Part 1: CME #125: What did We Learn in 2005?
Principal Faculty: Gary Goldenberg, M.D. Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 35-41 and successfully answering the questions found on pp. 42-43. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com. Estimated Time to Complete Activity: 2 hours Date of Original Release: December 2005 Expiration Date: December 2006 This activity has been planned and produced in accordance with ACCME essentials. Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Disclosure Policy: All faculty participating in Continuing Medical Education programs sponsored by The North American Center for Continuing Medical Education are expected to disclose to the audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: Dr. Goldenberg has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of his presentation. Learning Objectives: 1. Identify major studies and reports published in the past year. 2. Identify possible applications of new research data in order to improve patient care. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial Support: None Sponsor: NACCME Part 1: What did We learn in 2005? Dermatology is an exciting and constantly evolving field. Multiple advances have been made this year in all aspects of dermatological care, including medical, surgical and cosmetic dermatology. This manuscript will review the most important and most interesting studies and developments that occurred in the last year. Infectious Diseases Update Vaccination of the elderly to prevent herpes zoster and post-herpetic neuralgia. Oxman et al. evaluated the use of the varicella–zoster virus (VZV) vaccine in the elderly to prevent herpes zoster (HZ) and post-herpetic neuralgia (PHN).1 There were 38,546 adults 60 years of age or older enrolled in this randomized, double-blind, placebo-controlled trial. Study subjects received one subcutaneous injection of 0.5 ml of the investigational live attenuated Oka/Merck VZV vaccine or placebo. Every suspected case of HZ was evaluated by a hierarchical algorithm that incorporated the results of the polymerase-chain-reaction (PCR) assay performed at the central laboratory of the study, a virus culture at the local virology laboratory, and the final clinical diagnosis of the study’s clinical evaluation committee, consisting of five physicians with expertise in herpes zoster. The primary endpoint was the burden of illness due to HZ, a severity-by-duration measure of the total pain and discomfort associated with HZ. The secondary endpoint was the incidence of PHN, defined as pain lasting more than 90 days after disappearance of clinical lesions. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of post-herpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of HZ vaccine reduced the burden of illness due to HZ by 61.1% (p<0.001), reduced the incidence of PHN by 66.5% (p<0.001), and reduced the incidence of HZ by 51.3% (p<0.001). Two people in the treatment group had serious adverse events; one person developed asthma exacerbation and the second patient developed polymyalgia rheumatica. It is unclear if these events are related to the vaccine. This study makes a great argument for advising patients at risk for HZ to receive the “zoster vaccine”. Methicillin-resistant Staphylococcus aureus (MRSA). MRSA has become an increasing problem inside and outside the hospital setting. Fridkin et al. studied MRSA isolates from Atlanta, Baltimore and Minnesota.2 From 2001 through 2002, 1,647 cases of community-acquired MRSA infection were reported, representing between 8% and 20% of all MRSA isolates. The disease incidence was significantly higher among persons less than 2 years old than among those who were 2 years of age or older and among blacks than among whites in Atlanta. Six percent of MRