osteoporosis. immunosuppressive agents; 4) an increase in the glucocorticoid The following conditions qualified as major new or dose of Ն2.5 mg for at least 7 days for SLE-related reasons; or progressive organ disease. These conditions were assessed by 5) new use or increase in dosage of immunosuppressive agents the treating physician as being attributable to lupus or its or antimalarials for at least 7 days for SLE-related reasons or treatment and which occurred during treatment with the study hospitalization for new manifestation of SLE. drug or within 6 weeks after discontinuation of the study drug. Procedures. Scheduled evaluations at baseline and Central nervous system conditions were cerebrovascular acci- every 3 months included physical examinations, laboratory dent transverse myelitis, retinal vascular occlusion, new onset determinations, and scoring of the SLAM, the SLEDAI, of psychosis of Ͼ3 months’ duration, or new onset of seizures patient’s and physician’s global assessments using 100-mm that were refractory to therapy for at least 3 months. Renal visual analog scales (VAS), and the KFSS. conditions were new onset of end-stage renal disease or loss of Laboratory assessments were performed every 3 renal function that required dialysis for at least 3 months. months. Blood samples were drawn after an 8-hour fast but Pulmonary conditions were new or worsened pulmonary hy- were not timed to prasterone administration. Assessments pertension and/or interstitial lung disease with reduction in included anti–double-stranded DNA (anti-dsDNA) antibod- diffusion capacity, mean pulmonary artery pressure, and/or ies, C3 and C4 levels, IgG and IgM anticardiolipin antibodies, dyspnea at rest (New York Heart Association class IV). serum lipid levels (total cholesterol, HDL-cholesterol, calcu- PRASTERONE TREATMENT IN SLE 2861

Table 1. Baseline characteristics of the study patients, by treatment group* Intent-to-treat analysis group Active SLE group (all randomized patients) (baseline SLEDAI Ͼ2)

Placebo Prasterone Placebo Prasterone (n ϭ 192) (n ϭ 189) (n ϭ 146) (n ϭ 147) Age, mean years 43.8 44.4 43.6 43.8 Caucasian, % 71.4 77.2 67.8 74.8 Postmenopause, % 47.9 43.9 46.6 42.9 Prednisone dose, mean (median) mg/day 3.7 (2.5) 3.5 (3.8) 4.1 (5.0) 3.6 (5.0) Medication use, % Prednisone 53.7 54.5 58.2 56.5 Immunosuppressives 15.1 18.0 17.8 21.1 Antimalarials 60.9 54.0 59.6 48.3 Prednisone, immunosuppressives, or 79.7 82.0 80.8 79.6 antimalarials Composite responder index components, mean (median) score SLEDAI 5.8 (5.0) 6.5 (6.0) 7.34 (6.0) 8.04 (8.0) SLAM 12.0 (12.0) 12.2 (12.0) 12.46 (12.0) 12.69 (12.5) Patient’s global assessment 55.4 (57.0) 55.2 (57.0) 55.17 (56.7) 57.08 (58.5) KFSS 5.6 (5.7) 5.5 (5.9) 5.56 (5.7) 5.61 (5.9) Laboratory values, mean (median) [no. tested] DHEAS, ␮g/dl 103 (50) [n ϭ 163] 107 (61) [n ϭ 165] 91 (47) [n ϭ 121] 105 (61) [n ϭ 127] C3 complement, mg/dl 102.9 (102.0) [n ϭ 192] 104.3 (100.0) [n ϭ 187] 99.3 (97.0) [n ϭ 146] 99.1 (97.0) [n ϭ 146] C4 complement, mg/dl 17.9 (16.0) [n ϭ 192] 18.2 (17.0) [n ϭ 187] 17.0 (15.0) [n ϭ 146] 17.2 (15.0) [n ϭ 146] Anti-dsDNA antibody, IU/dl 23.45 (1.95) [n ϭ 192] 36.08 (2.6) [n ϭ 187] 29.4 (2.4) [n ϭ 146] 43.5 (3.4) [n ϭ 146] * Baseline values for some of the clinical laboratory tests were not obtained on all patients. SLE ϭ systemic lupus erythematosus; SLEDAI ϭ Systemic Lupus Erythematosus Disease Activity Index; SLAM ϭ Systemic Lupus Activity Measure; KFSS ϭ Krupp Fatigue Severity Scale; DHEAS ϭ dehydroepiandrosterone sulfate; anti-dsDNA ϭ anti–double-stranded DNA. lated LDL-cholesterol, and total triglycerides), serum chemis- there could be no a priori estimation of responder rates. tries, complete blood cell counts, urinalyses, and 24-hour urine Hence, the sample size of 300 randomized patients was based collections for creatinine clearance and protein quantitations. on practical, rather than statistical, calculations. Serum levels of 17␤-estradiol, testosterone, and DHEAS were The original protocol entry criterion required a SLAM measured at baseline and the last visit. To avoid unblinding, score of Ն7 for the definition of active disease. There was no these results were not reported to the investigators or study restriction on the SLEDAI score for patient entry. While the monitors until completion of the trial. All blood and urine double-blind study was ongoing, the protocol was subsequently assays were conducted at a central laboratory (Covance Lab- amended to incorporate a baseline SLEDAI score of Ͼ2asan oratories, Indianapolis, IN), with the exception of DHEAS additional entry requirement. This requirement was based levels, which were performed by radioimmunoassay at upon the outcome of an earlier Genelabs study, which revealed Genelabs Technologies. that SLE patients with little or no disease activity (SLEDAI The protocol was conducted in accordance with the Յ2) are likely to exhibit a high response regardless of treat- Declaration of Helsinki and was approved by the institutional ment (23). review board at each center. All patients gave written informed All randomized patients were included in the intent- consent. to-treat analysis of safety (n ϭ 381). All patients who met Statistical analysis. Given that this protocol utilized a criteria for active disease (SLEDAI Ͼ2) at both the baseline responder end point that had never been used in a clinical trial, and screening visits were included in the analysis of efficacy (n ϭ 293). Patients without postbaseline assessments were designated, by default, as nonresponders. Table 2. Number (percentage) of patients completing the study and The primary efficacy variable, proportion of respond- reasons for early withdrawal ers, was analyzed using a logistic regression model using Placebo Prasterone treatment as a factor. For secondary analyses, between- (n ϭ 192) (n ϭ 189) treatment comparisons of mean changes in disease activity indices (the SLEDAI and the SLAM), patient’s global assess- Completed study drug 142 (74.0) 124 (65.6) ment, and the KFSS, and laboratory values were analyzed Discontinued study drug early 50 (26.0) 65 (34.4) utilizing one-way analysis of variance, with treatment as a Lack of efficacy 9 (4.7) 11 (5.8) factor. Between-treatment comparisons for the number of Adverse event 11 (5.7) 27 (14.3) patients with specific adverse events or clinically important Other 30 (15.6) 27 (14.3) treatment-associated changes in laboratory values were per- 2862 PETRI ET AL

Table 3. Percentages of responders and patients with at least 1 definite SLE flare* Patients with at least 1 SLE flare‡

Responders† P

Placebo Prasterone P Placebo Prasterone SLE flare Time to first flare Patients with active SLE 44.5 (65/146) 58.5 (86/147) 0.017 34.2 (50/146) 24.5 (36/147) 0.097 0.066 All patients 42.2 (81/192) 51.3 (97/189) 0.074 29.7 (57/192) 23.8 (45/189) 0.266 0.195 * Active SLE was defined as a baseline SLEDAI score Ͼ2. Approximately 80% of patients in both treatment groups were receiving antimalarials, glucocorticoids, or other immunosuppressive agents at baseline. P values for the responders and for SLE flare were determined by logistic regression analysis using treatment as a factor. P values for time to first SLE flare were determined by log-rank test. Values are the percentage (number responding/number in group or the number with at least 1 SLE flare/number in group). See Table 1 for definitions. † A patient was classified as a responder if no clinical deterioration was observed and if the weighted average of measures of disease activity and health-related quality of life improved or did not deteriorate during treatment relative to baseline values (weighted average increase from baseline for the SLAM Յ1, for the SLEDAI Յ0.5, for the KFSS Յ0.5, and for the patient’s global assessment Յ10). ‡ An SLE flare was defined according to the following 5 criteria: 1) new or worse central nervous system lupus, vasculitis, or myositis requiring scoring on the SLEDAI and not present at a previous visit; 2) thrombocytopenia (Ͻ60,000 platelets/mm3), a hemoglobin value Ͻ7 gm/dl, or a decrease in the hemoglobin level of at least 3 gm/dl; 3) proteinuria with pyuria and/or hematuria treated with new use or increased dosage of glucocorticoids or immunosuppressive agents; 4) an increase in the glucocorticoid dose of Ն2.5 mg for at least 7 days for SLE-related reasons; or 5) new use or increase in dosage of immunosuppressives or antimalarials for at least 7 days for SLE-related reasons or hospitalization for new manifestation of SLE. formed using chi-square test or Fisher’s exact test. All statis- Primary outcome measure, responder analysis. P tical tests were 2-sided, and values less than or equal to 0.05 The overall responder rates among the intent-to-treat were considered significant. group were 42.2% (81 of 192 patients) in the placebo group and 51.3% (97 of 189 patients) in the prasterone RESULTS group (P ϭ 0.074) (Table 3). In the population with Ͼ Characteristics of the study patients. The trial active disease (SLEDAI 2), 44.5% (65 of 146 patients) was conducted at 27 office- or university-based rheuma- in the placebo group and 58.5% (86 of 147 patients) in P ϭ tology practices in the US, from February 1996 to June the prasterone group were responders ( 0.017). In a 1999. Three hundred eighty-one patients were random- post hoc analysis, significant differences between treat- ized to receive treatment: 189 in the prasterone group ment groups persisted with increasing SLEDAI scores and 198 in the placebo group. Treatment groups were (Figure 1). well balanced at baseline with regard to age, menopause Secondary outcome measures, time to SLE flare status, race, concomitant SLE medications, SLE scores, and mean changes in individual scoring instruments. DHEAS levels, and other important laboratory values. Among patients with active disease at baseline, fewer Approximately 80% of patients in both groups were patients in the prasterone treatment group experienced receiving standard SLE treatments at baseline, which a first flare during the study (24.5% taking prasterone included antimalarials, glucocorticoids, and/or other im- versus 34.2% taking placebo, P ϭ 0.066), and a trend for munosuppressive agents. There were no statistically prolongation in time to flare was seen among patients significant between-group differences in baseline char- who received prasterone (P ϭ 0.097) (Table 3). acteristics for either the all-patient intent-to-treat ana- There were no statistically significant between- lysis or the predefined patient group with active SLE group differences in change from baseline in any of the (baseline SLEDAI Ͼ2) (Table 1). individual components of the responder index (data not Seventy-four percent of the placebo group and shown), but statistically significant differences in individ- 65.6% of the prasterone group completed 1 year of ual components of the responder analysis resulted in treatment (Table 2). There were no meaningful differ- patients being classified as nonresponders (Table 4), ences in withdrawals across the 2 groups, except for suggesting a worsening of individual components of the withdrawals due to adverse events, for which 5.7% in the composite responder index in more of the placebo- placebo group and 14.3% in the prasterone group treated patients than prasterone-treated patients. The withdrew (P ϭ 0.005). The differences in withdrawals greatest differences between the prasterone and placebo primarily reflected androgenic adverse events in the treatment groups were defined by the proportion of prasterone group, the majority of which were mild, since patients reporting a worsening in the patient’s global there were no differences in the patterns of withdrawals assessment (10.9% of the prasterone group versus 22.6% for other types of adverse events. of the placebo group, P ϭ 0.007) and in the SLEDAI PRASTERONE TREATMENT IN SLE 2863

treated patients and 50 (26%) of the 192 placebo-treated patients (P ϭ 0.076). Early discontinuations were similar between treatment groups, with the exception of an increased number in the prasterone group withdrawing due to reported androgenic adverse events. Eleven patients (5.8%) with acne and/or hirsutism indicated these events as reasons for treatment discontinuation in the prasterone treatment group. Serious adverse events were reported in 14% (27 of 189 patients) in the prasterone group and 17% (33 of 192 patients) in the patients in placebo treatment groups, respectively. Fourteen of these events in the prasterone group and 16 in the placebo group resulted in treatment discontinuation. While there were no deaths in the prasterone treatment group, there were 5 deaths during or shortly after completion of treatment in the Figure 1. Percentage of responders to treatment with prasterone or placebo, by baseline Systemic Lupus Erythematosus Disease Activity placebo group, including 2 suicides, 1 death due to Index (SLEDAI) score. Values within the bars are the number pulmonary hypertension, 1 sudden death, and 1 death responding/number in group. from non-Hodgkin’s lymphoma 6 weeks following pro- tocol completion. Three patients were diagnosed as having cancer during the study, all of whom were in the scores (only 9.5% of the prasterone group versus 17.8% placebo group: the patient with non-Hodgkin’s lym- of the placebo group, P ϭ 0.039 (Table 4). phoma noted previously, 1 patient with carcinoma of the Although not defined in the specified analysis breast, and 1 patient with carcinoma of the lung. plan, it was of interest to assess responders among the Adverse events reported in 10% or more of the patients who were not receiving antimalarials, glucocor- active and control treatment populations are shown in ticoids, or other immunosuppressive agents at baseline Table 5. Androgenic adverse events, including acne and (ϳ20% of patients), given the high rate of background hirsutism, were more commonly reported in patients medication use in both treatment groups. Among pa- receiving prasterone (42%) than in patients receiving tients not receiving these medications at baseline and placebo (18%) (P Ͻ 0.05). Most androgenic complaints who had active disease at study entry (i.e., baseline were characterized as mild or moderate; none was SLEDAI Ͼ2), responder rates were 42.9% (12 of 28 severe. patients) in the placebo group and 70.0% (21 of 30 Adverse events such as myalgias, stomatitis (oral patients) in the prasterone group (P ϭ 0.037). ulcers), alopecia, and fever were reported less frequently Adverse events. Study drug administration was in patients receiving prasterone in comparison to pla- discontinued early in 65 (34%) of the 189 prasterone- cebo (Table 5). These differences were statistically sig-

Table 4. Patients with a baseline SLEDAI Ͼ2 who failed to meet individual response criteria, by treatment group* No. (%) of No. (%) of placebo group prasterone group Criterion (n ϭ 146) (n ϭ 147) P Clinical deterioration 13 (8.9) 15 (10.2) 0.705 Worsening of composite responder index component scores SLEDAI score 26 (17.8) 14 (9.5) 0.039 SLAM score 15 (10.3) 10 (6.8) 0.288 Patient’s global assessment score 33 (22.6) 16 (10.9) 0.007 KFSS score 21 (14.4) 16 (10.9) 0.367 * Patients could have failed to meet Ͼ1 criterion. Approximately 80% of patients in both treatment groups were receiving antimalarials, glucocorticoids, or other immunosuppressive agents at baseline. P values were determined by chi-square test. See Table 1 for definitions. 2864 PETRI ET AL

nificant for myalgias and oral ulcers, suggesting potential beneficial effects of prasterone treatment on some of the typical signs and symptoms of SLE. Treatment-associated changes in laboratory val- ues. Total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total triglyceride levels decreased in the prasterone treatment group, although decreases in LDL cholesterol were minimal (Figure 2). Treatment-associated de- creases in total cholesterol and HDL cholesterol were significantly greater in the prasterone group compared with the placebo group. Serum triglycerides were also statistically significantly decreased in the prasterone Figure 2. Mean baseline concentrations of lipids and mean change in group compared with the placebo group, in which they lipid levels from baseline to the last visit during treatment. Values above the x-axis represent the placebo group on the left and the ϭ P Ͻ 0.05 for within-treatment ء .were increased. Reductions in serum HDL cholesterol, prasterone group on the right total cholesterol, and triglyceride levels were evident in change from baseline. Tot-C ϭ total cholesterol; HDL-C ϭ high- the prasterone treatment group by month 3, and the density lipoprotein cholesterol; LDL-C ϭ low-density lipoprotein reductions were maintained with subsequent study drug cholesterol; Tot-TG ϭ total triglycerides. administration (data not shown). HDL cholesterol levels decreased from normal levels at baseline in 133 and 148 patients in the prasterone and placebo groups, respec- values compared with –2% in the placebo group (P ϭ tively, to below 40 mg/dl (the currently recommended 0.015). This decline was not associated with renal dete- lower limit for HDL cholesterol [32]) at the end of rioration or with institution of new immunosuppressive treatment in 38 patients receiving prasterone (26.6%) treatment. There were minor decreases in C4 comple- compared with 15 patients receiving placebo (10.1%) ment levels in both treatment groups, but the differences (P ϭ 0.001 by chi-square test). between groups were not significant. Mean Ϯ SD Mean serum levels of C3 complement declined in changes in anti-dsDNA levels from the baseline visit to the prasterone treatment group: –7% from baseline the last visit were 5.8 Ϯ 145.6 IU/ml (median 0.0) in the placebo group and 20.0 Ϯ 130.0 IU/ml (median 0.0) in the prasterone group; the differences between treatment Table 5. Adverse events reported by Ն10% of patients in either groups were not statistically significant. treatment group* Treatment-associated changes in levels. As expected, serum DHEAS values increased to No. (%) of No. (%) of placebo group prasterone group pharmacologic levels in the prasterone treatment group. Adverse event (n ϭ 192) (n ϭ 189) The mean DHEAS concentrations at the last visit were 811 ␮g/dl (median 607) in the prasterone treatment Rash 62 (32.3) 75 (39.7) Arthralgia 71 (37.0) 68 (36.0) group. These levels were unchanged in the placebo Acne 27 (14.1) 63 (33.3)† treatment group 120 ␮g/dl (median 50). Asthenia 51 (26.6) 45 (23.8) Serum testosterone levels increased in Arthritis 42 (21.9) 45 (23.8) Headache 56 (29.2) 42 (22.2) prasterone-treated patients, especially among those who Myalgia 69 (35.9) 42 (22.2)† were postmenopausal (Table 6). In contrast, treatment- Flu syndrome 42 (21.9) 39 (20.6) associated changes in estrogenic hormones were less Hirsutism 3 (1.6) 31 (16.4)† Stomatitis (mucosal ulcers) 44 (22.9) 28 (14.8)† consistent. In premenopausal women, no meaningful Depression 30 (15.6) 28 (14.8) changes in serum estradiol were evident in either the Alopecia 39 (20.3) 28 (14.8) prasterone-treated patients or the placebo-treated pa- Abdominal pain 30 (15.6) 27 (14.3) Fever 28 (14.6) 22 (11.6) tients (Table 6). Changes in estradiol levels in postmeno- Peripheral vascular disease 20 (10.4) 19 (10.1) pausal women were analyzed according to the presence Sinusitis 20 (10.4) 17 (9.0) or absence of hormone replacement therapy (HRT). Chest pain 20 (10.4) 14 (7.4) Patients reported by investigators to be postmenopausal * Approximately 80% of the patients in both treatment groups were but with baseline estradiol levels Ն20 pg/ml were ex- receiving antimalarials, glucocorticoids, or other immunosuppressive agents at baseline. cluded from this analysis as being perimenopausal. † P Ͻ 0.05 by chi-square test. Mean serum estradiol levels increased in postmeno- PRASTERONE TREATMENT IN SLE 2865

Table 6. Change in testosterone and estradiol levels, by menopause status* P

Change from Treatment Baseline Last visit Change baseline comparison Testosterone, mean (median) ng/dl Premenopausal patients Placebo (n ϭ 63) 20.5 (16.0) 19.3 (16.0) Ϫ1.2 (Ϫ2.0) 0.5541 0.0001 Prasterone (n ϭ 71) 23.8 (19.0) 58.9 (56.0) 35.0 (32.0) 0.0001 Postmenopausal patients Placebo (n ϭ 68) 20.4 (17.0) 18.2 (12.5) Ϫ2.1 (0.0) 0.1648 0.0001 Prasterone (n ϭ 52) 17.9 (12.5) 74.8 (54.0) 57.0 (41.5) 0.0001 Estradiol, mean (median), pg/ml Premenopausal patients Placebo (n ϭ 63) 97.8 (74.2) 88.9 (62.8) Ϫ8.9 (0.3) 0.5098 0.5884 Prasterone (n ϭ 71) 85.6 (63.9) 86.5 (65.2) 1.0 (1.5) 0.9367 Postmenopausal patients (no HRT)† Placebo (n ϭ 14) 2.5 (1.4) 2.3 (1.4) Ϫ0.1 (0.0) 0.8127 0.0003 Prasterone (n ϭ 18) 3.7 (1.9) 24.8 (22.2) 21.1 (19.4) 0.0003 Postmenopausal patients taking HRT Placebo (n ϭ 35) 104.4 (64.7) 82.4 (66.5) Ϫ22.0 (1.7) 0.2950 0.0210 Prasterone (n ϭ 30) 85.6 (79.4) 128.1 (105.1) 42.4 (34.1) 0.0170 * Not all patients had measurements of estradiol or testosterone levels at both baseline and the end of treatment. Therefore, the total number of patients does not equal the total number randomized. † At baseline, estradiol levels were Ͻ20 pg/ml, and the patients were not taking hormone replacement therapy (HRT). pausal patients receiving prasterone and HRT; however, had to have stable disease activity at baseline, without the cotreatment with HRT makes the interpretation of recent changes in cotreatments, including glucocorti- these findings difficult. In postmenopausal patients who coids, antimalarials, and immunosuppressives. Cotreat- were not receiving HRT, prasterone led to increases in ments with these drugs were required to be held at a serum estradiol levels that were similar to the levels fixed dosage for the duration of the study The high previously reported with low-dose HRT (33). There response rate (45%) in the placebo treatment group were no correlations between changes in sex hormone should be interpreted in the context that this was not a levels and responder outcomes (data not shown). true placebo-controlled trial, since most patients were cotreated with standard SLE therapies during the study. DISCUSSION Thus, the statistically significant improvement in the prasterone group (59% taking prasterone versus 45% In this double-blind, randomized, placebo- taking placebo were responders) is both statistically and controlled trial of prasterone treatment at 200 mg/day clinically meaningful. for up to 52 weeks, we found significant improvements in the patients taking prasterone. Significantly more pa- Deterioration in the mean postbaseline measures tients in the prasterone group than in the placebo group in any 1 of the scoring instruments relative to baseline or experienced either improvement or stabilization of dis- clinical deterioration caused a patient to be designated ease activity (P ϭ 0.017). as a “nonresponder.” Significantly more patients in the Given the complexity of SLE, it was important to placebo group as compared with the prasterone group assess the disease in its entirety, and this study was the failed to achieve responder status based on the SLEDAI first of its kind to utilize an innovative composite end or patient’s global assessment values. The latter is point that was designed to integrate all 3 SLE domains— particularly noteworthy, in that significant differences in disease activity, organ damage, and health-related qual- patient’s global assessments, in favor of prasterone, have ity of life—into an overall “responder” end point. Pa- also been reported in 2 other studies comparing praster- tients categorized as “responders” had to exhibit one with placebo (22,24). simultaneous improvement or stabilization in each of 2 As noted above, the protocol was amended to disease activity measures (SLEDAI and SLAM) and 2 incorporate baseline SLEDAI scores of Ͼ2 as an addi- quality of life measures (KFSS and patient’s global tional patient entry requirement while the double-blind assessment), without clinical deterioration. study was ongoing. This requirement was based upon the To qualify for enrollment in this study, patients outcome of an earlier Genelabs study, which revealed 2866 PETRI ET AL

that patients with little or no disease activity (SLEDAI no worsening in others, is also a successful outcome for Յ2) are not the most appropriate candidates for clinical lupus patients. study, since patients with little or no disease activity are Additionally, there were trends toward a lower likely to exhibit high response rates (23). The impor- number of patients with a first flare and a delay in time tance of requiring minimum disease activity as a crite- to disease flare among patients with active SLE who rion for enrollment into SLE clinical trials is consistent received treatment with prasterone. These findings are with the approach taken in other clinical trials of other qualitatively similar to those reported in a population of rheumatologic conditions. Taiwanese women with SLE, almost all of whom were Patients enrolled in this study represented a wide receiving cotreatment with glucocorticoids and/or immu- spectrum of SLE disease activity. The differences be- nosuppressives. In that study, there was a statistically tween treatment groups persisted with increasing base- significant delay in time to disease flare among patients line disease activity. This observation is similar to the treated with prasterone (24). findings in an earlier study assessing steroid-sparing Administration of prasterone appeared to be well properties of prasterone versus placebo, in which the tolerated in this randomized clinical trial. Reported greatest difference between placebo and prasterone adverse events were predictably related to known phar- treatment occurred in the groups with baseline SLEDAI macologic effects of androgenic steroids and were gen- scores Ͼ8 (23). The 2 instruments that provided the erally mild and primarily confined to acne and, to a greatest sensitivity to responder analysis appeared to be lesser extent, some hirsutism. the SLEDAI and the patient’s global assessment. While prasterone is a precursor of both andro- There were no significant differences between genic and estrogenic hormones, changes in estradiol treatment groups in the individual components of the levels in patients receiving prasterone were less consis- responder analysis, which may reflect the fact that most tent than changes in testosterone levels. In premeno- of the patients were receiving cotreatment with standard pausal patients, there were no differences in estradiol SLE therapies. Furthermore, only patients who had had levels between treatment groups. In postmenopausal stable disease and no change in treatments for at least 6 women receiving prasterone who were not also receiving weeks prior to entry into the study were eligible for HRT, there were modest increases in estradiol levels enrollment, and as such, the population we studied compared with placebo. During prasterone treatment, primarily comprised those with active, yet stable disease. mean estradiol concentrations were similar to the mean The responder analysis, however, required simultaneous serum estradiol concentrations observed during trans- stabilization or improvement across 4 variables (2 dis- dermal estradiol administration (33) and remained well ease activity measurement instruments, 2 health-related under the pretreatment baseline estradiol levels ob- quality of life measurements) and no clinical deteriora- served in SLE patients who were receiving HRT at tion, while holding cotreatments constant. It is in this baseline. Reported adverse events related to estrogenic composite end point that significant differences oc- effects, such as menometrorrhagia, thrombotic events, curred between treatment groups. or weight gain, were not increased in either premeno- The responder end point was designed to assess pausal or postmenopausal women receiving prasterone, simultaneous improvement or stabilization across all 3 suggesting that the biologic effects of prasterone are domains of lupus: disease activity, organ damage, and primarily androgenic rather than estrogenic. This is in health-related quality of life. As such, it was designed to contrast to postmenopausal women, in whom unop- assess a treatment effect on overall lupus disease. While posed estrogen therapy has been associated with a it would be desirable to determine how many patients menorrhagia rate as high as 66% (34). “improved” or how many “stabilized,” there is no estab- Clinical laboratory findings associated with pras- lished definition as to what constitutes improvement terone treatment in this randomized controlled trial also versus stabilization. Furthermore, due to the stringent reflected androgenic activity, including declines in HDL responder criteria in this trial, each of the scoring cholesterol and triglyceride levels. These findings have instruments and clinical deterioration was given equal also been observed in 2 other controlled studies with weight in the outcome. So, to improve in only some prasterone (23,24). scoring instruments while worsening in others would Reductions in triglyceride and HDL cholesterol deem a patient a “nonresponder.” Thus, we believe that levels with administration of androgenic hormones have overall stabilization, which is in fact reflective of a been reported to be a manifestation of increased hepatic combination of improvement in some instruments and lipase activity, which results in enhanced clearance of PRASTERONE TREATMENT IN SLE 2867

HDL particles (35–37). Thus, the decreases in HDL agents or large doses of glucocorticoids, which also do cholesterol and triglyceride levels may represent in- not necessarily provide the hoped-for efficacy and are creased reverse cholesterol transport (i.e., removal of associated with significant side effects. Prasterone could cholesterol from peripheral tissues via enhanced HDL bring benefits to patients who cannot or do not wish to clearance) rather than decreased production of HDL take additional therapies of immunosuppressive agents (38). However, since lupus is associated with increased or large doses of glucocorticoids. Prasterone is not cardiovascular morbidity and mortality (39) and since intended, however, to be a replacement for glucocorti- long-term studies will be needed to further characterize coids or immunosuppressive treatments that are needed these effects, it may be prudent to follow the National during acute flares of lupus. Cholesterol Education Program guidelines (32) while In summary, prasterone treatment improved or monitoring lipids in patients who are receiving praster- stabilized overall SLE disease activity in women with one. mild-to-moderate SLE. The most common adverse Although the mechanism that results in de- events associated with prasterone treatment were andro- creased serum levels of complement C3 levels is incom- genic in nature and included acne and hirsutism, which pletely defined, in vitro incubation of human peripheral were generally mild and treatable. blood mononuclear cells and bone marrow cells with DHEA has been demonstrated to reduce the production of IL-6 (16,17). Since IL-6 levels are elevated in active ACKNOWLEDGMENTS SLE (20,40) and can stimulate hepatic secretion of C3 as The authors greatly appreciate the advice of, and an acute-phase reactant (41), decreased levels of C3 careful study monitoring by, Karen Colbert and Bettina during prasterone treatment may reflect either a direct Sporkenbach. ACRO, Inc. (Morris Plains, NJ) were the statis- or an indirect effect on hepatic C3 production. De- tical consultants for the study. creased serum C3 complement levels were observed during administration of prasterone 200 mg/day to nor- REFERENCES mal premenopausal women who were participating in a 1. Wallace D. The clinical presentation of systemic lupus erythema- preclinical pharmacokinetic/pharmacodynamic study tosus. In: Wallace DJ, Hahn BH, Quismorio FP Jr, Klinenberg JR, (Genelabs, Inc.: unpublished observations), which is editors. Dubois’ lupus erythematosus. 5th ed. 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April 19th, 2001

NDA 21-239: GL701 for Systemic Lupus Erythematosus

Genelabs Technologies, Incorporated

5465.01 1 Presentation Outline Intoduction Marc Gurwith, MD, JD Vice President of Drug Development and Chief Medical Officer Genelabs Technologies, Inc.

Background Robert Lahita, MD, PhD Professor of Medicine New York Medical College

Efficacy Michelle Petri, MD, MPH Associate Professor of Medicine Johns Hopkins University School of Medicine

Statistical Frank Hurley, PhD Senior Scientist Quintiles

Safety Michelle Petri, MPH, MD

Clinical Perspective Murray Urowitz, MD, FRCPC Professor of Medicine University of Toronto 5466.02 2

Consultants

Allan Tall, MD Vibeke Strand, MD Professor of Medicine Clinical Professor of Medicine (VCF) Columbia University Stanford University

William Kramer, PhD Samuel S.C. Yen, MD, DSc President Professor of Reproductive Medicine Kramer Consulting LLC University of California at San Diego

Michael Madaio, MD Ronald F. van Vollenhoven, MD, PhD Professor of Medicine Associate Chief, Rheumatology University of Pennsylvania Karolinska Hospital

5467.03 3 GL701 (prasterone) • Prasterone is the USAN designation for DHEA • Prasterone is the synthetic equivalent of DHEA • GL701 is the Genelabs formulation of Prasterone O CH3

CH3

5468.01 HO 4 DHEA and SLE: Clinical Rationale • Sex distribution in SLE, 90% F : 10% M • Low levels of DHEA and other androgens in women with SLE 1-2 1. Lahita et al., 1987; 2. Verthelyi et al., 2001 • DHEA and testosterone further suppressed by corticosteroid use 3 3. Hedman et al., 1989 • IL-2 levels suppressed in SLE 4-5 œ In vitro (T lymphocytes) DHEA increased IL-2 production 6 • DHEA inhibits IL-6 secretion (mononuclear cells) 7 4. Alcocer-Varela and Alarcon-Segovia, 1982; 5. Linker-Israeli et al., 1983; 6. Suzuki et al., 1991; 7. Straub et al., 1998 5475.02 10 Study GL95-02 Baseline Endogenous DHEA-S and Testosterone Levels with and without Corticosteroid Treatment

Baseline DHEA-S Baseline Testosterone 200 30 180 25 160 ) l d / )

l 140 g

d 20 / n ( g 120 u e (

n o S 100 15 - r e A t E

80 s H o

10 t D 60 s e 40 T 5 20 0 0 No Prednisone Prednisone No Prednisone Prednisone N=145 N=183 N=172 N=202

5478.02 11 Safety

Michelle Petri, MD

5536.02 83 Presentation of Safety Data Safety Data Studies Deaths, SAE‘s, Pooled AE‘s and GL94-01 Withdrawals GL95-02 GL95-01*

Hormone Changes and Review of GL94-01 Reported Breast Cancers GL95-02 GL95-01

Changes in Laboratory Values GL94-01 GL95-02 GL95-01

*GL95-01: Open-label Safety Study with GL701 5537.02 84 Duration of Exposure to GL701

< 6 í 6 í 12 í 18 mos. mos. mos. mos. Number of female 641 387 242 138 patients/healthy volunteers

Duration of treatment by menopausal status: Number Pre-menopausal 229 150 86 Number Post-menopausal 158 92 52

5538.01 85 All Reported Deaths: GL701 Group (N = 495) Cause of Death Age On/off Study Respiratory failure 39 Off (14 wks.)

Pancreatitis 32 Off (9 mos.)

Cardiac arrest 46 Off (35 days)

SLE Complications 43 On Cerebrovascular complications 50 On

Respiratory insufficiency 67 Off (24 days) Metastatic carcinoid tumor 68 On recurrence Breast cancer 49 Off (15 mos.)

5554.01 86 All Reported Deaths: Placebo Patients who Never Received GL701 (N = 77) Cause of Death Age On/Off Study Pulmonary hypertension 35 On

Sudden death 65 On

Suicide 56 On

Suicide 47 On

Non-Hodgkin‘s lymphoma 47 Off (6 wks)

Respiratory failure 34 Off (2 mos)

5555.01 87 Breast Cancer Age 45 48 49 61 Treatment Placebo GL701 GL701 GL701 Duration of 0 362 days 730 days 455 days exposure

On/off study On study Off (15 mos.) Off (4 mos.) On study

Menopausal Pre Pre Pre Post status

HRT use No No No Yes

E/P Receptor Unknown œ / œ + / + œ / œ

Morphology Infiltrating Infiltrating Infiltrating Infiltrating lobular ductal ductal ductal

5548.02 97 Breast Cancer Incidence* Normalized for Period of Observation for all Patients and for those í 45 years of age

Treatment Cases/Pt-Years Cases/1000 Pt-Yrs

All Patients:

GL701 3/1573 1.9 Placebo 1/336 2.9

í 45 years:

GL701 3/206 4.6 Placebo 1/24 6.5

*Control rates (no HRT) reported as 3.9 per 1000 women years and unopposed estrogen use rates reported 4.4 per 1000 women years1 1. Schairer et al., 2000 5549.02 98 Implications: Effects on Hormones • Testosterone levels increased œ Androgenic effects observed were acne and hirsutism • Estradiol levels increased in post-menopausal women œ Increases consistent with those reported for hormone replacement therapy œ No increase in breast carcinoma œ one to two years observation œ No significant increase in vaginal bleeding œ No endometrial hyperplasia observed • Increased bone mineral density

5553.02 99 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

DATE: March 12, 2001

FROM: Claudia B. Karwoski, Pharm.D. Postmarketing Safety Evaluator Team Leader Division of Drug Risk Evaluation I, HFD-430

THROUGH: Julie Beitz, M.D., Director signed 3/13/01 Division of Drug Risk Evaluation I, HFD-430

TO: Jonca Bull, M.D. Acting Director Division of Antiinflammatory, Analgesic, and Ophthalmic Drug Products, HFD-550

SUBJECT: OPDRA Postmarketing Safety Review (PID 000665) Drug: Prasterone NDA 21-239 (Dehydroepiandrosterone-DHEA) Reaction: Summary of Spontaneous Postmarketing Case Reports

EXECUTIVE SUMMARY

This document provides an overview of postmarketing adverse events reported in association with the use of Dehydroepiandrosterone (DHEA). These cases were retrieved from the Adverse Event Reporting System (AERS), CFSAN’s postmarketing database, and the medical literature.

There were 65 postmarketing adverse event cases possibly associated with the use of DHEA. Other than the single report of worsening metastatic prostate cancer1 previously described in the review by Parivash Nourjah, Ph.D, entitled Epidemiologic evidence of DHEA in the etiology of neoplasia, there were no additional reports of neoplasia found in the any of the above databases or the medical literature.

Forty-two of the 65 cases fall into the following body systems: urologic/renal (5), reproductive/endocrine (5), cardiovascular (9), gastrointestinal (8), central nervous system (7), dermatological (7), and hematological (2). There were also five individuals with psychiatric adverse events and 17 cases with general symptoms or miscellaneous events that could not easily be categorized into a body system. Four of the 65 cases were published in the medical literature.1-4

Approximately 40% of the cases were concerning. The adverse events involving the urologic/renal, cardiovascular, and gastrointestinal body systems as well as the psychiatric adverse events were particularly concerning because they had the highest number of hospitalizations (> 50%). However, because the overall numbers of cases in each of these body systems were small and in many cases confounded by concomitant or co-suspect medication, we identified no clear safety signals with this product.

INTRODUCTION

Dehydroepiandrosterone (DHEA) is an endogenous hormone secreted by the adrenal cortex. It has been widely available in the US as a dietary supplement and promoted for its anti-aging effects as well as other uses. Prasterone (the pharmaceutical generic designation for DHEA) is currently under review in the Division of Anti-inflammatory, Analgesic, and Ophthalmic Drug Products (DAAODP), for the treatment of mild to moderate systemic lupus erythematosis (SLE) in women.

This serves as a companion document to the review by Parivash Nourjah, Ph.D, entitled Epidemiologic evidence of DHEA in the etiology of neoplasia which focused on a review of the literature for any published epidemiologic studies that examined cancer risk associated with exogenous DHEA administration. The primary objective in this review was to determine if there were any case reports in our postmarketing databases or the medical literature of neoplasia in association with the use of DHEA. Our secondary objective was to provide an overview of postmarketing adverse events reported in association with the use of DHEA

REVIEW OF SPONTANEOUS POSTMARKETING REPORTS

Selection of Cases

We searched AERS on February 13, 2001 for all reports with dehydroepiandrosterone and prasterone. We also requested a query of CFSAN’s adverse event reporting database for case reports with DHEA. Four additional case reports were found in the medical literature. All searches resulted in a total of 64 unique reports involving 68 consumers or patients. Three AERS reports were excluded because the drug products did not appear to contain DHEA. Below is an overall summary and summary by body system of the 65 cases.

Summary of Cases

Of the 65 cases identified in the AERS database, CFSAN ARMS database, and the medical literature, there was only one report of neoplasia1. This was summarized in Dr. Nourjah’s review and is described in the urologic/renal section below.

Forty-two of the 65 cases fall into the following body systems: urological/renal (5), reproductive/endocrine (5), cardiovascular (9), gastrointestinal (8), central nervous system (7), dermatological (7), and hematological (2). There were also five individuals with psychiatric adverse events and 17 cases with general symptoms or miscellaneous events that could not easily be categorized into a body system. Four of cases were published in the medical literature.

2 Approximately 40% of the cases were concerning. The adverse events involving the urologic/renal, cardiovascular, and gastrointestinal body systems as well as the psychiatric adverse events were particularly concerning because they had the highest number of hospitalizations (> 50%). The concerning cases are briefly summarized below but may be described in greater detail under the specific body system summaries.

· Urological/renal system -Literature case of worsening metastatic prostate cancer (1), increased symptoms of prostatism in patients with BPH (2), and renal failure (1). · Cardiovascular system - Literature case of cardiac arrhythmia with a positive rechallenge (1), other arrhythmia’s (4), MI (1), DVT (1), and hypertensive urgency (1). · Gastrointestinal system– liver failure (1) and hepatitis (3) · Psychiatric events – two patients with mania and one patient with psychosis required hospitalization.

The overall numbers of cases in each of these body systems were small and in many cases confounded by concomitant or co-suspect medication.

1. Urological and Renal Events

There are five cases involving the urologic or renal system. The cases involved all males. The patient’s ages were 5, 34, 68, and 71 years old (not reported-1). The events include resurgence of prostate carcinoma (1), worsening symptoms of prostatism (2), renal failure (1), and dysuria (1). The following additional information was noted in the cases.

DHEA daily dose: 25mg-2, 50mg-1, up to 700mg-1 (not reported-1) Time to onset: 2 to 180 days Outcome: Emergency room treatment/hospitalization-2, required intervention-3 Indications for use: Short stature-1 Increase muscle strength-1 Low hemoglobin (anemia)-1 Not reported-2 Dechallenge: Positive-3 Rechallenge: Positive-0 Event year: 1995-1, 1996-2, 1997-2 Reporter: Health care professional-3, Consumer-2

The literature case report (described in Dr. Nourjah’s review) involves a 68-year-old male with metastatic prostate cancer who was treated with escalating doses of DHEA (200 to 700mg per day) presumably for the treatment of anemia unresponsive to erythropoetin. His blood cells increased during DHEA eliminating his need for transfusions. However, the patient began to develop facial numbness, increase in prostate size, and difficulty voiding. His PSA levels increased to greater than 10,000 ng/mL (2726 ng/mL prior to DHEA). DHEA was discontinued and DES was initiated with improvement in symptoms and decrease in PSA. Although, he exhibited a positive

3 dechallenge after discontinuation of DHEA, his improvement may have been due to treatment with DES.1

There were two patients with a history of BPH who developed worsening symptoms. One case described increased symptoms of prostatism (not specified) after several months of DHEA. This patient was on Cardura and Dilacor at the time. The second case described difficulty urinating after taking DHEA for two weeks.

The renal failure case was reported by the patient’s mother and was not well described. She reported that her 34-year-old son took seven different dietary supplement products (including DHEA) for about one month and developed renal failure. He was hospitalized and partial renal function returned. No additional information was provided.

The last case involves a 5-year-old who started bedwetting (coded as dysuria) two days after taking DHEA 50mg per day for central core disease. He was taking many other concomitant dietary products including enzymes, vitamins and atomadine. All products were discontinued and his event abated.

2. Reproductive and Endocrine Events

There are five cases involving reproductive or endocrine events in patients ranging in age from 39 to 50 years old (mean-44.7, median-45). The cases involved three males and two females. The events include gynecomastia (1), resumption of menstruation (1), increased estrogen levels and hot flashes (1), hyperglycemia (1), and painful intercourse and hematuria (1). The following additional information was noted in the cases.

DHEA daily dose: 25mg – 3 (not reported-2) Time to onset: 7 days - 1, 30 days - 2, several months -1 (not reported-1) Outcome: No serious outcomes Indications for use: Menopausal symptoms-1 Immune system booster-1 Aging-1 Not reported-2 Dechallenge: Positive-4 Rechallenge: Positive-1 Event year: 1996-3, 1999-1 (not reported-1) Reporter: Health care professional-4, Consumer-1

None of the cases involved a serious outcome but four sought medical care from a physician. All cases are summarized below for your review. The first three were possibly related to the use of DHEA. Underlying disease and use of another product that was more temporally associated with the event confounded the last two cases.

AERS image # 1923242, CFSAN 11859, 1996 A 39-year-old male developed bilateral breast enlargement during use of DHEA 25mg per day for 1 to 1.5 months. They were described as very inflamed, bright red, and very

4 tender. He reported no relevant medical history or concomitant medications. The event reportedly abated after discontinuation of the DHEA.

AERS image # 2055734, CFSAN 12028, 1996 A 42-year-old female stated that she had not menstruated since February 1996. In December 1996, seven days after initiating DHEA 25mg per day, she started a full menstrual cycle.

AERS image # 2000126, 1997 A male consumer (age unknown) began using DHEA 10mg and then increased to 25mg after 2-3 weeks. Less than 1 month later, he experienced extreme pain during intercourse and observed large amounts of blood in both semen and urine. Urologists ruled out both cancer and STD as causes. He discontinued using the product and one week later his symptoms disappeared.

CFSAN 13543, 1999 A 48-year-old female complained of hot flashes. Was taking Rejuvex (for several months) and DHEA (duration unknown). She was status post hysterectomy with one ovary and was not receiving hormone replacement therapy. FSH, LH, and estradiol levels measured were measured and estradiol levels were noted to be markedly elevated 2777 pg/ml. Both products were discontinued for 2 months with levels normalizing (estradiol 54 pg/ml). Rejuvex was restarted and within two weeks the estradiol level was 498 pg/ml. Rejuvex contains several vitamins and ground up bovine endocrine organs.

AERS image # 1927333, CFSAN 12220, 1997 A 50-year-old Ethiopian male presented with fatigue, polyuria, and polydipsia and was found to have a blood sugar of 600. He was receiving DHEA 50mg per day for an unknown duration. His DHEA was discontinued and he was started on Glucotrol. With diet management and Glucotrol his blood glucose decreased to low normal and Glucotrol was discontinued. On follow up the reporter mentioned that the patient was subsequently diagnosed with late onset type I diabetes.

3. Cardiovascular Events

There are nine cases involving cardiovascular events in patients ranging in age from 23 to 72 years old (mean-44.7, median-45). The cases involved seven males and two females. The events include cardiac arrhythmias in five patients (unspecified-3, PVC’s-1, and SVT-1). The remaining four patients experienced chest pain and palpitations (1), myocardial infarction (1), deep vein thrombosis (1), and hypertensive urgency (1). The following additional information was noted in the cases.

DHEA dose: 25mg-3, 50mg-2, 100mg-1 (not reported-3) Time to onset: range of 1 to 120 days; mean-49, median 30 (not reported-2) Outcome: Death-1, hospitalization-3, emergency room-4, required intervention (unspecified)-1 Indications for use: Build muscle mass-1

5 Maintain general health-1 Treat decreased adrenal function expected with increased age-1 Not reported-6 Dechallenge: Positive-6 Rechallenge: Positive-1 Event year: 1996-1, 1997-4, 1998-2, 1999-1 (not reported-1) Reporter: Health care professional-8, Consumer-1

Possible cofounders were noted in three cases including the case resulting in death. The death involved a 37-year-old male who was found dead at home. The cause of death was not reported, however the medical examiner inquired whether any of eight dietary supplements could be responsible for a cardiac arrhythmia. One case involved a 72-year- old male who developed a DVT approximately one month after he initiated use of DHEA and DMSO. Both products were listed as suspect. Another case involved a 41-year-old male with a history of increased heart rate who was admitted to the ER for unspecified cardiac arrhythmia 2.5 months after starting DHEA and creatine. The remaining cases reported both a negative cardiac history and no concomitant medication (3) or they did not provide medical history information (3). Several interesting cases are summarized below for your review.

Literature Case Report, 1998 A 55-year-old male presented to an ER with palpitations two weeks after initiating DHEA 50mg. Benign premature atrial contractions (PAC) and some premature ventricular contractions (PVC) were noted. Work-up including thyroid-stimulating hormone levels, cardiac echocardiogram, potassium levels, and exercise stress test results were unremarkable. Past medical history was not provided other than his use of Redux for the previous 12 months, which had been discontinued two weeks before initiating DHEA. He was discharged on propranolol and continued use of DHEA for three months. Three to four months later, he reinitiated DHEA (presumably off beta-blocker) and within 36 hours arrhythmias recurred and PAC and PVC was noted on a Holter Monitor. The arrhythmias were controlled with atenolol and DHEA was discontinued.2

AERS Image # 3030083-5-00, direct report, 1997 A 45-year-old male was admitted for an acute MI that occurred during exercise. He received a thrombolytic agent with resolution. Cardiac catherization for recurrent pain showed “fairly normal coronary arteries with only mild irregularities with occluding thrombus in the right coronary artery”. His only reported cardiac risk factor was moderately elevated cholesterol. His cholesterol was 230, HDL 49, and LDL 160. Baseline values were not provided.

CFSAN # 12219, direct report, 1997 A 23-year-old male initiated use of DHEA to build up muscle tone. He was reported to have taken up to 20 tablets per day for 3 to 4 months. His mother (nurse) noticed that he had put on over 40 pounds of weight and decided to check his blood pressure, which was found to be in the range of 240/140. His blood pressure was confirmed in the ER. He was also noted to have elevated liver functions tests (LFT). . He was treated for hypertension.

6 Two weeks following discontinuation of DHEA his LFTs appeared to be returning to normal however his blood pressure remained labile.

4. Gastrointestinal System Events

There are eight cases involving gastrointestinal system adverse events in patients ranging in age from 21 to 63 years old (mean-41.6, median-43, not reported-3). The cases involved four males and four females. Serious events occurred in five individuals and include liver failure (1), hepatitis (3), abdominal pain requiring exploratory laparotomy, and possible GI bleed (1). Two patients experienced less severe reactions, which include unspecified stomach problems (1) and gas (1). The following additional information was noted in the cases.

DHEA daily dose: 25mg-1, 50mg-1, 200mg-1 (not reported-5) Time to onset: 14 days – 1, 60 days – 1, 11 months - 1 (not reported-5) Outcome: Hospitalization – 3 (not reported-5) Indications for use: SLE-1 Build muscle-1 Aging-2 Not reported-4 Dechallenge: Positive-3 Rechallenge: Positive-0 Event year: 1996-1, 1997-1, 1998-2 (not reported-4) Reporter: Health care professional-5, Consumer-3

There was one study report of a 36-year-old female with SLE who was hospitalized three times for recurrent abdominal pain. She had been enrolled in a clinical trial for SLE for ~10 months and was receiving DHEA 200mg/day. On her third admission she underwent exploratory laparotomy. The findings were not provided. The report mentioned that she had a history of previous abdominal surgery with possible adhesions.

There were three consumer reports. Two did not appear to be serious and only reported gas and “stomach problems. The third consumer claimed that she experienced vomiting with blood and blood per rectum for five days. She did not mention seeking medical treatment.

There were four liver related events. One physician reported two of the cases. He reported a 43-year-old female and a 45-year-old male who developed hepatitis while taking an unknown dose of DHEA. Neither of the reports were well documented other than stating that neither patient had a relevant medical history nor were they taking concomitant OTC medications. In both of the other two cases, concomitant medications might have played a role. These cases are described below for your review.

AERS image # 3193812-6-00 , 1998 A 21-year-old male experienced cold symptoms for 1-2 weeks and began taking acetaminophen 1-2 q4-6h prn (6-10gm). He was a wrestler and was taking DHEA 50mg

7 per day for approximately 2-3 months prior to the event. He had 8 beers/5 shots x 3 days w/APAP. Within two weeks he developed RUQ pain, dark urine, jaundice, and was admitted with hepatic failure. Underwent liver transplant. Although acetaminophen possibly in conjunction with alcohol are suspect, the role of DHEA cannot be dismissed.

CFSAN # 13200, 1998 A 63-year-old male was diagnosed with cholestatic hepatitis while taking an unknown dose of DHEA and Pantothenic Acid 8gm/day. This was discovered during blood donation. He presented with elevated ammonia, transaminases, bilirubin, and PT/INR. All viral hepatitis screening was negative. He was hospitalized for two days neurologically intact. No additional information was provided. The pantothenic dose was > 1000 times the recommended daily allowance for adults.

5. Central Nervous System Events

There are seven cases involving central nervous system events in patients ranging in age from 49 to 59 years old (mean-54.2, median-56, not reported-2). The cases involved four males and three females. Serious events occurred in three individuals and include transient ischemic attack (1), seizure (1), and sensory peripheral neuropathy (1). The remaining four patients experienced less severe reactions which include headaches (2), numbness (1), and sleepiness (1). The following additional information was noted in the cases.

DHEA dose: 25mg-3, 50mg-1, 100mg-1 (not reported-2) Time to onset: range of 3 to 90 days; mean-35, median-7 (not reported-2) Outcome: Hospitalization-1, disability-1, saw physician-3, (not reported-2) Indications for use: Maintain general health-1 Muscle pain-1 Entered study (Hormone Replacement Program)-1 Not reported-4 Dechallenge: Positive-3 Rechallenge: Positive-2 Event year: 1997-3, 1998-1, 1999-1, 2000-1 (not reported-1) Reporter: Health care professional-2, Consumer-5

The four cases involving headache, numbness, and sleepiness did not appear to be serious. In one case a mother reported an event (described in Psychiatric Adverse Event section of this document) in her son but also mentioned that she experienced migraine headaches while taking DHEA. One patient experienced numbness, coldness, and tingling of her face, scalp, and neck. Her neurological exam however was found to be normal.

There were three serious cases involving seizure, TIA, and Sensory Peripheral Polyneuropathy. The case involving seizure exhibited a positive rechallenge and did not appear to be confounded by past medical history or concomitant medication. Consumers reported two cases and in one case the event appeared to be more temporally related to

8 the concomitant use of another product. These cases are summarized below for your review.

AERS image # 20411530, CFSAN # 12603, 1997 A 51-year-old male reported having a TIA approximately two weeks after starting DHEA 25mg per day. He was diagnosed and hospitalized for three days. According to report, he underwent numerous tests which were negative (CT, MRI, ECG, and EEG)

CFSAN # 13160, 1998 A 56-year-old male had taken DHEA for three months and experienced two seizures during that time. He discontinued use for several months and then restarted and experienced a seizure after seven days. His past medical history and concomitant medications were not reported. An EEG, MRI and exam were found to be normal.

AERS image # 3551903-1-00, 2000 A 49-year-old male reported enrolling in a Hormone Replacement Program offered by the[ ]. As part of the program, he began taking DHEA 50mg per day, desiccated thyroid (Armour, 1gm per day), melatonin, B complex, testosterone cream, and human growth hormone (HGH) injections (4IU per week). After one month, he started to experience numbness in both feet. He discontinued use of the HGH for a few weeks and the problem disappeared. He restarted the injections and the numbness and pain came back. A second discontinuation did not result in resolution of his symptoms. He was diagnosed with Sensory Peripheral Polyneuropathy and reported that he was partially disabled (difficulty walking, pain interrupts sleep).

6. Dermatological Events

There are seven cases involving dermatological reactions in patients ranging in age from 29 to 83 years old (mean-58.2, median-62, not reported-1). The cases involved four males and three females. The events include rash in four patients (unspecified-3, macular erythematous eruption-1). The remaining three patients experienced alopecia (2), and acne with pustules (1). The following additional information was noted in the cases.

DHEA dose: 25mg-1, 50mg-3 (not reported-3) Time to onset: range of 4 to 55 days; mean-14.4, median 14 (not reported-2) Outcome: Required (unspecified) intervention-1, saw physician-1 (not reported-5) Indications for use: Aging-1 Hormone deficiency-1 Impotence-1 Not reported-4 Dechallenge: Positive-3 Rechallenge: Positive-0 Event year: 1995-1, 1997-3 (not reported-3) Reporter: Health care professional-4, Consumer-3

9 None of these cases reported a serious outcome as a result of the events. One case is summarized below for your review.

AERS image # 1933056, CFSAN # 12099, 1997 An 83-year-old male developed a macular erythematous eruption from the mid-thigh to his toes varying in diameter from 1mm to 1cm approximately seven weeks after starting DHEA. They were non-tender with no subcutaneous hemorrhage. The rest of the physical exam was normal. He was on concomitant Nicotine patches intermittently for 18 months. The rash reportedly began to fade after the DHEA was discontinued.

7. Hematological Events

There were two individuals that experienced hematological events. One case involves a 50-year-old male that presented with fever, cough, malaise, and aching approximately six weeks after starting DHEA 50mg per day. A complete blood count revealed a platelet count of 38K. DHEA was discontinued and a repeat CBC two and three weeks later was 69K and 122K, respectively. The patient did not appear to require hospitalization. He had a history of chronic low platelets secondary to a splenectomy. He also reported receiving a flu shot 1week prior to symptoms.

The second case involves a 46-year-old male who started taking DHEA 50mg BID on 4/14/99 and Celebrex 100mg BID on 4/26/99. On 5/3/99, he presented to his physician with bruising all over his chest, arms, and legs. He had not sustained any trauma. Celebrex was discontinued but it is unclear if DHEA was continued. No further information was provided.

8. Psychiatric Events

There are five individuals who experienced psychiatric events while receiving DHEA. Two of these cases were reported in the medical literature. The cases involved individuals ranging in age from 20 to 68 years old (mean 36.6, median-51). The cases involved three males and one female (not reported-1). The events include mania (2), manic depression (1), psychosis (1), and panic attacks (1). The following additional information was noted in the cases.

DHEA daily dose: 25mg-1, 50mg-1, 150mg-1, 200-300mg-1 (not reported-1) Time to onset: range of 40 to 120 days; (not reported-1) Outcome: Hospitalization-3 Indications for use: General health-1 Impotence-1 To increase energy-1 Not reported-2 Dechallenge: Positive-2 Event year: 1996-1, 1998-1, 1999-1 (not reported-2) Reporter: Health care professional-3, Consumer-2

10 All cases were confounded by either concomitant medication or other dietary products (3) and/or past psychiatric history (3). In one, the individual was taking five different dietary supplements including ephedrine and ephedra. A second was taking concomitant beef liver extract and a multivitamin. Another report listed Celexa as a co-suspect agent. Past psychiatry histories include history of panic attacks, history of manic depression, and history of daily alcohol consumption (possible alcoholism). Both literature reports is described below for your review.

Literature Case Report, 1999 A 68-year-old male with no documented psychiatric history was admitted to an inpatient psychiatric hospital after his family members noting increasingly odd behavior. Symptoms included agitation, delusional thinking, decreased sleep and appetite, and spending sprees which started approximately three months prior to admission. He had begun taking DHEA six months prior to admission at dose of 100mg daily. This dose was increased to 200-300mg per day. He had a history of daily alcohol use as much as one case of beer. On admission his use was said to be ~ two beers per day. Drug and urine screens were negative. He was treated with valproic acid and his symptoms improved. He was discharged seven days later.3

Literature Case Report, 1999 A 51-year-old male with no prior psychiatric history was involuntarily hospitalized because of grandiose delusions, expansive and irritable mood, and extreme psychomotor agitation. He had begun taking DHEA 50mg per day several months earlier to increase his energy level. He was also taking beef liver extract and a multivitamin. The severity of his psychosis necessitated the appointment of a temporary personal guardian. He was treated during his hospitalization with a combination of haloperidol and divaproex. He responded well and his symptoms disappeared after several weeks. 4

9. General Symptoms or Miscellaneous Adverse Events

There are 17 individuals who experienced general symptoms or miscellaneous events that could not easily be categorized into one organ system. The cases involved individuals ranging in age from 28 to 84 years old (mean-49.5, median-47, not reported-4). The cases involved nine males and six females (not reported-2). The following additional information was noted in the cases.

DHEA dose: 25mg-3, 35mg-1, 50mg-5, overdose-1 (not reported-7) Time to onset: range of 1 day to 1.5 years; mean-98, median 5 (not reported-4) Outcome: Hospitalization/ER-3, life-threatening-1, saw physician-3, required unspecified intervention-2 (not reported-8) Indications for use: Aging/to stay young-4 Maintain general health-2 Headache-1 Hormone supplement-1 Not reported-9 Dechallenge: Positive-12, negative-1

11 Rechallenge: Positive-1 Event year: 1996-4, 1997-6, 1998-1 (not reported-6) Reporter: Health care professional-10, Consumer-7

Overall most cases were not well documented. One interesting case involves a 41-year- old female who reports taking DHEA 25mg sublingually. After 2 weeks she developed a benign submandibular tumor. She stopped taking the product for 1 week and the tumor reduced in size. She took the product again orally and the tumor returned.

There were four patients that reported requiring hospitalization, emergency room treatment, and/or reported the event as life-threatening. One involved a female (who spoke little English) who may have taken an entire bottle of DHEA for a headache. She was hospitalized with a low-grade temperature and a low blood pressure (100/50). One patient reportedly developed an anaphylactic reaction after taking one dose of DHEA 50mg. She was given epinephrine and Benadryl with good results. An elderly male listed numerous subjective “serious” adverse events to a single dose of DHEA that he reported as life threatening and requiring hospitalization. His physician noted that he has a history of reporting drug reactions. The reactions include weakness, fatigue, ataxia, insomnia, decreased appetite, SOB, rapid heart rate, and sensation of doom. The last involves a 60- year-old male with severe HTN who became hypokalemic and syncopal after four days of DHEA. This was reported life threatening, however no additional information was provided.

The remaining cases listed numerous adverse events that in most cases did not appear to be serious and generally resulted only in discontinuation of DHEA and/or other products. These events include weakness, insomnia, headache, CP, indigestion, constipation, tremors, dizziness, fainting spells, depression, muscle cramps, nightmares, guilt feelings, shortness of breath, weight gain, swelling of neck, malaise, memory loss, arm numbness, venous distension, chest heaviness, tinnitus, possible drug interaction, feet tingling, tachycardia, and hyperactivity.

CONCLUSIONS

There were 65 postmarketing adverse event cases possibly associated with the use of DHEA. Other than the single report of worsening metastatic prostate cancer previously described in the review by Parivash Nourjah, Ph.D, entitled Epidemiologic evidence of DHEA in the etiology of neoplasia, there were no additional reports of neoplasia found in the any of the above databases or the medical literature.

Forty-two of the 65 cases fall into the following body systems: urologic/renal (5), reproductive/endocrine (5), cardiovascular (9), gastrointestinal (8), central nervous system (7), dermatological (7), and hematological (2). There were also five individuals with psychiatric adverse events and 17 cases with general symptoms or miscellaneous events that could not easily be categorized into a body system. Four cases were published in the medical literature.

12 Approximately 40% of the cases were concerning. The urologic/renal, cardiovascular, gastrointestinal, and psychiatric adverse events were particularly concerning because they had the highest number of hospitalizations (> 50%). However, because the overall numbers of cases in each of these body systems were small and in many cases confounded by concomitant or co-suspect medication, we identified no clear safety signals with this product.

REFERENCES

1. Jones J.A., Nguyen A., Straub M, Leidich R, Veech R.L., and Wolf S. Use of DHEA in patient with advanced prostate cancer: a case report and review. Urology 1997; 50:784-8. 2. Sahelian R, Borken S. Dehydroepiandrosterone and cardiac arrhythmia. Ann Intern Med 1998; 129(7): 588. 3. Markowitz JS, Carson WH, Jackson CW. Possible dihydroepiandrosterone- induced mania. Biol Psychiatry 1999; 45(2): 241-2. 4. Kline MD, Jaggers ED. Mania onset while using dehydroepiandrosterone. Am J Psychiatry 1999; 156(6): 971.

Signed _3/12/01______Claudia B. Karwoski, Pharm.D.

13

Scientific Verdict Still Out on DHEA

PERHAPS NO drug better illustrates search are being used deceptively to sell cal College of Virginia, Richmond, told the problem with the US Dietary Supple- DHEA to the public, he says. For ex¬ how DHEA for many years had the repu¬ ment Health and Education Act of 1994 ample, the Web page on the Internet for tation of a "snake oil" because of the than does the adrenal hormone dehy-$ Life Plus Vitamins promotes its own brand overzealous way some scientists had droepiandrosterone (DHEA). of DHEA with the following claim: "Dr. been promoting it. Although mounting evidence suggests A. Schwartz, a researcher at Temple Uni¬ "One can almost hear the hucksters that DHEA may have a broad range of versity, has now proven beyond question, calling out: 'Come get your DHEA, come clinical uses, the effects ofthe DHEA's effectiveness in control." your Fountain of Youth. Cures all long-term weight get " substance are unknown. But that hasn't "That's totally false," says Schwartz, that ails you. Helps you live forever,' prevented the creation of a large and who has been studying the metabolic Nestler wrote. "DHEA was reputed to growing market for what many are call- effects of DHEA since the 1970s. "No remedy almost any bodily ill, even though ing a miraculous "Fountain of Youth." human data exist whatsoever that show evidence for the beneficial effects of DHEA has become the latest drug of DHEA can help a person lose weight. DHEA in humans was virtually nonex¬ choice for talk shows and reports in the Rodent studies show some type of an- istent and its cellular or molecular mecha- print and broadcast media, where it is tiobesity effect, but its mechanism is nism(s) ofaction remained a mystery. Be¬ being touted as an "antidote for aging" still not known." cause ofthis nefarious reputation, DHEA and a "superhormone" that can help burn What is known is that mice and rats research was regarded by many as a du¬ fat, build muscle mass, boost libido, are not humans; circulating DHEA se¬ bious, or at best, avant garde adventure." strengthen the immune system, prevent rum levels in rodents are about 5 orders According to Nestler, some physicians heart disease, cancer, and non\p=m-\insulin-$ of magnitude lower than levels in hu¬ are unjustifiably dispensing DHEA "in a dependent diabetes, retard memory loss, mans and other primates, he says. To cavalier fashion for almost any indica¬ help in the treatment of systemic lupus produce weight loss, rodents must be tion. ... Although the results of human erythematosus, and prevent or slow the given high doses of hormones that are DHEA studies appear promising and tan¬ progression of Alzheimer and Parkin- known to be androgenic in humans. The talizing, as evidenced by the reports in son diseases. low doses that many people are now this volume of the Annals, they need to All this, despite the fact that not one taking as supplements (25 to 50 mg/d, be confirmed in large-scale and properly of these benefits has yet been demon- which is sufficient to raise serum levels controlled studies. A beneficial effect of strated in a large randomized placebo- in the elderly to levels normally found in DHEA administration in humans has not controlled clinical trial. What's more, young adults) probably are not andro¬ yet been firmly established, and we know some animal and epidemiologie studies genic, he adds, but they probably are virtually nothing about the side-effect suggest that higher serum levels of the not very effective either. profile of chronic DHEA administration. hormone may be associated with in¬ According to Schwartz, the health food Without confirmed beneficial actions in creased risk for ovarian and perhaps industry, with the help of some physi¬ humans and a better understanding of prostate or other types of cancers. cians, is exposing large numbers of associated risks, it does not seem rea¬ Fulfilling the intent of many of its sup¬ people to a drug whose long-term ef¬ sonable to dispense DHEA." porters, the US Dietary Supplement fects are unknown. In addition, virtu¬ However, many in addition to physi¬ Health and Education Act of 1994 has ally nothing is known about DHEA's cians now are prescribing and dispens¬ partially short-circuited the nation's drug interactions with other drugs. ing DHEA. Advertisements in newspa¬ and The law pers and and on the Internet developing testing system. 'Call of the Hucksters' magazines allows a wide variety of substances to be are promoting and offering the "anti¬ sold for human consumption without ap¬ Schwartz's concerns are shared by dote to aging" directly to the public. "If proval from the Food and Drug Admin¬ many of his colleagues who took part in you are searching for the Fountain of istration (FDA), as long as they are sold the international conference, Dehydro- Youth, DHEA is a must" says one such as "dietary supplements" and the prod¬ (DHEA) and Aging, in article recently posted to the Internet uct labeling includes no "drug intent." Washington, DC, June 17-19, 1995. Al¬ newsgroup, misc.health.alternative. The "This whole thing has gotten out of though speakers at the conference, which article promotes a "colloidal" form of hand," says Arthur Schwartz, PhD, pro¬ was sponsored by the New York Acad¬ DHEA called "LiquidLightning Meta- fessor of microbiology, Fels Institute for emy of Sciences, spoke optimistically D-10" and claims that DHEA's "cogni¬ Cancer Research and Molecular Biology, about the many potential clinical uses tion-enhancing benefits for Alzheimer's Temple University School of Medicine, for DHEA, they also urged caution in and Parkinson's patients have been Philadelphia, Pa. "There's no evidence promoting or prescribing the drug to proven in clinical studies." that this hormone is found in any food— the public until much more is known Other advertisements are recruiting unless, of course, you consider primate about the hormone's long-term effects. people to join in multilevel marketing of adrenal glands food. So why is it being In his introduction to Dehydroepi- DHEA with promises of a "faster, surer sold as a food supplement? This is as androsterone (DHEA) and Aging: An¬ way to wealth." One company's DHEA crazy as health food stores being allowed nals of the New York Academy of Sci¬ Internet web page is illustrated with 4 to sell supplements." ences (1995;774:ix-xi), an editor of the photographs across the page: a table full Schwartz, a pioneer in DHEA research, Annals volume and conference orga¬ of fruits and vegetables, captioned "The has begun to speak out against the media nizer, John E. Nestler, MD, Division of Problem" (the "nutrient" DHEA is not hype, in part because his name and re- Endocrinology and Metabolism, Medi- found in foods); a bottle of one of the

Downloaded from jama.ama-assn.org at Overlook Hospital Library on March 28, 2011 company's nutritional supplements, cap- "Given the diverse nature of DHEA's Medicine Department of Pathology, Salt tioned "The Solution;" a white-smocked putative biologic actions, it seems likely Lake City, and colleagues. man holding a bottle ofthe supplements, that several independent mechanisms Attempts to vaccinate elderly patients captioned "The Creator;" and a fist full for DHEA action may be operative." with antigens to which they have never of $20 bills, captioned "The Opportu¬ Among the research reported at the been exposed often result in failure to nity." The usual retail price for a month's conference was a pilot study that sug¬ elicit the desired immune response. In supply of DHEA in 25-mg to 50-mg daily gests DHEA may improve mood, en¬ contrast, immune responses are usually doses is approximately $15. ergy, libido, and, in some cases, memory induced more reliably when the anti¬ in the In the open- gens have been encountered. What Is DHEA? performance elderly. previously label study, 3 men and 3 women 51 to 72 This suggests that immunologie memory The hormone is made in exceptionally years of age, who had major depression remains intact during the aging process, large quantities as the sulfated form as defined by the American Psychiatric Araneo and colleagues said. (DHEAS) by the adrenal cortex only in Association's Diagnostic and Statisti¬ The researchers reported the results primates and a few nonprimate species. cal Manual ofMental Disorders, Third of 2 double-blind, randomized, placebo- Only humans and apes show the curious Edition, and low basal serum levels of controlled clinical studies that tested the life pattern of having very high prenatal DHEA, were given 30 mg to 90 mg of adjuvant potential of DHEAS. In one serum levels of DHEA and DHEAS that DHEA a day orally for 4 weeks, said study, elderly volunteers were vacci¬ drop to virtually none after birth, then Owen M. Wolkowitz, MD, Department nated with tetanus toxoid (to elicit an rise sharply at puberty and reach very of Psychiatry, University of California, antigen recall response). In the other, high levels during young adulthood, and San Francisco. He and colleagues evalu¬ the volunteers received the 1994-1995 finally drop progressively until only neg¬ ated patients weekly using the 21-item licensed trivalent influenza vaccine (to ligible levels are left in old age. Hamilton Depression Rating Scale, Beck elicit a primary response). While the average serum level of Depression Inventory, Symptom Check¬ The tetanus study involved 66 men DHEAS in men 25 to 34 years of age list 90, and Bunny-Hamburg Global De¬ over age 65 years, of whom 36 received ranges around 6.44±2.29 µ ß/ , it falls pression Rating, along with a test of placebo and 30 received DHEAS. The to 1.15±0.52 µ 1ß/ in men age 75 to 84 verbal memory. All of the depression hormone appeared to have no significant years, and DHEA serum levels fall from evaluations showed significant improve¬ adjuvant effect or a detrimental effect on 15.91 ±6.05 nmol/L to 5.36+1.68 nmol/L ment during treatment, which returned the outcome of tetanus immunization. (Dehyroepiandrosterone (DHEA) and to baseline after the treatment was In the influenza vaccine study, 67 el¬ Aging: Annals of the New York Acad¬ gradually withdrawn. One of the 6 pa¬ derly men and women were given placebo emy of Sciences. 1995:774:121-127). The tients was treated for 5 additional or 50 mg of DHEAS orally for 2 consecu¬ decline rate for both DHEA and DHEAS months with an increase in DHEA dos¬ tive days starting on the day of vaccina¬ is relatively constant at about 2% per age after 4 months. Improvement in her tion. Serum samples were collected the year. Most studies show that the levels depression was found to be dose related. day before the first drug dose and 28 days in young women are 10% to 30% lower "These preliminary results raise the and 90 days after vaccination. The re¬ than in young men, but the sex differ¬ possibility that age- and/or illness-asso¬ searchers found that significantly more of ences appear to decline with age. ciated decreases in circulating DHEA the volunteers who had a 4-fold increase The hormone is a universal precursor and DHEAS levels in depressed patients in influenza hemagglutination inhibition of a number of androgenic and estro- may be pathophysiologically relevant (HAI) titers after vaccination had been genie products that are made by periph¬ and are amenable to pharmacologie given DHEAS compared with those given eral tissues to supply local requirements, treatment," Wolkowitz reports. Larger, placebo, and the overall increase in HAI says Fernand Labrie, MD, PhD. Labrie, double-blind, placebo-controlled trials titers was highest in the DHEAS-treated at Le Centre Hospitalier de l'Université are under way. group. They conclude that further studies Laval (Quebec), CHUL Research Cen¬ Research by Etienne-Emile Baulieu, should justify the use of DHEAS as an ter, has introduced the term "intracri- MD, INSERM, Le Kremlin-Bicetre, adjuvant for antigens that represent pri¬ nology" to describe how individual tis¬ France, and colleagues presented at the mary responses in the elderly. sues use a series of DHEA-metabolizing conference suggests that DHEA is a neu- Heart Disease? enzymes to transform the precursor hor¬ roactive that has multiple Preventing mone into much more physiologically ac¬ pharmacologie effects on the nervous sys¬ Some epidemiologie studies have found tive sex steroids. tem. These investigators are calling for an association between low DHEA se¬ Speaking at the New York Academy trials aimed at offsetting the profound rum levels and heart disease and some of Sciences conference, Labrie estimated decrease in DHEA serum levels in the have not. At the conference, Elizabeth that "30% to 50% of total androgens in elderly. "The nervous system is one of Barrett-Connor, MD, and Deborah Good- men are synthesized in peripheral intra- the most important potential targets of man-Gruen, MD, Department of Family crine tissues from inactive adrenal pre¬ the prospective trials under consider¬ and Preventive Medicine, University of cursors, whereas in women, peripheral ation," Baulieu said. "Experimental data California, San Diego, School of Medi¬ estrogen formation is even more impor¬ on the control of mood changes and re¬ cine, La Jolla, updated what they say is tant. Intracrinology represents an eco¬ inforcement of memory storage, com¬ the only prospective community-based nomical system which requires minimal bined with clinical evidence of DHEA study of the association of natural amounts of hormone to exert maximal activity on the nervous system in vivo DHEAS serum levels and fatal cardio¬ function. In classic endocrine systems, in humans, based on electroencephalo- vascular disease outcomes in men and large amounts of hormones are needed graphic data, are very encouraging." women. The 19-year follow-up study of with only a small fraction used for regu¬ 1029 men 30 to 82 years and 942 the Immune aged lation while the rest is degraded." Boosting System women aged 50 to 88 years showed a A recent groundswell in human Evidence that DHEA may be an ef¬ statistically significant, modestly reduced DHEA-related research suggests that fective vaccine adjuvant for elderly pa¬ risk of death from cardiovascular disease the hormone may have a wide variety of tients was presented by Barbara A. Ara- (relative risk [RR]=0.85) in men who had therapeutic applications, says Nestler: neo, PhD, University of Utah School of higher DHEAS serum levels, but a non- Downloaded from jama.ama-assn.org at Overlook Hospital Library on March 28, 2011 significant increased risk of fatal cardio¬ lated increases in insulin resistance," the be converted to potent androgens, such vascular disease (RR=1.11) in women investigators conclude. as testosterone, which can masculinize with higher levels. Other possible therapeutic uses of women. While the effects of DHEA on David M. Herrington, MD, MHS, Di¬ DHEA have been reported elsewhere. the development or promotion of pros¬ vision of Cardiology, Bowman Gray For example, a study found that the hor¬ tate cancer are unknown, there is evi¬ School ofMedicine, Winston-Salem, NC, mone may help patients with systemic dence to suggest that DHEA may in¬ reported on 2 studies that looked at lupus erythematosus (Arthritis Rheum. crease some women's risk for ovarian DHEA and DHEAS plasma levels in 1994;37:1305-1310). Not surprisingly, such cancer. In a nested, case-control prospec¬ patients undergoing elective coronary reports have whetted the interest of re¬ tive study ofserum samples collected from angiography and in a group of cardiac searchers in studying—and the appetite more than 20 000 residents of Washing¬ transplant patients at risk for acceler¬ of the public for buying—this latest "in" ton County, Maryland, Kathy J. Helzl- ated cardiac allograft vasculopathy. Tis¬ drug. In a commentary (Lancet. 1995; souer, MD, Department of Oncology, sue culture, animal studies, and epide¬ 345:1193-1194), Joe Herbert, MD, Cam¬ Johns Hopkins University School ofMedi¬ miologie studies suggest that DHEA bridge Centre for Brain Repair, Univer¬ cine, Baltimore, Md, found that the risk may inhibit atherosclerosis through its sity of Cambridge in England, says, of ovarian cancer was associated with in¬ potent antiproliferative effects. The re¬ "Enough is known or suspected to war¬ creased levels of DHEA and DHEAS sults of his study support those find¬ rant investigation of DHEA(S) as an (JAMA. 1995;274:1926-1930). ings: their data "suggest that low plasma effective, worthwhile, and relatively risk- If people are going to take DHEA, they levels of DHEA may facilitate, and high free replacement therapy in advancing should do so as part of a clinical trial so levels may retard, the development of age. This can only be done by a controlled that its risks and benefits can be followed, coronary atherosclerosis and coronary prospective trial of DHEA treatment; says Temple's Schwartz. At the very least, allograft vasculopathy," Herrington says. no amount ofcorrelational evidence, how¬ no one should take this drug without his "These observations are consistent with ever carefully collected, is enough." or her physician's knowledge. It would be our of coronary athero¬ unwise for younger than 30 years understanding The FDA's Position people sclerosis as a complex multifactorial dis¬ to take DHEA because the supplements ease process in which DHEA may play "The FDA hasn't formally reviewed might suppress the body's natural pro¬ a small but important role." the data concerning DHEA," said Rob¬ duction of the hormone. If used at all, it The findings of a clinical study by ert Moore, PhD, senior regulatory sci¬ should be used as a replacement therapy Robert L. Jesse, MD, Division of Car¬ entist in the agency's Office of Special in older people whose serum DHEA lev¬ diology, Medical College of Virginia, Nutritionals, Washington, DC, in an in¬ els have declined substantially. Richmond, suggest that DHEA inhibits terview. "We would advise physicians Some experts recommend that DHEA platelet aggregation. In a study of 10 to recognize that this substance isn't an serum level be measured before a per¬ healthy men aged 23 to 35 years, 5 were approved drug for any indication." son takes supplements. Patients also given placebo and 5 received 300 mg of The FDA in 1985 responded to the first should be informed that they are not DHEA 3 times a day for 14 days. The wave of Fountain of Youth fever over going to boost their DHEA levels with rate of platelet aggregation did not DHEA by prohibiting over-the-counter Mexican yam (Dioscorea mexicana) or change in any of the placebo group, but sales of the drug. That ban was ended wild yam (Dioscorea villosa) products was prolonged in 4 ofthe 5 in the DHEA- by passage of the health food industry- that are being touted as containing natu¬ treated group. In 1 of the 4, platelet backed Dietary Supplement Health and ral precursors for the body's production aggregation was inhibited completely. Education Act of 1994. The law shifted of the hormone, says Schwartz. None of the men reported any adverse the burden onto the FDA to prove that John Renner, MD, clinical professor of effects while taking DHEA and none a nutritional supplement is harmful be¬ family medicine, University of Missouri, was able to tell if he was taking DHEA fore the agency could regulate its sale. Kansas City, School of Medicine and or the placebo. "Inhibition of platelet As a result, many powerful and poten¬ president of Consumer Health Informa¬ activity by DHEA may contribute to tially dangerous drugs can now be mar¬ tion Research Institute, also recommends the putative antiatherogenic and car- keted as nutritional supplements with¬ that people not take DHEA on their own. dioprotective effects of DHEA," Jesse out proof of safety or efficacy. Recalling that impurities in tryptophan— concludes. "Physicians need to routinely ask their the superstar food supplement of a few about the food years ago—led to a number of deaths Insulin and patients supplements they Sensitivity Lupus are taking," says Moore. "That's the only and hundreds of cases of eosinophilia- Some researchers believe that DHEA way we can find out if there are ad¬ myalgia syndrome, Renner notes that may protect against non-insulin-depen¬ verse reactions to the supplements." there is still no governmental regulation dent diabetes. In a 3-week, randomized, Without being asked, people who think of the potency and purity of so-called double-blind, placebo-controlled trial of of supplements as "natural"—and there¬ nutritional supplements. 15 postmenopausal women, Gordon fore harmless—are not going to men¬ "If people do take it, then I recom¬ Wright Bates, Jr, MD, then at the De¬ tion taking them to their physicians. Phy¬ mend that they keep track of the batch partment of Obstetrics and Gynecology, sicians should report all suspect adverse number by saving the original bottle University of Tennessee, Memphis, and reactions to any dietary supplement to along with the last 5 pills and that they colleagues at Baylor College of Medicine, the FDA's MEDWatch program by call¬ store it in a cool dark place," Renner Houston, Tex, found that insulin sensi¬ ing (800) FDA-1088. says. Asked how long the samples should was (P=.04) enhanced be he said, "Until the legal statute tivity significantly Other Caveats kept, in women given 50 mg of DHEA a day of liability runs out." He also recom¬ compared with women receiving placebo. Some evidence exists thatjustifies con¬ mends against buying from a mail order "Whether this effect is reproducible in cern about the safety of DHEA supple¬ establishment or from any fly-by-night larger studies remains to be determined. ments. According to Nestler, there has operation. "Buy it from a large health If DHEA supplementation in aged sub¬ been at least one published report oftran¬ food chain that can afford to be sued in jects enhances insulin sensitivity, DHEA sient hepatitis associated with DHEA use case of adverse reactions," he says. replacement may help attenuate age-re- by a woman. Large doses of DHEA can \p=m-\byAndrew A. Skolnick Downloaded from jama.ama-assn.org at Overlook Hospital Library on March 28, 2011

HIGHLIGHTS OF PRESCRIBING INFORMATION • PRASTERA® may in certain patients elevate serum levels These highlights do not include all the information needed of 5-dehydroepiandrosterone, testosterone or estrogen to use PRASTERA® safely and effectively. See full above the normal range for healthy, non-afflicted women prescribing information for PRASTERA®. of similar age. Periodic measurement of serum hormones is prudent. (§7.2.1) PRASTERA® prasterone oral softgels 200mg are for oral • Hypertension may occur with prasterone treatment. use only. Monitor blood pressure closely. (§6.3.2)

INDICATIONS AND USAGE PRASTERA® prasterone 200 mg oral softgels is a medical ADVERSE REACTIONS food indicated in female patients with mild to moderate, active The most common adverse event with PRASTERA® is acne. (SLEDAI >2) systemic lupus erythematosus (SLE) to restore This is generally treatable with topical anti-acne medication. serum 5-dehydroandrosterone sulfate to levels typical of (§6.1) women without SLE. In Phase III clinical trials in female Another common adverse reaction is hirsutism. Both acne and patients with mild to moderate active SLE, prasterone 200 mg hirsutism are reversible on cessation of prasterone. (§6.1) was associated with reduced risk of auto-immune flare. (§§1, 6.2, 6.4, 6.5) To report SUSPECTED ADVERSE REACTIONS, contact QPharma Pharmacy Fulfillment Services, Inc. at 1- 888_742-7620 or FDA (1-800-FDA-1088 or DOSAGE AND ADMINISTRATION www.fda.gov/medwatch) or your doctor. The recommended dose is one (1) softgel daily. (§2)

DRUG INTERACTIONS DOSAGE FORMS AND STRENGTHS • PRASTERA® may interact with certain psychiatric drugs. 200mg oral softgel capsules supplied in a convenience (§8) package with ibuprofen oral tablets 300mg. (§3) • Concomitant administration of PRASTERA® with endogenous testosterone or estrogens, or dietary CONTRAINDICATIONS supplements containing DHEA or dehydroepiandrosterone, • Known hypersensitivity to any of its ingredients. (§4) is not generally recommended unless serum sex hormone • Undiagnosed abnormal genital bleeding. (§4) levels are monitored, because of the potential to elevate levels above the ranges considered normal in healthy • Known, suspected or history of breast cancer. (§4, §6.5) individuals. (§§7.1, 7.2.1, 8, 10, 16.3) • History of, or known, deep vein thrombosis, pulmonary embolism, arterial thromboembolic disease (e.g., stroke, USE IN SPECIFIC POPULATIONS myocardial infarction). (§4) • Not recommended for use in nursing nor pregnant women, • Hypercholesterolemia or ischemic heart disease. (§4, pediatric patients, or men (safety data is lacking). (§9)

§7.2.4) • Hepatic or renal impairment (pharmacokinetic data See § 16 for PATIENT COUNSELING INFORMATION. lacking). (§4, §7.2) • Breast-feeding or known or suspected pregnancy. (§4) Revised: 05/2013 • History of psychiatric disorder. (§4, §8)

WARNINGS AND PRECAUTIONS • PRASTERA® is not intended for use in nursing or pregnant women, children nor males (safety data is lacking). (§§4, 9) • PRASTERA® use may be prohibited by certain athletic anti-doping regulations. (§9.5)

TABLE OF CONTENTS

1 INDICATIONS AND USAGE 6.3.1 Hypertension 6.4 REDUCED RISK OF DEATH 2 DOSAGE AND ADMINISTRATION 6.5 REDUCED RISK OF BREAST CANCER 2.1 GENERAL INSTRUCTIONS 6.6 OTHER SERIOUS ADVERSE EVENTS 2.2 SPECIAL PRECAUTIONS 7 SAFETY 3 DOSAGE FORMS AND STRENGTHS 7.1 RELATIONSHIP OF DOSE TO SAFETY 4 CONTRAINDICATIONS 7.2 CLINICAL LABORATORY EVALUATION 7.2.1 Serum Hormone Levels 4.1 ALLERGY WARNING 7.2.2 Serum Creatinine 5 WARNINGS AND PRECAUTIONS 7.2.3 Serum Complement 6 ADVERSE REACTIONS 7.2.4 Serum Lipids 7.2.5 Liver Function 6.1 INCREASED RISK OF ACNE AND 7.2.6 Renal Function HIRSUTISM 7.2.7 Proteinuria 6.2 REDUCED RISK OF MYALGIA AND OTHER 7.2.8 Hematuria FLARE SYMPTOMS 7.3 POST-MARKETING EXPERIENCE 6.3 OTHER COMMON ADVERSE EVENTS 8 DRUG INTERACTIONS 12.2.6 Special Populations 13 PRE-CLINICAL TOXICOLOGY 9 USE IN SPECIFIC POPULATIONS 14 CLINICAL STUDIES 9.1 MALES 9.2 PATIENTS WITH ACTIVE SLE DISEASE 14.1 REDUCTION IN RISK OF FLARE 9.3 PREGNANCY 14.1.1 Clinical Study GLB96-01 9.4 PEDIATRIC USE 14.1.2 Clinical Study GL95-02 9.5 ATHLETIC ANTI-DOPING 14.2 REDUCTION IN RISK OF DEATH 10 OVERDOSE 14.2.1 Clinical Study GL94-01 15 HOW SUPPLIED / DOSAGE AND 11 DESCRIPTION HANDLING 12 CLINICAL PHARMACOLOGY 16 PATIENT COUNSELING INFORMATION 12.1 PHARMACODYNAMICS 16.1 PATIENT / CAREGIVER INSTRUCTIONS 12.2 PHARMACOKINETICS 16.2 BENEFITS 12.2.1 Time To Peak Concentration 16.3 OTHER MEDICATIONS 12.2.2 Absorption 16.4 ADVERSE REACTIONS 12.2.3 Distribution 16.5 PREGNANCY 12.2.4 Metabolism 17 MEDICATION GUIDE 12.2.5 Excretion

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE Oral prasterone (200mg per day) in female patients with active systemic lupus erythematosus (SLE) has in several blinded, placebo-controlled randomized clinical studies been associated with a reduced risk of auto-immune flare, §§6.2, 14.1.1, and a reduced risk of death from any cause, §§6.4, 14.2. Patients with SLE may have depressed serum levels of 5-dehydroepiandrosterone sulfate (5-DHEAS). Oral prasterone has been shown to restore SLE patients’ serum 5-DHEAS levels. Prastera® oral softgels are intended for use in patients for whom medical evaluation shows a depressed serum level of DHEA and thus a distinctive need for exogenous DHEA. Prastera® oral prasterone softgels are intended to be used under medical supervision, for a patient receiving active and ongoing medical supervision, wherein the patient obtains medical care on a recurring basis for, among other things, instructions on the use of this product. Prastera® oral prasterone softgels are intended for the dietary management of SLE by meeting the distinctive nutritional requirement of women with mild-to-moderate active SLE. Prastera® oral prasterone softgels are intended for oral intake only. Prastera® does not cure, treat, mitigate or prevent SLE. To the contrary, patients taking Prastera® will continue to have SLE, and thus may require other appropriate therapy.

2 DOSAGE AND ADMINISTRATION

2.1 General Instructions The recommended dose is one 200mg Prastera® oral prasterone softgel daily, with or without food.

2.2 Special Precautions None. 3 DOSAGE FORMS AND STRENGTHS Prastera® oral prasterone is provided as oral softgels. Each softgel contains 200mg of prasterone (>99% pure). Inactive ingredients: olive oil NF, gelatin NF, beeswax NF, lecithin NF, titanium dioxide USP. 4 CONTRAINDICATIONS Prastera® oral softgels should not be used in patients with any of the following conditions: a) Known hypersensitivity to prasterone (or the dietary supplement DHEA), testosterone, estrogens or any component of Prastera® oral prasterone softgels. §4.1. b) Undiagnosed abnormal genital bleeding. c) Known, suspected, or history of breast cancer. §6.5. d) Active deep vein thrombosis, pulmonary embolism or history of these conditions. e) Active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. §6.3.2. f) Patients with hypercholesterolemia, §7.2.4, or ischemic heart disease. g) Liver disease or renal impairment (pharmacokinetic data lacking). h) Known or suspected pregnancy; breast-feeding (safety data lacking). i) Patients with or a history of psychiatric disorders (risk of exacerbation). The risk of mania may be increased during concomitant use with antidepressants (tricyclic or SSRIs) and/or alcohol, or with high prasterone doses, or in patients with a history of mood disorders.

4.1 Allergy Warning Prastera® oral prasterone softgels contain no milk, eggs, fish, crustacean shellfish, tree nuts, wheat, peanuts or soy bean. 5 WARNINGS AND PRECAUTIONS PRASTERA® is not intended for use in children, nor males, nor women who are breastfeeding, pregnant, or who expect to become pregnant. §9. Monitoring of blood pressure, serum lipids, serum sex hormones is prudent. See Clinical Laboratory Evaluation, §§7.2.1, 7.2.4. 6 ADVERSE REACTIONS The most-frequent adverse reactions observed in placebo-controlled, blinded clinical studies GL94-01, GL95-01, GL95-02 and GLB96-01 are as follows:

6.1 Increased Risk of Acne and Hirsutism Acne was the most frequently reported adverse event. Acne was reported less frequently by African American patients, in approximately 26%, compared to approximately 36% in Caucasian patients. The second most-frequent adverse event was hirsutism. In study GLB96-01 involving patients of Chinese extraction, hirsutism was not reported; this may indicate a decreased racial susceptibility to hirsutism. Acne and hirsutism were both reversible on cessation of prasterone therapy. In addition, both were more likely to be reported early in treatment; patients who had not developed these within the first 6 months of exposure are less likely to develop them later.

6.2 Reduced Risk of Myalgia and Other Flare Symptoms Placebo-treated patients had higher incidences of myalgia, joint disorder, anorexia, nasal ulcers and LE skin rash than did prasterone-treated patients. These differences may be due to the decreased risk of flare observed in prasterone-treated patients. §14.1.

6.3 Other Common Adverse Events No adverse events increase in frequency with longer duration of treatment. The Table displays all adverse events reported in a frequency of 10% or greater from either the 200 mg dose group or the placebo group for the pooled double-blind phases of Studies GL94-01 and GL95-02. Because the number of patients who received prasterone 100 mg was substantially fewer, adverse events for this group are only presented for those adverse events which were reported in > 10% of either placebo or prasterone 200 mg patients.

ADVERSE EVENTS WITH FREQUENCY >10%* (pooled GL94-01 and GL95-02 results) Placebo 100mg 200mg COSTART TERM N=256 N=63 N=253 Rash 77 (30.1%) 14 (22.2%) 93 (36.8%) Acne 39 (15.2%) 28 (44.4%) 91 (36.0%) ** Arthralgia 95 (37.1%) 15 (23.8%) 88 (34.8%) Asthenia 70 (27.3%) 23 (36.5%) 68 (26.9%) Headache 76 (29.7%) 17 (27.0%) 60 (23.7%) Arthritis 58 (22.7%) 17 (27.0%) 57 (22.5%) Myalgia 79 (30.9%) 14 (22.2%) 55 (21.7%) ** Pain Abdomen 34 (13.3%) 8 (12.7%) 41 (16.2%) Flu Syndrome 46 (18.0%) 1 (1.6%) 40 (15.8%) Stomatitis Ulcer 50 (19.5%) 15 (23.8%) 38 (15.0%) Hirsutism 6 (2.3%) 7 (11.1%) 36 (14.2%) ** Fever 39 (15.2%) 9 (14.3%) 36 (14.2%) Depression 33 (12.9%) 5 (7.9%) 35 (13.8%) Alopecia 48 (18.8%) 7 (11.1%) 35 (13.8%) Infection 37 (14.5%) 18 (28.6%) 26 (10.3%) Sinusitis 33 (12.9%) 4 (6.3%) 22 (8.7%)

Pain Chest 27 (10.5%) 5 (7.9%) 22 (8.7%) *Frequency > 10% in either prasterone 200 mg or placebo patients. ** P< 0.05, Placebo vs. prasterone 200 mg.

For adverse events occurring in < 10% of patients, the following showed an absolute difference of at least 3% between placebo or prasterone 200 mg, or, if less than 3% difference, the difference was significant (p < 0.05):

ADVERSE EVENTS WITH FREQUENCY <10% AND AT LEAST A 3% OR A SIGNIFICANT DIFFERENCE (pooled GL94-01 and GL95-02 results) Placebo prasterone 200 mg COSTART TERM N=256 N=253 Less Frequent in Prasterone Anorexia 10 (3.9%) 2 (0.8%) ** Nasal Septum Disorder (nasal ulcers) 14 (5.5%) 5 (2.0%) ** Rash Lupus Erythematosus 13 (5.1%) 4 (1.6%) ** Joint Disorder 14 (5.5%) 4 (1.6%) ** More Frequent in Prasterone Creatinine Increase 0 (0.0%) 6 (2.4%)** Hypertension 7 (2.7%) 20 (7.9%) ** Hematuria 1 (0.4%) 9 (3.6%) ** Insignificant Difference Back Pain 16 (6.3%) 24 (9.5%) Pharyngitis 14 (5.5%) 6 (2.4%) Dyspnea 22 (8.6%) 11 (4.3%) Lymphadenopathy 21 (8.2%) 12 (4.7%)

** P< 0.05, Placebo vs. prasterone 200 mg.

The pattern of adverse events in clinical study GLB96-01 showed a similar, but not identical pattern. Acne was the most common adverse event; this may reflect the fact that almost all patients were also receiving corticosteroids. This may also reflect racial differences in sensitivity to prasterone. By contrast, hirsutism was not reported at all in GLB96-01.

ADVERSE EVENTS REPORTED BY AT LEAST 10% OF EITHER TREATMENT GROUP (GBL96-01) Placebo Treatment N= 59 N= 61 Arthralgia 37 ( 62.7%) 39 ( 63.9%) Acne * 17 ( 28.8%) 36 ( 59.0%)* Pharyngitis 32 ( 54.2%) 34 ( 55.7%) Myalgia 24 ( 40.7%) 28 ( 45.9%)

Headache * 37 ( 62.7%) 26 ( 42.6%)* Pain Abdomen 25 ( 42.4%) 23 ( 37.7%) Asthenia 19 ( 32.2%) 18 ( 29.5%) Cough Increase 18 ( 30.5%) 18 ( 29.5%) Dizziness 19 ( 32.2%) 15 ( 24.6%) Pain Chest 11 ( 18.6%) 14 ( 23.0%) Dyspnea 8 ( 13.6%) 14 ( 23.0%) Rash 16 (27.1%) 14 ( 23.0%) Fever 17 ( 28.8%) 13 ( 21.3%) Alopecia 8 ( 13.6%) 13 ( 21.3%) Pain 8 ( 13.6%) 11 ( 18.0%) Diarrhea 11 ( 18.6%) 11 ( 18.0%) Rhinitis 13 ( 22.0%) 11 ( 18.0%) Stomatitis Ulcer 17 ( 28.8%) 10 ( 16.4%) Pain Back 10 ( 16.9%) 9 ( 14.8%) Edema 6 ( 10.2%) 9 ( 14.8%) Injury Accident 6 ( 10.2%) 8 ( 13.1%) Insomnia 7 ( 11.9%) 8 ( 13.1%) Pruritus 7 ( 11.9%) 8 ( 13.1%) Infection* 15 ( 25.4%) 6 ( 9.8%)* Dry Eye 10 ( 16.9%) 6 ( 9.8%) Vomit 8 ( 13.6%) 5 ( 8.2%) Peripheral Edema 8 ( 13.6%) 5 ( 8.2%) Rash Lupus Erythematosus 7 ( 11.9%) 5 ( 8.2%) Conjunctivitis 7 ( 11.9%) 5 ( 8.2%) Nausea 9 ( 15.3%) 4 ( 6.6%)

*P-value<0.05, Treatment vs. Placebo, chi-square test

Of adverse events reported by at least 10% of patients, acne was the only event significantly more frequent in the treatment group. Headache and infection were more frequent in the placebo group. Of the adverse events reported with an incidence of less than 10%, the only statistically significant difference was for seborrhea (0 placebo vs. 5 treatment patients).

6.3.1 Hypertension Hypertension was reported as an adverse event more frequently in the prasterone 200 mg group than placebo. When measures of increased (changed) blood pressure were included, there appeared to be no difference between the groups. Whether prasterone increases hypertension is thus not clear.

6.4 Reduced Risk of Death In the GL94-01, GL95-01 and GL95-02 placebo-controlled clinical studies (pooled data), the placebo group experienced 6 deaths in 77 patients, a risk of death of 7.8%. In contrast, the prasterone group (pooled treatment and cross-over) experienced 8 deaths in 495 patients, a risk of death of 1.6%. The risk of death from any cause was therefore five times higher in the placebo group.

6.5 Reduced Risk of Breast Cancer In the GL94-01, GL95-01 and GL95-02 placebo-controlled clinical studies (pooled data), incidence of breast cancer was 1 in 336 patient-years (0.29%) for placebo and 3 in 1573 patient- years (0.19%) for prasterone (pooled treatment and cross-over). Prasterone was thus associated with reducing the risk of breast cancer by one third. For patients over 44 years of age, the difference between placebo and prasterone groups was more pronounced. For women at least 45 years of age, the rate of breast cancer was 1 in 24 patient-years (4.2%) for placebo and 3 in 206 patient-years (1.5%) for prasterone treatment and cross-over patients. Prasterone was thus associated with reducing the risk of breast cancer by two thirds.

6.6 Other Serious Adverse Events Adverse events that were assessed as “severe” occurred in similar frequencies in both treatment and placebo groups, with asthenia being the most common adverse event reported as severe in both placebo and treated patients. Although the patient numbers are small, abdominal pain reported as a severe adverse event occurred in 6 treated 200 mg patients, 2 treated 100mg patients, and no placebo patients. Serious adverse events occurred in 39 200 mg, 7 100 mg, and 47 placebo patients participating in GL94-01 and GL95-02. However, only 3 serious adverse events were considered possibly related, 2 in the placebo group (one suicide and one patient with menomettrorhagia) and one in 200 mg (a patient with an acute psychosis). In the Taiwan study, serious adverse events were reported in a significantly higher proportion of patients in the placebo group than in the treatment group. In most cases, the types of serious adverse events reported were consistent with SLE flares or hospitalization for manifestations of SLE, rather than adverse effects of the study drug.

SEVERE ADVERSE EVENTS OCCURRING IN AT LEAST 2 PATIENTS* (GL94-01 and GL95-02) Placebo prasterone 100 mg prasterone 200 mg COSTART TERM N=256 N=63 N=253 Asthenia 22 (8.6%) 4 (6.3%) 22 (8.7%) Headache 11 (4.3%) 1 (1.6%) 8( 3.2%) Arthralgia 6 (2.3%) 3 (4.8%) 6 (2.4%) Pain Abdomen 0 (0%) 2 (3.2%) 6 (2.4%) Rash 5 (2.0%) 1 (1.6%) 6 (2.4%) Arthritis 2 (0.8%) 3 (4.8%) 5 (2.0%) Dyspnea 1 (0.4%) 0 (0%) 4 (1.6%) Depression 4 (1.6%) 1 (1.6%) 2 (0.8%) Diabetes Mellitus 0 (0%) 0 (0%) 2 (0.8%) Emotional Lability 0 (0%) 0 (0%) 2 (0.8%) Infection 0 (0%) 4 (6.3%) 2 (0.8%) Myalgia 5 (2.0%) 1 (1.6%) 2 (0.8%) Pain 1 (0.4%) 0 (0%) 2 (0.8%) Pain Chest 4 (1.6%) 1 (1.6%) 2 (0.8%) Paresthesia 1 (0.4%) 0 (0%) 2 (0.8%) Pleural Disorder 1 (0.4%) 0 (0%) 2 (0.8%) Vasculitis 0 (0%) 1 (1.6%) 2 (0.8%) Joint Disorder 2 (0.8%) 0 (0%) 1 (0.4%) Peripheral Edema 2 (0.8%) 2 (3.2%) 0 (0%) Sepsis 2 (0.8%) 0 (0%) 0 (0%) Cyst 2 (0.8%) 0 (0%) 0 (0%) Thinking Abnormal 2 (0.8%) 0 (0%) 0 (0%)

*Frequency at least 2 patients in either prasterone 200 mg or placebo

7 SAFETY

7.1 Relationship Of Dose To Safety Neither adverse events nor laboratory values showed a dose relationship.

7.2 Clinical Laboratory Evaluation

7.2.1 Serum Hormone Levels In the placebo-controlled trials, testosterone was increased in a dose related manner in SLE patients, both pre- and post-menopausal, receiving prasterone; and androgenic adverse events such as acne and hirsutism showed an increased frequency, as did lipid changes usually associated with administration of androgens. In non-pregnant women, the most serious risks associated with increased levels of testosterone would be virilization, i.e., evidence of irreversible androgenic changes such as deepening of the voice, androgenic alopecia, or clitoral

hypertrophy. Such events were not reported in the prasterone clinical trials. However, the long- term risks of the increased testosterone levels caused by prasterone are not yet known.

7.2.2 Serum Creatinine In the pooled data from GL94-01 and GL95-02, 0 of 256 patients in the placebo group had creatinine increase reported as an adverse event, while 6 of 253 patients (2.4%) in the prasterone 200 mg group had this adverse event, p=0.015, placebo vs. prasterone 200 mg. Although there was an imbalance in the few patients with creatinine increase reported as an adverse event, overall serum creatinine (as judged by a mean or median increase in serum creatinine) did not increase in any of the groups, and also there was no difference in change in creatinine between groups. Taken as a whole, these findings suggest renal dysfunction, as identified by increased serum creatinine, was quite uncommon, and generally not related to the findings of increased proteinuria, new onset hematuria or decreased C3.

7.2.3 Serum Complement Prasterone caused an increased number of patients (in comparison to placebo) to have a decrease in C3, the decline in C3 was not associated with renal dysfunction, suggesting the effect may be mediated by a reduction in complement synthesis rather than an enhancement of consumption. The medical literature suggests that a decline in serum complement may be a direct effect of suppression of complement production by androgens.

7.2.4 Serum Lipids Decreases in lipids, particularly HDL-C and triglycerides, were consistently seen in studies of prasterone. The reduction was most evident for HDL-C and triglycerides, less so for total cholesterol and minimal for LDL cholesterol. These findings suggest that administration of prasterone consistently causes an early, but not progressive, decrease in serum lipids, primarily HDL-C and triglycerides. Reduction in HDL-C observed with prasterone may not necessarily signify an increased risk of atherosclerosis. However, it would be prudent to follow NCEP guidelines while monitoring lipids in patients receiving prasterone.

7.2.5 Liver Function There were no changes of potential significance in liver function tests (ALT, AST, alkaline phosphatase, or total bilirubin) within and between the treatment groups. Equally, serum , phosphorus, uric acid, total protein and albumin showed no clinically relevant differences between treatment groups, or changes from baseline. In the Taiwan study, there were no clinically significant differences in liver function tests though the placebo group demonstrated increases in SGOT and SGPT.

7.2.6 Renal Function BUN and creatinine levels did not change during study and were similar within or between treatment groups. Mean changes in 24-hour urine protein excretion increased in all treatment groups, but to a greater extent in prasterone patients. However, a few patients with very high values impacted 24-hour urine protein; and median changes were only slightly higher in the prasterone groups. In the Taiwan study, there were no differences between treatment groups.

Creatinine showed a mean increase from baseline of 0.2 mg/dl (an increase of 2.8%) in the prasterone treatment group. However, the mean was influenced by one patient with an increase of 6.1 mg/dl and the group median change was 0.0 mg/dl. No patient in the prasterone treatment group had a shift from a normal baseline value to a high value at final visit.

7.2.7 Proteinuria There was a higher mean change from baseline for 24 urinary protein with prasterone: the mean change was 44.9 mg/24 hours for placebo, and 329.4 mg/24 hours for the prasterone 200 mg group, respectively. Less than 5% of patients with pre-existing proteinuria in the treatment group demonstrated a meaningful increase in proteinuria.

7.2.8 Hematuria There does not appear to be a difference between placebo and prasterone for new hematuria accompanied by SLE renal involvement, as manifested by changes in urinary protein excretion, increased creatinine, or new therapy for renal SLE.

7.3 Post-Marketing Experience The following adverse reactions have been reported with unregulated dietary supplements containing DHEA or dehydroepiandrosterone. These reactions have been reported voluntarily from populations of uncertain size, the identity, purity and strength of the product used was not always known, and none these patients were taking concomitant prednisone or other first-line SLE therapy. It is therefore not always possible to reliably establish a causal relation to prasterone exposure. Cardiovascular Effects: Benign premature atrial contractions and occasional premature ventricular contractions occurred in a 55-year-old man after administration of DHEA; DHEA was discontinued and arrhythmias controlled by beta-blockers.1 Hepatic Effects: No significant changes in transaminases or other hepatic function tests were seen during long-term use (e.g., 6 months).2,3 One case of hepatitis has been reported in a patient with high pre-treatment anti-nuclear antibody (ANA) titers; causality is uncertain.4 Psychiatric Effects: Manic reactions during DHEA use (50 to 500 mg daily) have been described.5,6 Risk factors for development of mania / psychosis are considered to be higher doses, combined use with antidepressants (tricyclics or selective serotonin-reuptake inhibitors) or alcohol or benzodiazepines, young patients (20 to 30 years, due to peaking endogenous dehydroepiandrosterone levels), and cytochrome P450 polymorphisms (poor metabolizers). 8 DRUG INTERACTIONS There is no known pharmacokinetic effect (bioavailability, pharmacokinetics, or pharmacodynamics) of prasterone on prednisone or hydroxychloroquine, with the possible exception of increasing the magnitude of a decrease in triglycerides seen with hydroxyquinoline. Informal reports indicate that prasterone may theoretically interact with one or more of the following drugs: carbamazepine, phenothiazines (e.g., acetophenazine, chlorpromazine, chlorprothixene, ethopropazine, fluphenazine, mesordiazine, methdilazine, perazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, propiomazine, thioridazine, trifluoperazine, triflupromazine), citalopram; escitalopram; clozapine, conjugated estrogens; estherified estrogens; estradiol; estradiol cypionate; estropipate; ethinyl estradiol,

fluoxetine, fluvoxamine; haloperidol, lithium, loxapine, molindone, olanzapine, paroxetine, quetiapine, risperodone, sertraline, testosterone, triazolam and valproic acid. For further information on potential interactions with these drugs, please see The Cochrane Review monograph for prasterone. 9 USE IN SPECIFIC POPULATIONS

9.1 Males The placebo-controlled, double-blind clinical studies involved women. Use in men at this time is not recommended because data is lacking.

9.2 Patients with Active SLE Disease In the GL94-01 and GL95-02 clinical studies, the difference in responder rates between placebo and prasterone increased with increasing baseline SLEDAI.

9.3 Pregnancy Safety and effectiveness in nursing and pregnant women has not been established. Use is not recommended.

9.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use in pediatric patients is not recommended.

9.5 Athletic Anti-Doping Prasterone use is prohibited by certain athletic anti-doping regulations. 10 OVERDOSE Oral prasterone of up to 1.6 grams per day has not provoked overdose in post-menopausal women.7 In case of suspected overdose, Prastera® softgels should be discontinued and the patient should be treated symptomatically. 11 DESCRIPTION PRASTERA® prasterone oral softgels are oblong, bi-colored white and blue, liquid- filled soft gelatin capsules for oral administration. Each PRASTERA® prasterone oral O softgel contains 200mg prasterone (>98% pure), in an olive oil NF vehicle. Prasterone is chemically identical to the naturally-occurring pro- hormone 5-dehydroepiandrosterone secreted by the adrenal cortex, H gonads and brain tissue. It is designated chemically as (3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl- H H 3,4,7,8,9,10,11,12,13,14,15,16 –dodecahydro-1H- HO cyclopenta[a]phenanthren-17(2H)-one. Its molecular weight is 288.424 g/mol. Its molecular formula is C19H28O2. 12 CLINICAL PHARMACOLOGY Prastera® oral prasterone softgels are an oral dosage form of prasterone (pharmaceutical grade), chemically identical to prasterone of native human origin, in a lipophilic vehicle.

12.1 Pharmacodynamics Oral prasterone has been shown to increase serum levels of 5-DHEAS. The precise mechanism by which normal serum levels of 5-DHEAS may act to reduce the risk of auto- immune flare and death is not known.

12.2 Pharmacokinetics

12.2.1 Time To Peak Concentration Oral prasterone reaches a peak serum concentration at 1.5 to 2 hours after administration.8,9 In healthy young women (mean age, 30 years) receiving prasterone 200 mg daily (given with prednisone), mean peak plasma levels on day 29 of prasterone and 5-DHEAS were 1.3 mcg/dL (13 ng/mL) and 942 mcg/dL (9.4 mcg/mL), and occurred in 2 hours and 2.4 hours, respectively, after administration.10 In elderly women (mean, 69 years) and elderly men (mean, 69 years), mean peak plasma concentrations (times to peak levels) after a single 200-mg micronized oral dose were 27 ng/mL (1.4 hours) and 22 ng/mL (1.3 hours) in elderly women and men, respectively. After a single 200 mg dose, mean serum levels of 5-DHEAS increased 5-fold in men (to 7 mcg/mL) and 21-fold in women (to 7.5 mcg/mL) relative to baseline healthy levels; the time to peak serum levels of 5-DHEAS were shorter in women than men (2.1 versus 3.3 hours).11

12.2.2 Absorption During two weeks of daily administration (200 mg), plasma levels (and times to peak levels) of both 5-dehydroepiandrosterone and its sulfated metabolite did not change significantly in either women or men, indicating a lack of accumulation.12

12.2.3 Distribution Approximately 10% to 20% of prasterone is bound to serum protein; approximately 80% to 90% of 5-DHEAS is bound to protein.13 5-DHEAS penetrates the blood-brain barrier; cerebro- spinal fluid levels of 5-DHEAS range from 0.2% to 5% of corresponding plasma levels.14, 15

12.2.4 Metabolism Oral prasterone is sulfated to 5-DHEAS ester in the intestine and liver by sulfotransferases.16 Prasterone and 5-DHEAS are converted in peripheral tissues to androstenedione,17 ,18 estradiol, and ,19 ,20 7-oxo-prasterone,21 and testosterone.22 It remains controversial whether the pharmacologic effects of 5-DHEAS are direct, or due solely to its conversion to other metabolites.23

12.2.5 Excretion Prasterone (200mg dose) elimination half-life: young women, 11 hours; elderly men, 7 hours.24 In elderly women, the elimination half-life progressively declined, from about 12 hours (day 1), to 9 hours (day 8), to 7 hours (day 15).25 5-DHEAS half-life: young women, 12 hours; elderly men, 20-25 hours; elderly women, 24-27 hours.26

12.2.6 Special Populations The pharmacokinetics of Prastera® oral prasterone softgels have not been assessed in low body weight or obese patients. There is insufficient information available from placebo- controlled clinical trials to compare prasterone pharmacokinetics in different racial groups, nor for patients with renal or hepatic impairment. 13 PRE-CLINICAL TOXICOLOGY The non-clinical literature indicates that prasterone may be either chemo-protective or carcinogenic, depending on the model. Prasterone may thus be inhibitory or stimulatory to hormone-senentive tumors. The literature, however, suggests that prasterone is less potent than its androgenic and estrogenic metabolites. Similarly to androgenic and extrogenic compounds, it is expected to be difficult to define the carcinogenic potential of prasterone.27 14 CLINICAL STUDIES The placebo-controlled studies (GL94-01, GL95-01, GL95-02 and GLB96-01) had very different study designs and efficacy endpoints. Pooling of efficacy data is thus not meaningful. Consequently, results are presented by individual study.

14.1 Reduction In Risk Of Flare

14.1.1 Clinical Study GLB96-01 GLB96-01 was a six month, multi-center, randomized, parallel group, double-blind, placebo-controlled study of prasterone (200mg daily) in predominately (+84%) pre- Prasterone menopausal (mean age = 32 years) Asian women with active SLE (97% had baseline SLEDAI score > 2). The treatment group (n = 60) had a somewhat higher baseline SLEDAI (Mean (Median) baseline SLEDAI = 8.2 (8.0)). The placebo group (n = 59) a somewhat lower baseline SLEDAI (Mean (Median) baseline SLEDAI = 6.6 (6.0)). In this study, the Time to first flare (p = 0.044) treatment group had fewer patients with at least one definite flare. The number of patients with definite flares in the treatment group was 46.0% less than in the placebo group (18.3% vs. 33.9%, p = 0.044 based on survival analysis using Cox model). The Time to First Definite Flare Survival Curve for GBL96-01 is shown here. The percent of patients without a definite flare began to diverge after 28 days of treatment, and widened progressively. There was a statistically-significant decrease in the number of patients who experienced at least one flare as compared to the placebo group

14.1.2 Clinical Study GL95-02 Study GL95-02 was a 12 month, multi-center, randomized, parallel group, double-blind, placebo-controlled study of prasterone (200mg daily) in women (n = 346) with active SLE (SLAM score >7 excluding ESR, SLEDAI score >2) receiving <10 mg/day prednisone (or its equivalent of other cortico-steroids). A secondary efficacy variable (flare) was defined as a modified SELENA definition flare. Three hundred eighty one (381) patients were randomized, of whom 346 were in the per- protocol population. For all patients, 47/176 (27%) of placebo and 37/170 (22%) of prasterone patients experienced a definite flare. Time to First Definite Flare Survival Curve in ITT Population (Study 95-02) is shown in the survival curve. For the subset of patients with a baseline SLEDAI>2, treated patients had a 23.7% decrease in the risk of experiencing at least one definite flare, compared to placebo. During the study period, 41/133 (31%) of placebo patients and 31/132 (23.5%) of prasterone patients experienced a definite flare. See bar chart. Thus, for patients with a baseline SLEDAI>2, treated patients had a 23.7% decrease in the risk of experiencing at least one definite flare, compared to placebo (p=0.201, log-rank test for time to first definite flare).

% of Patients With Definite Flare (Baseline SLEDAI >2)

Placebo, 31%

Prast erone, 24%

14.2 Reduction In Risk of Death In the GL95-02 study (discussed above), five placebo patients died, and no prasterone- treated patients died. These data show a statistically significant and clinically meaningful reduction in risk of death by any cause. In the GL94-01, GL95-01 and GL95-02 clinical trials (pooled data), the prasterone treated group (including prasterone-treated crossover patients) experienced 8 deaths among 495 patients, or a risk of death of 1.62%. In contrast, the placebo group experienced 6 deaths among 77 patients, or a risk of death of 7.80%.

14.2.1 Clinical Study GL94-01 Study GL94-01 compared the proportion of patients achieving sustained reduction of daily corticosteroid dose, without worsening of signs and symptoms of SLE (“Responders”), in placebo (n = 64) and prasterone 200 mg (n = 64) groups for about 7 months. For all randomized patients, 26/64 (41%) placebo and 35/64 (55%) prasterone 200 mg patients responded: a strong trend in favor of prasterone (p = 0.110). For patients with baseline SLEDAI >2, 13/45 (29%) placebo and 23/45 (51%) prasterone 200mg patients responded (p = 0.031). 15 HOW SUPPLIED / DOSAGE AND HANDLING Prastera® (prasterone, pharmaceutical grade) softgels 200mg are oblong, bi-colored blue and white soft, liquid filled gelatin capsules, NDC 55607-798-21. Store at not more than 25° C (77° F). Excursions are permitted to 15° C to 30° C (59° F to 86° F). See United States Pharmacopoeia, Controlled Room Temperature. Protect from excessive moisture or humidity. Dispense in a tight, light-resistant container as defined in USP/NF, using a child-resistant closure system, accompanied by a Patient Insert and in a convenience pack together with clindamycin phosphate topical pledgets. Keep out of reach of children. Manufactured for: Health Science Funding, LLC 55 Madison Avenue, 4th floor Morristown, NJ 07960 [email protected]

16 PATIENT COUNSELING INFORMATION See Medication Guide (§17) for specific patient instructions.

16.1 Patient / Caregiver Instructions Inform patients of the following information before initiating therapy with PRASTERA® and periodically during the course of on-going therapy. Encourage patients to read the Medication Guide that accompanies each prescription dispensed, prior to using PRASTERA®.

16.2 Benefits Oral prasterone 200 mg / day reduced the risk of auto-immune flare, §§6.2, 14.1, and significantly reduced the risk of death, §§6.4, 14.2, in placebo-controlled, randomized, blinded

clinical studies (GL94-01, GL95-01, GL95-02 and GLB96-01) in female patients with Systemic Lupus Erythematosus. Results observed in clinical trials may not, however, reflect the rates observed in practice. PRASTERA® does not cure, mitigate, treat or prevent the patient’s underlying SLE. To the contrary, the patient will continue to have SLE. The patient therefore should continue to be monitored by a physician and should continue other therapy (e.g., prednisone, NSAID) as believed appropriate. Oral prasterone reduced the risk of auto-immune flare and death. See above. PRASTERA® may not, however, make the patient feel significantly different on a day-to-day basis. This does not mean PRASTERA® is not working; it may take at least six months of continuous therapy to achieve a statistically-significant reduction in risk of flare and death. §14.

16.3 Other Medications PRASTERA® is a synthetic form of 5-dehydroepiandrosterone. PRASTERA® should not be combined with dietary supplements containing “DHEA” or “dehydroepiandrosterone.” PRASTERA® is a precursor to testosterone and estrogens. If PRASTERA® is used in conjunction with testosterone or estrogens, levels of serum testosterone and estrogens should be monitored closely to assure levels do not exceed the range seen in healthy women of similar age.

16.4 Adverse Reactions PRASTERA® may cause acne. Your Prastera® includes a topical anti-acne drug should you need it. Prasterone-associated acne is reversible on cessation of prasterone therapy. PRASTERA® may cause hirsutism, reversible on cessation of prasterone therapy. PRASTERA® may cause hypertension, §6.3.2, and/or changes in serum lipids, §7.2.4, or serum hormone levels, §7.2.1. These should be monitored, and are reversible on cessation of prasterone therapy.

16.5 Pregnancy Instruct patients who are nursing, pregnant or intending to become pregnant, not to use PRASTERA®.

17 MEDICATION GUIDE PRASTERA® is a copy of a naturally-occurring pre-hormone. W omen with SLE often have depressed levels of this pre-hormone; your doctor has prescribed PRASTERA® for you, to supplement your body’s level of this pre-hormone. Use PRASTERA® exactly as your doctor tells you. You likely will not feel any different taking PRASTERA®. This does not mean that it is not working, so keep taking it unless your doctor tells you not to, or unless you feel you are having an adverse reaction to it. In clinical studies, oral prasterone reduced lupus patients’ risk of auto-immune flare and death. PRASTERA® does not, however, cure, mitigate, treat or prevent SLE. Thus, even after taking your PRASTERA®, you will continue to have SLE. You therefore should continue to see your physician and should continue other therapy your physician believes appropriate. PRASTERA® may cause acne. If so, we’ve included a mild topical anti-acne product for you in your kit. If that does not work, talk with your health care provider because acne should go away simply by stopping PRASTERA®. PRASTERA® may cause hirsutism (unwanted body hair). This is reversible by stopping taking PRASTERA®. PRASTERA® may cause abdominal pain, hypertension, and/or changes in serum lipids or serum hormone levels; your doctor may want to monitor these. Tell your doctor what other drugs or dietary supplements you are taking. If you are taking PRASTERA®, you should not use any dietary supplement containing “DHEA” or “dehydroepiandrosterone.” If you are pregnant, intending to become pregnant, or are nursing, do not use PRASTERA®. Store PRASTERA® at not more than 25° C (77° F), and protect from excessive moisture or humidity. Keep out of reach of children. For medical advice about suspected side effects, call your doctor. You may report suspected side effects to your doctor, or the FDA at 1 (800) 332-1088, or your pharmacist. Manufactured for: Health Science Funding, LLC 55 Madison Avenue, 4th floor Morristown, NJ 07960 info@ healthsciencefunding.com

© 2012 Health Science Funding, LLC. All rights reserved. Patent pending. The PRASTERA name, PRASTERA device, product color scheme and package configuration are each trademarks of Health Science Funding, LLC.

1 Sahelian R & Borken S: Dehydroepiandrosterone and cardiac arrhythmia. Ann Intern Med 1998; 129(7):588. 2 Morales AJ, Haubrich RH, Hwang JY, et al: The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age- advanced men and women. Clin Endocrinol 1998; 49:421-432. 3 Villareal DT, Holloszy JO, & Kohrt WM: Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol 2000a; 53:561-568. 4 Buster JE, Casson PR, Straughn AB, et al: Postmenopausal steroid replacement with micronized dehydroepiandrosterone: preliminary oral bioavailability and dose proportionality studies. Am J Obstet Gynecol 1992; 166(4):1 163-1170. 5 Dean CE: Prasterone (DHEA) and mania. Ann Pharmacother 2000b; 34(12):1419-1 422. 6 Pies R: Adverse neuropsychiatric reactions to herbal and over-the-counter "antidepressants". J Clin Psychiatry 2000; 61(11 ):81 5-820. 7 Mortola, J.F. et al., The Effects of Oral Dehydroepiandrosterone Supplementation in Early and Late Menopause, Gynecol. Endocrinol. vol. 14 pp. 342-63 (2000). 8 Arlt W, Justl H-G, Callies F, et al: Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83:1928-1 934. 9 Meno-Tetang GML, Blum RA, Schwartz KE, et al: Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J Clin Pharmacol 2001; 41(1 1):1 195-1 205. 10 Meno-Tetang GML, Blum RA, Schwartz KE, et al: Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women. J Clin Pharmacol 2001; 41(1 1):1 195-1 205. 11 Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older adults. J Clin Pharmacol 2000b; 40(6):596- 605. 12 Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older adults. J Clin Pharmacol 2000b; 40(6):596- 605. 13 Longcope C: Dehydroepiandrosterone metabolism. J Endocrinol 1996; 1 50(suppl):S1 25-S1 27. 14 Barrett-Connor E, von Muhlen D, Laughlin GA, et al: Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo study. J Am Geriatr Soc 1999; 47:685-691. 15 Friess E, Schiffelholz T, Steckler T, et al: Dehydroepiandrosterone - a neurosteroid. Eur J Clin Invest 2000; 30(Suppl 3):46-50. 16 Sulcova J, Hill M, Hampl R, et al: Effects of transdermal application of DHEA on the levels of steroids, gonadotropins and lipids in men. Physiol Res 2000; 49(6):685-693. 17 Haning RV Jr, Flood CA, Hackett RJ, et al: Metabolic clearance rate of dehydroepiandrosterone sulfate, its metabolism to testosterone, and its intrafollicular metabolism to dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone in vivo. J Clin Endocrinol Metab 1991; 72(5):1 088-1095; Morales AJ, Haubrich RH, Hwang JY, et al: The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age- advanced men and women. Clin Endocrinol 1998; 49:421-432. 18 Bird CE, Murphy J, Boroomand K, et al: Dehydroepiandrosterone: kinetics of metabolism in normal men and women. J Clin Endocrinol Metab 1978; 47(4):81 8-822. 19 Schwarz HP: Conversion of dehydroepiandrosterone sulfate (DHEA-S) to estrogens and testosterone in young non-pregnant women. Horm Metab Res 1990; 22(5):309-310. 20 Arlt W, Justl H-G, Callies F, et al: Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83:1928-1 934. 21 Davidson M, Marwah A, Sawchuk RJ, et al: Safety and pharmacokinetic study with escalating doses of 3- acetyl-7-oxo-dehyd roepiand rosterone in healthy male volunteers. Clin Invest Med 2000; 23(5):300-310.

22 Arlt W, Justl H-G, Callies F, et al: Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83:1928-1 934. 23 Davidson M, Marwah A, Sawchuk RJ, et al: Safety and pharmacokinetic study with escalating doses of 3- acetyl-7-oxo-dehyd roepiand rosterone in healthy male volunteers. Clin Invest Med 2000; 23(5):300-310. 24 Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older adults. J Clin Pharmacol 2000b; 40(6):596- 605. 25 Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older adults. J Clin Pharmacol 2000b; 40(6):596- 605. 26 Frye RF, Kroboth PD, Kroboth FJ, et al: Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple- dose administration in healthy older adults. J Clin Pharmacol 2000b; 40(6):596- 605. 27 Wilson, Susan D., Non-Clinical Evaluation of GL701 [prasterone]: NDA 21-239 (April 19, 2001).

Health Science Funding, LLC

13 September 2012

Dr. Benson SILVERMAN, M.D. Director – Infant Formula & Medical Foods (Dept DHK3) CPK- 1 Bldg., Room 4C-095 5100 Paint Branch Road College Park, MD 20740 [email protected] BY ELECTRONIC MAIL

Re: Medical Food Package Insert Review

Dear Dr. Silverman, Almost two years ago, you generously took your time to discuss with me the regulation of medical foods. I’d like to ask you for some further guidance. We’re readying the commercial launch of a new medical food. We’re simply taking a product already freely on sale, and restricting it to prescription access to assure a physician stays involved. We have several placebo-controlled, double-blinded randomized clinical studies supporting efficacy. (These studies were done to support an NDA, but the Sponsor ran out of money. We thus have perhaps the most thorough efficacy and toxicology package in the history of medical foods.) => Might I ask you to look at our proposed package insert (enclosed) and let me know if you would like any required changes? I enclose a copy of our draft insert, together with copies of several of the supporting clinical studies. If you like, I can also send pharmacology, toxicology, etc., but I sense the enclosed information may be adequate for the current inquiry.

55 Madison Avenue, 4th floor Morristown, New Jersey 07960-7397 U.S.A. HEALTH SCIENCE FUND ING , LLC 13 September 2012 Page 2

Many thanks in advance for your help, and please let me know if you need anything further! Kind regards, HEALTH SCIENCE FUNDING, LLC

/s/ Mark Pohl, Tel. + 1 (973) 984-0076 [email protected] Enclosures: PRASTERA® package insert (13 Sept 2012 draft) Chang et al. (2002) Petri et al. (2002) Petri et al. (2004)

Health Science Funding, LLC

5 November 2012

Dr. Benson SILVERMAN, M.D. Director – Infant Formula & Medical Foods (Dept DHK3) CPK- 1 Bldg., Room 4C-095 5100 Paint Branch Road College Park, MD 20740

Re: Medical Food Package Insert Review

Dear Dr. Silverman, Many thanks for your letter of Oct. 17th. From it, I understand that your office does not generally do pre-marketing reviews, but in this case you have done me the courtesy of taking the extra effort to review our proposed insert nonetheless. Many thanks for your help. Might I ask for a bit more help? Your letter mentions “serious questions and concerns.” Might I ask what those questions and concerns are? With that information, I can perhaps provide acceptable answers and fixes for you. Many thanks in advance for your help, and I look forward to hearing from you soon, HEALTH SCIENCE FUNDING, LLC

/s/ Mark Pohl, Tel. + 1 (973) 984-0076 [email protected]

55 Madison Avenue, 4th floor Morristown, New Jersey 07960-7397 U.S.A.

Health Science Funding, LLC

27 November 2012

Dr. Benson SILVERMAN, M.D. Director – Infant Formula & Medical Foods (Dept DHK3) CPK- 1 Bldg., Room 4C-095 5100 Paint Branch Road College Park, MD 20740

Re: Medical Food Package Insert Review

Dear Dr. Silverman, I trust this note finds you well. Having received no response to my letter of 05 November (copy enclosed), I sense that you have thought through my proposed product and its accompanying labeling, and now see how it all comports with the statute. We're thus planning to launch commercially as soon as stability testing is complete. Thus, with my apologies in advance for any inconvenience, if you have any lingering concerns, objections or questions, you'll need to let me know exactly what they are (email is fine, [email protected]) not later than close of business (Washington, D.C. time) on Friday Dec. 7th, 2012. If I don’t hear from you by then, I’ll assume the agency has no objections. Many thanks in advance for your help, and I look forward to hearing from you soon, HEALTH SCIENCE FUNDING, LLC

/s/ Mark Pohl, Tel. + 1 (973) 984-0076 [email protected]

55 M adison Avenue, 4th floor M orristow n, N ew Jersey 07960-7397 U .S.A.

11 December 2012, 15:09 Ms. Shawne Sugs-Anderson from the FDA Medical Foods staff (202) 402-1459, calling in response to a letter dated Nov. 27th that we just received about the ... intended launch of product that contains DHEA.

We definitely have some concerns regarding the product.

Primarily, the assumption that because this product contains an ingredient that is commonly used as a dietary supplement that somehow that automatically allows it to be used in medical food, and that couldn't be farther from the truth.

The other issue is that we acknowledge that the ingredient proposed to be used on included in the product could or may be effective in managing the symptoms of certain individuals with SLE, we are not aware of any distinctive nutritional requirements that have been established by medical or scientific evaluation for SLE.

Many products, naturally occurring as well as formulated, will provide benefits to individuals affected affected by multiple diseases and conditions. However, efficacy alone does not qualify a product to be marketed as a Medical Food.

First and foremost, the product must meet the burden of the statutory definition of medical food.

Based on the materials you provided, along with other publicly-accessible studies and resources, this product does not appear to meet that standard.

So please by all means get back in touch with us. Bye { w Ç    C  W a  t  t  [  /  a  !a  t " [[# b % 5 &'('&)*+ **++ !a Ç  { .!/  {#  !{# { .!/ " / 0%

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Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions W arning Letters Inspections, Compliance, Enforcement, and Criminal Investigations Pan American Laboratories, LLC

Public Health Service Department of Health and Human Services Food and Drug Administration College Park MD 20740 NOV 20 2009 Eric M. Wingerter President Pam American Labs, L.L.C. 4099 Highway 190 Covington, Louisiana 70433

WARNING LETTER

Re: CFSAN-OC-10-02

Dear Mr. Wingerter: This is to advise you that the Food and Drug Administration (FDA) reviewed your websites at the Internet addresses http://www.neevoprenatal.com and http://www.pamlab.com in November 2009. Your Neevo caplets prenatal product is labeled as a "medical food," and the labeling claims on your websites represent the product as a medical food for the dietary management of those women under a physician's treatment for vitamin deficiency throughout pregnancy, postnatal and the lactating periods. In addition, your product is indicated for the distinct nutritional requirements of older obstetrician (OB) patients, high-risk pregnancies and DB patients with the methylenetetrahydrofolate reductase (MTHFR) folate polymorphism. This product is misbranded under Section 403(a)(l) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 343(a)(l)], because the label is false and misleading in that the product is labeled and marketed as a medical food but does not meet the statutory definition of a medical food in the Orphan Drug Act [21 U.S.C. § 360ee(b)(3)] or the criteria set forth in 21 C.F.R. 101.9(j)(8). The Orphan Drug Act defines "medical food" as "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation." The regulation in 21 C.F.R. 101.90)(8) sets forth criteria to clarify the statutory definition of a medical food. Specifically, this regulation provides that a food is a medical food only if: i. It is a specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding tube; ii. It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone; iii. It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation; iv. It is intended to be used under medical supervision; and v. It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food. FDA considers the statutory definition of "medical food" to narrowly constrain the types of products that fit within this category.1 In addition to other criteria, medical foods must be for the dietary management of a specific disorder, disease, or condition for which there are distinctive nutritional requirements and must be intended to be used under medical supervision.2 Patients with such a disorder, disease, or condition must have a limited capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or have other special medically determined nutrient requirements, which cannot be managed by the modification of the normal diet alone.3 Medical foods are not those simply recommended by a physician as part of an overall diet to reduce the risk of a disease or condition.4 As discussed further below, your prenatal product as reviewed on the aforementioned websites does not meet the regulatory criteria for a medical food. Your website and the labeling information promotes your product for women planning to become pregnant, pregnant women (including older women), high-risk pregnant women, women with the MTHFR polymorphism (pregnant or nonpregnant), and post-partum women (including lactating women). Specifically, your product is intended for the dietary management of planned pregnancy (with/without MTHFR polymorphism), pregnancy (high-risk, in older women, with MTHFR polymorphism), postpartum and lactating women with distinctive nutritional requirements for specific nutrients, primarily L-Methyfolate and folic acid,5 and some or all of the following nutrients: vitamin E, vitamin C, vitamin D3, vitamin BI, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin B12, biotin, calcium, iron, , copper, and . Pursuant to 21 C.F.R. 101.9(j)(8)(ii), a medical food must be intended for a patient who has a limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone. While your website states that the patients for whom your product is intended have "distinct nutritional requirements" and implies that diet alone may not supply the full amount of nutrients necessary for women who are pregnant, planning to become pregnant, or are lactating, there is no available evidence that the levels of folic acid and other micronutrients necessary for pregnancy or lactation cannot be achieved by the modification of the normal diet alone. To the contrary, it is not only possible, but practicable for women who are pregnant, planning to become pregnant, or lactating to follow the 10M and FDA recommendations for folic acid intake within a normal diet. Specifically, given the widespread fortification of flours, breads, cereals, pastas, rice, and other grain products with folic acid as required by FDA regulations,6,7 and the variety of available foods in which folic acid occurs naturally,8 it would not be difficult for a woman to consume up to 800 micrograms of folic acid per day (FDA's recommended daily folic acid consumption for pregnant women) through diet alone. Furthermore, folic acid can be readily obtained from dietary supplements, such as folic acid tablets and multivitamins containing folic acid. Because the Neevo prenatal product is intended for the dietary management of a condition with nutrient requirements that can be met through the modification of the normal diet alone, this product does not meet the regulatory criterion for medical foods set forth in 21 C.F.R. 101.9(j)(8)(ii). Accordingly, your product is misbranded within the meaning of Section 403(a)(1) of the Act because the label is false or misleading in that the product is labeled as a medical food but does not meet the definition of a medical food. This letter may not be an all inclusive review of your websites or the products your firm markets. It is your responsibility to ensure that all products marketed by your firm are in compliance with the requirements of the Act and all applicable regulations. Failure to promptly correct violations may result in regulatory action being initiated by FDA without further notice, such as seizure and/or injunction. In addition to the violation described above, we have a comment on the label for your Neevo prenatal product, which appears to contain an NDC number. For your information, NDC numbers are intended for uniquely identifying drugs and should not be used on the labels of products that are not drugs. The presence of an NDC number on a product that is not a drug may be a false or misleading representation that misbrands the product under Section 403(a)(1) of the Act. Please respond in writing within 15 working days from your receipt of this letter. Your response should outline the specific actions you are taking to correct these violations and to prevent similar violations. You should include in your response documentation such as revised labels, or other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, we expect that you will explain the reason for the delay and state when you will correct any remaining violations. Your response should be directed to Quyen Tien, Compliance Officer, Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Compliance, Division of Enforcement, 5100 Paint Branch Parkway (HFS-608), College Park, Maryland 20740. If you have any questions regarding this letter, please contact Mr. Tien at the above address or by phone at 215-717-3705.

Sincerely, /S/ Roberta F. Wagner Director Office of Compliance Center for Food Safety and Applied Nutrition cc: FDA New Orleans District Office ______1 See 56 Fed. Reg. 60366, 60377 (Nov. 27, 1991); see also Guidance for Industry: Frequently Asked Questions About Medical Foods, May 2007. 2 See 21 U.S.C. § 360ee(b)(3); see also 56 Fed. Reg. at 60377. 3 See 21 C.F.R. 101.9(j)(8)(ii); see also 56 Fed. Reg. at 60377. 4 See 56 Fed. Reg. at 60377. 5 The Institute of Medicine recommends that adults consume at least 400 mcg folic acid each day, that lactating women consume at least 500 mcg each day, and that pregnant women consume at least 600 mcg each day. FDA recommends that adults consume 400 mcg folic acid each day and that pregnant and lactating women consume 800 mcg folic acid each day. 6 See 21 C.F.R. 136.115, 137.165, 137.185, 137.235, 137.260, 137.305, 137.350, 139.115, 139.122, & 139.155. 7 See Final Rule, Food Standards: Amendment of Standards of Identity for Enriched Grain Products to Require Addition of Folic Acid, 61 Fed. Reg. 8781 (March 5, 1996). Under FDA's folic acid fortification program, which became effective January 1998, the agency requires manufacturers to add from 0.43 mg to 1.4 mg of folic acid per round of product to enriched flour, bread, rolls and buns, farina, corn grits, cornmeal, rice, and noodle products. 8 Folate occurs naturally in a variety of foods, including liver; dark-green leafy vegetables such as collards, turnip greens, and Romaine lettuce; broccoli and asparagus; citrus fruits and juices; whole-grain products; wheat germ; and dried beans and peas, such as pinto, navy and lima beans, and chickpeas and black-eyed peas; see also "How Folate Can Help Prevent Birth Defects, FDA Consumer, February 1999.

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Ganeden Biotech Inc. 08-Dec-06

Department of Health and Human Services Public Health Service Food and Drug Administration Cincinnati District Office Central Region 6751 Steger Drive

Cincinnati, OH 45237-30977 Telephone: (513) 679-2700 FAX: (513) 679-2761

December 8, 2006 VIA FEDERAL EXPRESS WARNING LETTER CIN-07-31056-07 Andrew R. Lefkowitz President and Chief Executive Officer Ganeden Biotech, Inc. 5915 Landerbrook Drive, Suite 304 Mayfield Heights, OH 44124-4034 Dear Mr. Leflcowitz: An Investigator from the U.S. Food and Drug Administration (FDA) performed an inspection of your facility from August 30, 2006 to August 31, 2006. During the inspection, the investigator collected labels and other labeling from some of your products, including Digestive AdvantageTM Lactose Intolerance Therapy, Digestive AdvantageTM Children's Lactose Intolerance Therapy, Dermal AdvantageTM Psoriasis, Digestive AdvantageTM Constipation Therapy, Arthritis AdvantageTM Arthritis Therapy, Digestive AdvantageTM Crohn's & Colitis Therapy, Digestive AdvantageTM Gas Prevention Therapy, and Digestive AdvantageTM Irritable Bowel Syndrome. FDA has reviewed your labels and labeling for,these products and found serious violations of the Federal Food, Drug, and Cosmetic Act (the Act). You can find the Act and its implementing regulations on FDA's website at http://www.fda.gov1 Your products are labeled as "medical foods," and the product names and labeling claims represent the products as intended for use for diseases and other medical conditions. However, your products do not meet the definition of a medical food in 21 USC 360ee(b)(3), which defines a medical food as a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. The regulations further define a medical food as one that is intended for the dietary management of a patient who has special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone [21 CFR 101.96)(8)(ii)]. Your products are not medical foods because the diseases and conditions described in the product labels do not have distinct nutritional requirements established by medical evaluation and because the products do not have any unique impact on the dietary management of those diseases and conditions beyond that which could be achieved by modification of the normal diet alone. Misbranded Foods Your products Digestive AdvantageTM Lactose Intolerance Therapy, Digestive AdvantageTM Children's Lactose Intolerance Therapy, Dermal AdvantageTM Psoriasis, Digestive AdvantageTM Constipation Therapy, Arthritis AdvantageTM Arthritis Therapy, Digestive AdvantageTM Crohn's & Colitis Therapy, Digestive AdvantageTM Gas Prevention Therapy, and Digestive

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AdvantageTM Irritable Bowel Syndrome are misbranded within the meaning of Section 403(a)(1) of the Act 21 U.S.C. § 343(a)(1)] because the labels are false or misleading in that the products are labeled as medical foods but do not meet the definition of a medical food. In addition, since they are not medical foods and are not subject to the exemption from nutrition labeling afforded to medical foods, your products are also misbranded within the meaning of Section 403(q)(1) of the Act [21 U .S.C. § 343(q)(1)] because the labels do not bear nutrition labeling in the Nutrition Facts format, as required in 21 CFR 101.9. New Drugs Furthermore, the names of your products below and claims in their labeling indicate that the products are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Similar claims and testimonials appear on your website at http://www.ganedenbiotech.com. Examples of disease claims in your product labeling include the following: • Dermal AdvantageTM Psoriasis "For Daily Dietary Management of Psoriasis," "[H]elps to eliminate the symptoms of psoriasis," and "Helps Relieve: Redness, Cracking, Flaking, and Irritation." • Digestive AdvantageTM Once Daily Chronic Constipation Therapy. "For Those Who Suffer From Chronic Constipation" and "Helps Relieve Chronic Constipation." • Arthritis AdvantageTM Once Daily Arthritis Therapy "Clinically Proven to Reduce Pain & Increase Mobility" and "For Daily Dietary Management of Arthritis." • Digestive Advantage TM Once Daily Crohn's & Colitis Therapy "For Daily Dietary Management of Crohn's & Colitis," "Helps Reduce Episodes of Diarrhea" and "In a recent clinical study patients with Crohn's noted a 40% reduction in episodes of diarrhea. Experience the results for yourself." • Digestive Advantage TM Once Daily Irritable Bowel Syndrome "Clinically Proven to Manage Abdominal Pain and Bloating" and "For Daily Dietary Management of Irritable Bowel Syndrome." These claims, including the product names, are evidence that your products are intended for use as drugs within the meaning of Section 201(g)(1)(B) of the Act. Your products are also new drugs under section 201(p) of the Act because there is no evidence that these products are generally recognized as safe and effective for their intended uses. New Drugs may not be legally marketed in the U.S. without prior approval from FDA as described in section 505(a) of the Act [21 U.S.C. § 355(a)]. The above violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. It is your responsibility to ensure that products marketed by your firm comply with the Act and its implementing regulations. The Act authorizes the seizure of illegal products and injunctions against manufacturers and distributor of those products. You should take prompt action to correct these deviations and prevent their futures recurrence. Failure to do so may result in enforcement action without further notice. Federal agencies are advised of the issuance of all Warning Letters about drug products so that they may take this information into account when considering the award of contracts. Please notify this office, in writing, within fifteen (15) working days of the receipt of this letter, as to the specific steps you have taken to correct the violations noted above and to assure that similar violations do not occur. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed. Your response should be directed to Stephen J. Rabe, Compliance Officer at the address listed above. You can contact Mr. Rabe at 513-679-2700 ext. 163 with any questions regarding this letter. Sincerely, /S/ Carol A. Heppe District Director Cincinnati District

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Efficas, Inc. 28-Sep-07

Department of Health and Human Services Public Health Service Food and Drug Administration College Park, MD 20740

SEP 28 2007 WARNING LETTER CERTIFIED MAIL RETURN RECEIPT REQUESTED Efficas, Inc. 7007 Winchester Circle Suite 120 Boulder, CO 80301 Re : CFSAN-OC-07-0 5 Dear Sir or Madam : This is to advise you that the Food and Drug Administration (FDA) obtained a sample packet of your Efficas Care ™product and promotional literature entitled "efficas care ™ for ALLERGIES and ASTHMA" at the American Society of Pharmacognosy (ASP) conference in Portland, Maine during the week of June 14, 2007. FDA has reviewed the labeling for Efficas Care on your website at http://www.efficas.com, as well as the label of the sample packet we collected. This review found serious violations of the Federal Food, Drug, and Cosmetic Act (the Act). You can find the Act and its implementing regulations on FDA's website at http://www.fda.gov1 Your product is labeled as a "medical food," and the labeling claims on the sample packet and on your website represent the product as a medical food for the dietary management of allergies and asthma. However, your product does not meet the definition of a medical food in 21 U.S.C. § 360ee(b)(3), which defines a medical food as a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. Your product is not a medical food because, although allergies and asthma are diseases, neither has distinct nutritional requirements that are based on recognized scientific principles and established by medical evaluation. Misbranded Food Your product is misbranded within the meaning of Section 403(a)(1) of the Act [21 U.S.C. § 343(a)(1)] because the label is false or misleading in that the product is labeled as a medical food but does not meet the definition of a medical food. New Drug Furthermore, the therapeutic claims in your labeling indicate that the product is intended for the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Similar claims and testimonials also appear on your website. Examples of these claims in your product labeling include the following: •"efficas care for ALLERGIES and ASTHMA " • "Efficas Care™ is clinically proven to reduce leukotrienes that cause allergy and asthma symptoms ." • "More than 70% of sufferers report that Efficas Care™ relieves most or all of their allergy and asthma

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symptoms." • "In clinical trials, when Efficas Care ™ was added to a daily diet, the product of leukotrienes was suppressed in 75% of asthmatics." • (testimonial) "Now after 8 months of taking Efficas Care ™, I am completely free of asthma, off asthma medication ..." • "Efficas Care is a non-prescription medical food developed to safely and naturally inhibit the body's production of leukotrienes. Efficas Care contains a unique combination of two essential fatty acids found in nature, GLA and EPA, in just the right amounts and ratio to effectively block the production of leukotrienes. Leukotrienes are inflammatory molecules produced by immune cells in your body. They are involved in the inflammatory response and cause the narrowing of the airways, increased mucus production and tissue swelling associated with both allergies and asthma." • (testimonial) "I am eighteen years old and suffered from pollen allergies for most of my childhood, with severe congestion, watering eyes and frequent colds.I took weekly allergy shots for four years, with little relief. I was also on a daily regimen of Allegra, Singulair and Nasacort nose spray. I started taking Efficas Care this past summer, about 6 months ago. At first, the difference was subtle. .. but after a few months the improvement was dramatic! My symptoms are so minimal, I have entirely stopped all of my medications, and cut back my allergy shots to once a month. Even during the worst of the pollen season, I never need any medication. The only thing I have done to bring about this miraculous turn-around in my health is take Efficas Care daily." These claims are evidence that your product is intended for use as a drug within the meaning of Section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)]. Your product is also a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)] because this product is not generally recognized as safe and effective for its intended uses. New drugs may not be legally marketed in the U.S. without prior approval from FDA as described in section 505(a) of the Act [21 U.S.C. § 355(a)]. The above violations are not meant to be an all-inclusive list of deficiencies in your product and its labeling. It is your responsibility to ensure that products marketed by your firm comply with the Act and its implementing regulations. The Act authorizes the seizure of illegal products and injunctions against manufacturers and distributor of those products. You should take prompt action to correct these deviations and prevent their future recurrence. Failure to do so may result in enforcement action without further notice. Federal agencies are advised of the issuance of all Warning Letters about drug products so that they may take this information into account when considering the award of contracts. In addition to the violations described above, we have the following comments concerning the label of your 0.43 oz Efficas Care packets handed out as promotional samples at the ASP conference. Even if your product was a medical food, it would not comply with the labeling requirements for a medical food because: • The label does not include a statement of identity as required by 21 CFR 101.3. • The label does not provide a list of ingredients as required by 21 CFR 101.4. • The label does not provide the address of the manufacturer, packer or distributor as required by 21 CFR 101.5. For your information, the statement "This unit is not for individual retail sale" does not exempt a promotional sample of a food from bearing the required label information. Please notify this office, in writing, within fifteen (15) working days of the receipt of this letter, as to the specific steps you have taken to correct the violations noted above and to assure that similar violations do not occur. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed. Your response should be directed to Quyen Tien, Compliance Officer, Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Compliance, Division of Enforcement, 5100 Paint Branch Parkway (HFS-608), College Park, Maryland 20740. If you have any questions about this letter, please contact Mr. Tien at 215-717-3705. Sincerely, Joseph R. Baca Director Office of Compliance Center for Food Safety and Applied Nutrition

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3 of 3 5/21/2012 11:15 AM 2009 > Nestle Healthcare Nutrition, 12/3/09 http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2009/uc...

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Nestle Healthcare Nutrition, 12/3/09

Public Health Service Department of Health and Human Services Food and Drug Administration College Park. MD 20740 DEC 03 2009

David Yates President Nestle HealthCare Nutrition 10801 Red Circle Drive Minnetonka, Minnesota 55343 WARNING LETTER Re: CFSAN-OC-10-04 Dear Mr. Yates: This is to advise you that the Food and Drug Administration (FDA) reviewed your websites at the Internet addresses http://www.Nestle-Nutrition.com, www.NestleNutritionStore.com, and http://www.kidessentials.com in November 2009. Your BOOST Kid Essentials Nutritionally Complete Drink (Vanilla, Chocolate, and Strawberry flavors) is promoted on your websites as a "medical food," and the labeling claims on your websites represent the product as a medical food for the medical condition of "failure to thrive" and also for "pre/post surgery, injury or trauma, chronic illnesses." As discussed further below, this product is misbranded under Section 403(a)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 343(a)(1)], because the label is false or misleading in that the product is labeled and marketed as a medical food but does not meet the statutory definition of a medical food in the Orphan Drug Act [21 U.S.C. § 360ee(b)(3)] or the criteria set forth in 21 C.F.R. 101.9(j)(8). Furthermore, this product is promoted for conditions that cause it to be a drug under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)]. The therapeutic claims on your website establish that this product is a drug because it is intended for use in the cure, mitigation, treatment, or prevention of disease. The marketing of this product with these claims violates the Act. Misbranded Food The Orphan Drug Act defines "medical food" as "a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation." The regulation in 21 C.F.R. 101.9(j)(8) sets forth criteria to clarify the statutory definition of a medical food. Specifically, this regulation provides that a food is a medical food only if: i. It is a specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding tube; ii. It is intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone; iii. It provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation; iv. It is intended to be used under medical supervision; and v. It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires

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medical care on a recurring basis for, among other things, instructions on the use of the medical food. FDA considers the statutory definition of "medical food" to narrowly constrain the types of products that fit within this category.1 In addition to other criteria, medical foods must be for the dietary management of a specific disorder, disease, or condition for which there are distinctive nutritional requirements and must be intended to be used under medical supervision.2 Patients with such a disorder, disease, or condition must have a limited capacity to ingest, digest, absorb, or metabolize ordinary foodstuffs or certain nutrients, or have other special medically determined nutrient requirements, which cannot be managed by the modification of the normal diet alone.3 Medical foods are not those simply recommended by a physician as part of an overall diet to reduce the risk of a disease or condition.4 As discussed further below, your BOOST Kid Essentials Nutritionally Complete Drink product as reviewed on the aforementioned websites does not meet the regulatory criteria for a medical food. There is no evidence that patients with the medical condition of "failure to thrive" have distinctive nutritional requirements or unique nutrient needs, as required by the statute and by 21 C.F.R. 101.9(j)(8). This condition could arise due to a number of reasons, including inappropriate dietary intake or defective utilization by the body. Because of this, the nutritional requirements and nutrient needs of individuals with this condition vary widely among patients. In addition, there is no distinctive nutritional requirement for "pre/post surgery, injury or trauma, chronic illnesses," as the nutritional requirements of individuals with these conditions vary greatly based on the specific circumstances of each individual. No established distinctive nutritional requirement exists for the conditions for which your product is promoted as a medical food, and your BOOST Kid Essentials Nutritionally Complete Drink product therefore does not meet the statutory or regulatory definition of a medical food. Accordingly, your product is misbranded within the meaning of Section 403(a)(1) of the Act [21 U.S.C. § 343(a)(1)] because the label is false or misleading in that the product is labeled as a medical food but does not meet the definition of a medical food. New Drug Under section 201(g)(1)(B) of the Act [21 U.S.C. § 321(g)(1)(B)], articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease are drugs. The therapeutic claims on your websites establish that your BOOST Kid Essentials Nutritionally Complete Drink product is intended to be used as a drug. The marketing of this product with these claims violates the Act. Specific examples of claims in your product labeling that promote your product as a drug are as follows: • "[F]or pre/post surgery, injury or trauma, chronic illnesses ...." • "Lactobacillus [an ingredient in your product] is one of the most widely studied genera of probiotics, proving numerous health benefits across many illnesses." • "If your child has stomach problems, such as diarrhea caused by antibiotics, probiotics [an ingredient in your product] may help rebuild a healthy colony of good bacteria ..." • "Antioxidants [found in your product] ... can help kids fight off sickness at school, the playground, at home, or anywhere on-the-go." • "Clinical benefits include ... reducing number of days with viral diarrhea, reducing the risk of necrotizing enterocolitis (NEC) ...." In addition, when scientific publications are used commercially by the seller of a product to promote the product to consumers, such publications may become evidence of the product's intended use. For example, under 21 CFR 101.93(g) (2)(iv)(C), a citation of a publication or reference in the labeling of a product is considered to be a claim about disease treatment or prevention if the citation refers to a disease use and if, in the context of the labeling as a whole, the citation implies treatment or prevention of a disease. The following are examples of reference citations used to market your product for disease treatment and prevention on your website: • "Ivan A et al. Validation of the probiotic concept: Lactobacillus reuteri confers broad-spectrum protection against disease in humans and animals. Microbial Ecology in Health and Disease 2000;12(4)." • "Johnston BC et al. Probiotics for the prevention of pediatric antibiotic-associated diarrhea (review). Cochrane Database Syst Rev 2007;2: 1-34." • "Szajewska H et al. Probiotics in gastrointestinal diseases in children: hard and no-so-hard evidence of efficacy. J Pediatr Gastroenterol Nutr 2006;42(5):454-75." • "Weizman Z et al. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics 2005;115:5-9." Your product is not generally recognized as safe and effective for the above referenced uses and, therefore, it is also a new drug under section 201(P) of the Act [21 U.S.C. § 321(p)]. New drugs may not be legally marketed in the United States without prior approval from FDA as described in section 505(a) of the Act [21 U.S.C. § 355(a)]. FDA approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate that the drug is safe and effective. The above violations are not meant to be an all-inclusive list of deficiencies in your products or their labeling. It is your responsibility to ensure that all of your products are in compliance with the laws and regulations enforced by FDA. You should take prompt action to correct these violations. Failure to promptly correct these violations may result in regulatory actions without further notice, such as seizure and/or injunction. Please respond, in writing, within 15 working days from receipt of this letter. Your response should include the actions you plan to take in response to this letter, including an explanation of each step being taken to correct the current violations

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and prevent similar violations. Include any documentation necessary to show that correction has been achieved. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. Your response should be directed to Quyen Tien, Compliance Officer, Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of Compliance, Division of Enforcement, 5100 Paint Branch Parkway (HFS-608), College Park, Maryland 20740. If you have any questions regarding this letter, please contact Mr. Tien at the above address or by phone at 215-717-3705. Sincerely, /s/ Roberta F. Wagner Director Office of Compliance Center for Food Safety and Applied Nutrition cc: FDA Minneapolis District Office

______

1 See 56 Fed. Reg. 60366, 60377 (Nov. 27, 1991); see also Guidance for Industry: Frequently Asked Questions About Medical Foods, May 2007. 2 See 21 U.S.C. § 360ee(b)(3); see also 56 Fed. Reg. at 60377. 3 See 21 C.F.R. 101.9(j)(8)(ii); see also 56 Fed. Reg. at 60377. 4 See 56 Fed. Reg. at 60377.

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Garden of Life, Inc. 11-May-04 Public Health Service Department of Health and Human Services' logoDepartment of Health and Human Services Food and Drug Administration 555 Winderley Pl., Ste. 200

Maitland, FL 32751

CERTIFIED MAIL RETURN RECEIPT REQUESTED WARNING LETTER FLA-04-31 May 11, 2004 Robert U. Craven, CEO Garden of Life inc. 5500 North Village Blvd. Suite 202 West Palm Beach, Florida 33407-1901 Dear Mr. Craven: From January 8 to January 23, 2004, the Food and Drug Administration inspected your firm at 1449 Jupiter Park Drive, Jupiter, Florida. During this inspection, the investigator collected copies of product labels, brochures, advertising materials, and other documents. Our review of these materials finds that your products are in violation of the Federal Food, Drug, and Cosmetic Act (the Act). You can find the Act and implementing regulations on our Internet web site at www.fda.gov1. Products Labeled as Dietary Supplements Under the Act, articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man are drugs [Section 201(g)(1)(B) of the Act]. We have reviewed labeling (including promotional materials) for a number of your products and have found the labeling to include disease claims that cause your products to be drugs as defined in section 201 (g)(1)(B) of the Act. These claims include:

Q-Zyme (OmegaZyme):

Brochure:

Amylase - —Acts in association with lipase to digest fragments of viruses and reduce inflammation and infections.“

Lactase - —May be beneficial for those suffering from irritable bowel syndrome.. . .“

Papain - —Used to treat chronic diarrhea and celiac disease. Treats gastrointestinal discomfort due to intestinal parasites.“

Poten-Zyme Cat‘s Claw Extract - —Cat‘s claw has been used . . . as a treatment for . . . urinary track infections and arthritis.“

The product brochure also contains claims that imply that this product is useful for the treatment or prevention of numerous diseases, including colon cancer and arthritis.

Primal Defense:

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Trifold:

Testimonial: —this product is the primary therapy I employ on a routine basis, especially as a treatment for patients suffering from inflammatory bowel disease.—

Testimonial: —I am enthusiastic about Primal Defense as a treatment for Autism. . . .“

—[Been shown to drastically reduce populations of yeast, parasites and bad bacteria in the intestines.“

Fungal Defense:

Trifold:

—Powerful Anti-Candida Formula“

—Contains Potent Anti-Yeast and Anti-Fungal Compounds. . . [Certain conditions can cause fungi to multiply, weakening the immune system and causing infection. . . Fungal Defense delivers nature‘s most effective anti-yeast and anti-fungal compounds to actively help eliminate Candida from your body.. . .Fungal Defense contains the most powerful anti-fungal substances found in nature. Wild Oregano and Olive Leaf Extracts are recognized for their potent anti-fungal, anti-bacterial, anti-viral, and anti-parasitic properties.“

Taken together, statements in this document imply that the product will treat Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD). For example, the section titled, ”What is Candida“ states —[yeast overgrowth.. .is especially prevalent in hyperactive children and those with ADD and ADHD,“ and the section titled, —A Word on Diet“ states that —[t]he powerful ingredients in Fungal Defense are specifically targeted to destroy yeast.. .“

Extra Virgin Coconut Oil:

Trifold:

—Contains Antibacterial, Antiviral, Anti-fungal Properties“

—Helps to improve HDL and LDL Cholesterol Ratios“

—Coconut oil has been shown to . . . help prevent bacterial, viral and fungal infections.“

Fruits of Life:

Product information sheet

—Research has shown that rheumatoid arthritis, chronic fatigue and even certain types of cancer are the direct result of free radical damage. The destruction of healthy cells may be avoided by simply adding.. . Fruits of Life to your daily diet.“

Raisin: —contain . . . a phytonutrient shown to have cancer-prevention effects. “ —Raisins are a rich sources of polyphenols and proanthocyanidins, which are recommended in prevention and treatment protocols for cardiovascular disease, cancer.. . asthma, diabetes, liver disease, cataracts, and macular degeneration.“

Flavonoids: —Flavonoids contain antibacterial and antiviral properties.. . ." —The flavonoids present in Fruits of Life . ..strengthen and repair . . . cardiac irregularities arising from a decrease in blood flow and arterial blockage.“

Ellagic Acid: —Ellagic acid helps inhibit four different types of cancer causing agents.. . “ —ellagic acid reduces the incidence of birth defects, promotes wound healing, reduces and reverses chemically induced liver fibrosis, and is helpful in the fight against heart disease.“

Lists the following diseases and implies the product is useful in preventing or treating them: cancer, arteriosclerosis, high blood pressure, diabetes, arthritis, gout, kidney disease, chronic fatigue, osteoporosis, asthma, allergies, obesity, and tooth and gum diseases.

FYI - For Your Inflammation:

Tri-fold:

—FYI consists of cartilage building proteins and mucopolysaccharides.. ., systemic enzymes, and specific whole foods and herbs . . . . These compounds contain powerful anti-bacterial and antiviral properties..“

Taken together, claims in this document imply that the product will treat disease such as arthritis. Examples of these claims include the following: —Components of FYI have been Clinically Proven to

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Reduce Effects of Inflammation;“ and —Contains Herbs that may Inhibit the COX-2 Inflammation process.“

Product information sheet

Lists the following disease claims and implies the product treats or prevents them: fibromyalgia, osteoarthritis, rheumatoid arthritis, bursitis, scleroderma, asthma, allergies, lupus, Chrons‘ and colitis.

Papain - —Papain is valuable as an anti-inflammatory agent as well as the ability to reduce the tissue irritation and joint inflammation in rheumatoid arthritis.“

Chicken Collagen Type II - —contains anti-inflammatory properties and has been clinically demonstrated to decrease pain and discomfort stemming from joint disorders.“

Poten-Zyme Cat‘s Claw Extract - —has been extensively used to treat a wide range of illnesses including asthma, urinary tract inflammation, inflammatory bowel disease, arthritis, rheumatism.. .."

RM-10:

Trifold:

—Potent Anti-Viral, Anti-Bacterial, and Anti-Fungal properties“

Testimonial: —It is effective in all degenerative autoimmune conditions“

—Surviving Cancer at 80“

Product catalog

Lists the following diseases and implies the product is useful in treating or preventing them: hepatitis, cancer, diabetes, AIDS, rheumatoid arthritis, Lupus

RevivAlI Classic:

Product information sheet

—Plant fats (phytosterols and sterolins) have been found to be effective in balancing immune response and useful in the treatment of autoimmune diseases like lupus and multiple sclerosis, as well as infectious diseases such as HIV, tuberculosis, and hepatitis C“

—Malignancies: Phytosterols and sterolins may block the development of tumors in the colon, breast, and prostate glands..."

In addition, the book, PATIENT Heal Thyself, references a number of diseases and states, —make these health supplements to alleviate symptoms and get well.“ For example, your product, Primal Defense, is promoted for the treatment of autoimmune diseases such as Diabetes Type I, Grave‘s Disease, Lupus, Multiple Sclerosis, Myasthenia Gravis, Rheumatoid Arthritis, and Scleroderma, and —Brain Health“ diseases such as Alzheimer‘s Disease and Parkinson‘s. Your product, Zero Gravity, is promoted for the treatment of obesity and obesity-related diseases, such as cancer, diabetes, and heart disease. The book is considered labeling for your products, as it accompanies the products. Based on the claims noted above, these products are drugs under the Act, since they are intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man [Section 201 (g)(1)(B) of the Act]. Because the products are not generally recognized as safe and effective when used as labeled, they are also new drugs as defined in section 201 (p) of the Act. Under section 505 of the Act, a new drug may not be legally marketed in the United States without an approved New Drug Application (NDA). Under the Act, as amended by the Dietary Supplement Health and Education Act, dietary supplements may be legally marketed with claims to affect the structure or function of the body (structure/function claims), if certain requirements are met. FDA has published a final rule intended to clarify the distinction between structure/function claims and disease claims. This document is available on the Internet at http://vm.cfsan.fda.gov/~lrd/fr000106.html2 (codified at 21 C.F.R. § 101.93(g)). The manufacturer of a dietary supplement containing a —structure/function“ claim in the product‘s labeling must have substantiation that the claim is truthful and not misleading [21 U.S.C. § 343(r)(6)(B)] Medical Foods During the inspection, the investigator also collected copies of labels for your products labeled as medical foods, RM-10 OM, Primal Defense OM, Perfect Food OM, and Living Multi OM. These products do not meet the definition of medical food in 21 USC 360ee(b)(3), which defines a medical food as a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. The regulations further define a medical food as one that is intended for the dietary management of a patient who has special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the diet alone [21 CFR 101.9(j)(8)(ii)]. Your products RM-10 OM, Primal Defense OM,

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Perfect Food OM, and Living Multi OM are not medical foods because the product labels do not indicate that the products are intended for the specific dietary management of a disease or conditions for which distinctive nutritional requirements are established. Further, the diseases and conditions described in the product labeling do not have distinctive nutritional requirements and the products do not have any unique impact on the dietary management of those diseases and conditions beyond that which could be achieved by modification of the normal diet alone. Because these products do not meet the definition of a medical food, they are not subject to the exemption from nutrition labeling afforded medical foods. Therefore, your products RM-10 OM, Primal Defense OM, Perfect Food OM, and Living Multi OM are misbranded within the meaning of section 403(q)(1) of the Act because the labels do not bear nutrition labeling in the appropriate format as prescribed in 21 CFR 101.9. In addition, the labeling for the products RM-10 OM and FYI OM bears claims that indicate they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease in man. Examples of these claims include the following:

Original Medicine Wholefood Nutrition brochure:

RM-10 OM

—RM-10 OM....is known to improve the immunity of patients suffering from different conditions. An abnormally functioning immune system exposes you to many conditions such as; AIDS, Cancer, Allergies, M.S, Fibromyalgia, Diabetes, Syndrome X, Hepatitis, Rheumatoid Arthritis“

—Mushrooms and other foods have been used for centuries to defend against disease.“

FYI OM

—The following diseases, among others, produce inflammation: Alzheimers, Artherosclerosis, Cancer, Cardiovascular Disease, Osteoporosis, Arthritis, Stroke. FYI-OM‘s blend of foods has shown moderation of inflammation.. .“

These claims are evidence that the products are intended for use as drugs within the meaning of Section 201(g)(1)(B) of the Act. These products are new drugs under section 201 (p) of the Act because there is no evidence that these products are generally recognized as safe and effective for their intended uses. Therefore, they may not be legally marketed in the United States without approved new drug applications (section 505 of the Act). The above violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. It is your responsibility to ensure that products marketed by your firm and all labeling for such products comply with the Act and its implementing regulations. Labeling may include your websites www.gardenoflifeusa.com and www.silverspringsupplements.com , flyers, trifolds, product catalogs, books promoting your products, compact disks, training materials, and other sources. The Act authorizes the seizure of illegal products and injunctions against manufacturers and distributors of those products. You should take prompt action to correct these deviations and prevent their future recurrence. Failure to do so may result in enforcement action without further notice. Please advise this office, in writing within fifteen (15) working days of the receipt of this letter, as to the specific steps you have taken to correct the violations noted above and to assure that similar violations do not occur. If corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed.

We note that in your January 30, 2004 letter to Ms. Susan Corrales, you indicated that the medical food products are no longer being sold; however, they are still shown on your Internet web site. In addition, your letter states that the product materials are being revised and that the book PATIENT Heal Thyself will no longer be made available. Please provide the final version of any product brochures or accompanying materials that will be used. Your reply should be addressed to Shari H. Shambaugh, Compliance Officer, U.S. Food and Drug Administration, 555 Winderley Place, Suite 200, Maitland, Florida 32751. Sincerely, /s/ Emma R. Singleton Director, Florida District

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Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions W arning Letters Inspections, Compliance, Enforcement, and Criminal Investigations

Physician Therapeutics, LLC 4/8/10

Public Health Service Department of Health and Human Services Food and Drug Administration Los Angeles District Pacific Region 19701 Fairchild

Irvine, CA 92612-2506 Telephone: 949-608-2900 FAX: 949-608-4415

WARNING LETTER

CERTIFIED MAIL RETURN RECEIPT REQUESTED

April 8, 2010

W/L 14-10

William Shell, M.D. CEO Physician Therapeutics, LLC 2980 N. Beverly Glen Circle, Suite 301 Los Angeles, California 90077-1735

Dear Dr. Shell:

On (b)(4), FDA issued a warning letter to (b)(4), (copy attached). As explained more fully in that warning letter, certain drug products that (b)(4) has manufactured are new drugs that lack approved applications as required under the Federal Food, Drug, and Cosmetic Act (the Act). Based on information obtained during FDA's inspection of from (b)(4), your firm contracted or otherwise arranged with (b)(4) manufacture one or more drug products that your firm distributes. These drug products include, but are not necessarily limited to:

• Theracodophen-650 Convenience Pack (Hydrocodone 10 mg, Acetaminophen 650 mg, and Theramine);

• Strazepam Convenience Pack (Temazepam 15 mg and Sentra PM);

• Gabazolamine-0.5 Convenience Pack (Alprazolam 0.5 mg and GABAdone);

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• Gaboxetine Convenience Pack (Fluoxetine 10 mg and GABAdone);

• Trazamine Convenience Pack (Tradazone 50 mg and Sentra PM);

• Senophylline Convenience Pack (Theophylline 100 mg and Sentra PM);

• Therapentin-60 (Gabapentin 200 mg and Theramine);

• Prazolamine (Carisoprodol 350 mg and Theramine);

• Sentradine (Ranitidine 150 mg and Sentra PM);

• Therafeldamine (Piroxicam 20 mg and Theramine)

The above products are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321 (g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, they are "new drugs" within the meaning of section 201(P) of the Act [21 U.S.C. § 321(P)] because they are not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in their labeling. Under sections 301 (a) and (d) and 505(a) of the Act [21 U.S.C. §§ 331(a), (d) and 355(a)], a new drug may not be introduced into or delivered for introduction into interstate commerce unless an FDA approved application is in effect for the drug. Based on our information, you do not have any FDA-approved applications on file for these drug products.

Additionally, because the above prescription drug products are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written for them so that a layman can use these products safely for their intended uses, as described in 21 C.F.R. § 201.5. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(1) (1) of the Act [21 U.S.C. § 352(1)(1)]. Because the products lack required approved applications, they are not exempt under 21 C.F.R. § 201.115 from the requirements of section 502(1)(1) of the Act. The introduction or delivery for introduction into interstate commerce of these products without approved new drug applications violates sections 301(a) and (d) of the Act [21 U.S.C. §§ 331(a) and (d)].

Further, as explained in the warning letter dated (b)(4) to (b)(4) the above drug products are adulterated under 21 U.S.C. § 351(a)(2)(B), and thus your firm may not introduce or deliver them for introduction into interstate commerce, 21 U.S.C. § 331(a).

The violations cited in this letter are not intended to be an all-inclusive statement of violations that may exist in connection with your products. In particular, violations cited in this letter are not necessarily limited to drug products manufactured by (b)(4) and may apply to all drug products that you market and distribute without FDA-approved applications. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your film complies with all requirements of federal law and FDA regulations.

You should take prompt action to Correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure, and,' injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts.

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Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction. If you no longer market the above products, your response should so indicate, including the reasons that, and the date on which, you ceased production.

Your reply should be sent to:

Daniel Cline, Acting Director Los Angeles District Domestic Compliance Branch U.S. Food & Drug Administration 19701 Fairchild Irvine, CA 92612

If you have any questions regarding this letter, please contact John J. Stamp, Compliance Officer, at (949) 608-4464.

Sincerely, /S/ Alonza E. Cruse District Director

Enclosure cc: Acting Branch Chief Food and Drug Branch California Department of Public Health 1500 Capitol Avenue-MS 7602 P.O. Box 997413 Sacramento, CA 95899-7413

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http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm208680.htm 6/10/2013 Warning Letter to Metagenics, Inc. http://www.casewatch.org/fdawarning/prod/2003/metagenics.shtml

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Department of Health and Human Services Public Health Service Food and Drug Administration Los Angeles District 19701 Fairchild

Irvine, California 92612-2506 Telephone (949) 608-2900

CERTIFIED MAIL Return Receipt Requested

October 1, 2003

WARNING LETTER

W/L 53-03

Jeffrey J. Katke, CEO Metagenics, Inc. 100 Avenida La Pata San Clemente, California 92673

Dear Mr. Katke:

Investigators from the U.S. Food and Drug Administration (FDA) performed an inspection of your facility from May 6, 2003, to May 19,2003. During the inspection, the investigators collected labels from your products UltraClear®, UltraMeal®, UltraInflamX™, and UltraGlycemX™. FDA reviewed the labels for these products and found that the labels cause the products to violate the Federal Food, Drug, and Cosmetic Act (the Act) in several respects.

The products are labeled as “medical foods,” and are represented on the labels as intended for use with a variety of medical conditions. The products do not meet the definition of a medical food in 21 USC 360ee(b)(3), which defines a medical food as a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation. The regulations further define a medical food as one that is intended for the dietary management of a patient who has special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the diet alone [21 CFR 101.9(j)(8)(ii)]. Your products UltraClear®, UltraMeal®, UltraInflamX™, and UltraGlycemX™ are not medical foods because the diseases and conditions described in the product labels do not have distinct nutritional requirements and because the products do not have any unique impact on the dietary management of those diseases and conditions beyond that which could be achieved by modification of the normal diet alone.

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Because UltraClear®, UltraMeal®, UltraInflamX™, and UltraGlycemX™ do not meet the definition of a medical food, they are not subject to the exemption from nutrition labeling afforded medical foods. Therefore, your products are misbranded within the meaning of Section 403(q)(1) of the Act because the labels do not bear nutrition labeling in the appropriate format, as prescribed in 21 CFR 101.9. In addition, your products bear label claims suggesting that they are useful in the treatment of various diseases. These claims include:

UltraClear’ is formulated to nutritionally support overall liver detoxification activity and the removal of potentially harmful toxins associated with health conditions such as food allergies, chronic fatigue syndrome, . . . and migraine headaches.

“UltraMeal® is . . .designed to nutritionally support the management of conditions associated with altered body composition, including . . . hypertension . . . .”

“UltraInflamX™ NUTRITIONAL SUPPORT FOR INFLAMMATION” and “UltraInflamX™ is designed to nutritionally support patients with chronic inflammatory conditions, such as osteoarthritis, rheumatoid arthritis, psoriasis and eczema, as well as other conditions associated with excessive inflammation.”

“Designed to provide nutritional support for those with insulin resistance, or type 2 diabetes, UItraGIycemX™ promotes a healthy insulin and glucose response.”

The presence of the above referenced claims indicates that the products are intended to treat, cure, or mitigate diseases. Such claims are evidence that the products are intended for use as drugs within the meaning of Section 201(g)(1)(B) of the Act. The products are new drugs under section 201(p) of the Act because there is no evidence that these products are generally recognized as safe and effective for their intended uses.

Therefore, they may not be legally marketed in the United States without approved New Drug Applications (Section 505 of the Act). These products are also misbranded within the meaning of Section 502(f)(1) of the Act because the labeling fails to bear adequate directions for use. The above violations are not meant to be an all-inclusive list of deficiencies in your products and their labeling. It is your responsibility to ensure that products marketed by your firm comply with the Act and its implementing regulations.

The Act authorizes the seizure of illegal products and injunctions against manufacturers and distributors of those products. You should take prompt action to correct these deviations and prevent their future recurrence. Failure to do so may result in enforcement action without further notice.

Please advise this office, in writing, within fifteen (15) working days of the receipt of this letter, as to the specific steps you have taken to correct the violations noted above and to assure that similar violations do not occur. If corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed.

Your response should be directed to Mr. Larry Stevens, Compliance Officer, U.S. Food and Drug Administration, 19900 MacArthur Blvd., Suite 300, Irvine, CA 92612.

Sincerely, /s/

Alonza E. Cruse Director, Los Angeles District

2 of 3 5/21/2012 12:14 PM Warning Letter to Metagenics, Inc. http://www.casewatch.org/fdawarning/prod/2003/metagenics.shtml

This page was posted on July 9, 2005.

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3 of 3 5/21/2012 12:14 PM MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

DATE: February 20, 2001

FROM: Parivash Nourjah, Ph.D. Signed 02-26-01 Division of Postmarketing Drug Risk Assessment I, HFD-430

THROUGH: Julie Beitz, M.D. Signed 02-21-01 Director, Division of Postmarketing Drug Risk Assessment I HFD-430

TO: Kent Johnson, M.D. Division of Anti-Inflammatory, Analgesic, and Ophthalmologic Drug Products HFD-550

SUBJECT: Epidemiologic evidence of DHEA in the etiology of neoplasia PID#: D000665

SUMMARY We are not aware of any published epidemiologic studies that examine the cancer risk associated with exogenous dehydroepiandrosterone (DHEA) administration. However, one case-report was found to describe the medical condition of a patient with advanced prostate cancer after receiving DHEA. The cancer condition worsened after receiving DHEA, but when the patient stopped taking DHEA, the cancer regressed. Since the discontinuation of DHEA was accompanied by the initiation of estrogen therapy, the association of exogenous use of DHEA with the cancer progression is unclear.

In general the epidemiologic studies reviewed in this report have many limitations. Temporal precedence bias, small size, inability to control for confounding variables, and the method of DHEA measurement

1 are among the most common limitations of studies reviewed in this report. No meaningful conclusion about the association of exogenously administered DHEA and cancer risk can be made based on these epidemiologic studies of endogenous levels of DHEA.

INTRODUCTION This consult follows Dr. Brinker’s comprehensive report on the relationship of endogenous sex hormones and etiology of cancer dated January 4, 2000. The purpose of this consult is to review the literature again to identify any reports on exogenous use of DHEA and cancer risk.

In general, the epidemiological data addressing the association of endogeneous DHEA with cancer are very limited and the results are conflicting. The studies varied in study design and size, method of DHEA assessment, stage of cancer and ability to control for confounding variables. The study designs are either prevalence case-control or nested case-control studies. In general, the temporal association between DHEA levels and cancer cannot be established in prevalence case-control studies. In these studies, one cannot determine whether the change in DHEA level is caused by the cancer or whether any change in DHEA level is a predisposing factor for cancer. The size of the studies is often very small,so that, adjustment for confounding variables (even if they were collected) is not possible. In most studies reviewed, some of the important confounding variables were controlled by conducting a matched design followed by matched analysis.

In recent years, DHEA can be found at local health food stores, supermarkets, pharmacies, and Web pages from many companies, and is advertised as an antiaging agent. Therefore, any recent study of DHEA and cancer should consider both the use of DHEA as a dietory supplement and the level of endogenous DHEA. None of the recent studies ascertained any information on the exogenous use of DHEA. The method of measuring DHEA is also crucial and often is far from perfect in these studies. DHEA levels in serum change by diurnal and menstrual cycles. Thus any studies which examine DHEA should consider these cyclic sources of variability in their design.

2 We found one case-report study from the literature in which the author suggested that the administration of DHEA to patients with prostate cancer should be done with caution.

METHOD We conducted a literature search by using the National Library of Medicine’s PubMed search engine to identify epidemiological studies. We used neoplasia and DHEA to identify the studies. For the purpose of this report, we selected those studies which were not reported by Dr. Brinker previously.

STUDY SUMMARIES Prostate Cancer: Stahl et al (1992) conducted a prevalence case-control study to compare the DHEA levels in 19 prostate cancer patients with the DHEA levels in 23 age-matched controls. The DHEA level was assayed by RIA kits. They found that the levels of both DHEA and DHEAS (DHEA-sulfate) were significantly lower in prostate cancer patients than the control group. This study lacked any information on the quality of DHEA samples.

Comstock et al (1993) conducted a nested case-control study within a cohort of volunteers who participated in a [ ] Blood Bank study. From August to November 1974, 25,620 volunteers donated blood to study serum factor precursors of cancer. Comstock et al compared the DHEA/DHEAS level of 81 prostate cancer patients with 81 age-sex-race matched controls. All the cancer patients were diagnosed for the first time between 1974 and 1987. All blood specimens were frozen after donation and rethawed before reading. The serum samples of cases and their controls were assayed on the same day. DHEA/DHEAS levels were assayed by using radioimmunoassay (RIA) kits from Wein Laboratory. Although not statistically significant, this study showed that both DHEA and DHEAS levels were lower in prostate cancer patients than their control group. The authors noted no dose-response association with either DHEA or DHEAS. One potential limitation of this study is

3 temporal precedence bias. The possibility of this bias cannot be ruled out, since the latency of prostate cancer is long and the cancer patients could have had cancer at the time of blood donation.

Jones et al (1997) published a case report in which a patient with advanced prostate cancer was treated with DHEA. The administration of DHEA flared up his cancer while it reduced some of his symptoms. Upon the discontinuation of DHEA, the size and firmness of the prostate diminished, and the level of prostate-specific antigen (PSA) and testosterone decreased. Since the discontinuation of DHEA was followed by the initiation of estrogen therapy, it is not clear whether the improvement of his cancer was due to estrogen therapy or due to the discontinuation of DHEA. It is noteworthy that the patient was previously unresponsive to hormonal therapy, and whether the DHEA treatment had any impact on his conversion to being responsive to estrogen therapy is an interesting question.

Ovarian cancer Helzlsouer et al (1995) conducted a nested case-control study within the [ ] blood blank study. They identified 31 newly diagnosed ovarian cancers between 1975 and 1989. For these cases, 62 controls were matched on age, menopausal status, and for premenopausal women, the number of days from the beginning of the last menstrual period. Serum samples were frozen at –70° C after donation and thawed right before preparing the aliquots for this study. The DHEA/DHEAS levels were assayed by using RIA kits and performed for each case and matched control set at the same day. The investigators showed that the levels of DHEA/DHEAS in serum were much higher in cases than controls. There could have been a temporal precedence bias in this study since the cases were identified within a year of blood donation. Whether some women had cancer at the time of blood donation is unknown. Weight, a known risk factor for ovarian cancer, was not collected, so the study could not control for its effect.

Breast cancer: Zumoff et al (1981) conducted a prevalence case-control study, in which the 24-hr mean levels of

4 serum dehydroisoandrosterone (DHA) level and dehydroisoandrosterone sulfate (DHAS) of 11 women with primary operable breast cancer were compared with 37 healthy women. The DHA level was assayed by the radioimmunoassay technique as described by Rosenfeld and the DHAS was assayed by radioimmnoassay as described by Nieschlag. The study showed that postmenopausal breast cancer patients had higher DHA and DHAS plasma levels than the healthy women, while the premenopausal breast cancer patients had lowered DHA and DHAS than controls.

Solid tumors: Lissoni et al(1998) conducted a prevalence case-control study to examine the association of DHEAS with stage of cancer. The study consisted of 70 patients with solid tumors and 100 age-sex-matched healthy controls. The histologic types of cancer were: gastrointestinal tract tumors:28; breast cancer: 24; non-small cell lung cancer: 18. There were 28 patients without and 42 patients with distant metastases. Blood sera were collected in the morning after an overnight fast, and DHEAS was assayed by RIA method using commercially available kits. The result of this study showed that irrespective of tumor histologic types, the serum level of DHEAS was similar between early cancer patients and the control group. Advanced cancer patients had much lower DHEAS levels than controls.

DISCUSSION DHEA and DHEA-Sulfate are major adrenal secretory products in humans. They possess androgenic activity as they are metabolized to steroids such as testosterone. Thus, the association of testosterone and estrogen on the risk of breast cancer and prostate cancer can shed some light on the association of DHEA and neoplasia. While the evidence for an association between testosterone and the risk of prostate cancer is still conflicting, there is substantial evidence of an association between estrogen and breast cancer.

There are epidemiologoic studies which directly examined the association between endogenous DHEA and cancer risk; however, the epidemiologic evidence for an association is not consistent. For prostate

5 cancer, two epidemiologic studies [Stahl (1992) and Comstock (1993)] showed that cancer patients had lower DHEA levels than their non-cancer counterparts. Based on these studies, one might expect that DHEA therapy may improve the prostate cancer, however, the result from the case-report [Jones(1997)] suggests that the use of exogenous DHEA may worsen prostate cancer.

For ovarian cancer, compared to prostate cancer, a different result is suggested for the association of endogenous DHEA and cancer risk. The serum DHEA level was found to be higher in ovarian cancer patients than the control counterparts [Helzlsouer (1995)]. The association of DHEA and breast cancer could be different in pre- and post-menopausal women. In postmenopausal women, a positive association between DHEA level and breast cancer was reported by Cauley(1999) and Zumoff (1998) studies. The latter study showed that in premenopausal women, the level of endogenous DHEA was lower in breast cancer patients than the healthy controls.

In general the epidemiologic studies reviewed in this report have many limitations. Temporal precedence bias, small size, inability to control for confounding variables, and the method of DHEA measurement are among the most common limitations of studies reviewed in this report. No meaningful conclusion about the association of exogenously administered DHEA and cancer risk can be made based on these epidemiologic studies of endogenous levels of DHEA.

____Signed by______Signed by______Parivash Nourjah, Ph.D. Anne Trontell, M.D. Epidemiologist Deputy Director

6 REFERECES

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Comstock G.W., Gordon G.B., and Ann w Hsing: The relationship of serum dehydroepiandrosterone and its sulfate to subsequent cancer of the prostate: cancer epidemiology, Biomarkers and prevention 1993 Vol 2, 219-221

Lissoni P, Rovelli F, Giani L, Mandala M, Meregalli S, Barni S, Confalonieri G, Bonfanti A. Dehydroepiandrosterone sulfate (DHEAS) secretion in early and advanced solid neoplasm: Selective deficiency in metastatic disease. Int J Biol Markers 1998; 13:154-157.

Helzisourer K.J., Alberg A.J., Gordon G.B., Longcope C., Bush T.L, Hoffman S.C., Comstock G.W.: Serum gonadotropins and steroid hormones and the development of ovarian cancer. JAMA 1995; 274:1926-1930.

Jones J.A., Nguyen A., Straub M, Leidich R, Veech R.L., and Wolf S.: Use of DHEA in patient with advanced prostate cancer: a case report and review. Urology 1997 50:784-788.

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Stahl F., Schnorr D, Pitz C., and Dorner G: Dehydroepiandrosterone (DHEA) levels in patients with prostatic cancer, heart disease and under surgery stress. Exp Clin Endocrinol 1992, Vol 99, 68-70.

Zumoff, b., Levin, J., Rosenfeld R.S., Markham, M. Strain, G. W. and Fukushima, D.K. Abnormal 24- hr mean plasma concentrations of DHEA and DHEA-sulfate in women with primary operable breast cancer. Cancer Res. 41:3360-3363, 1981

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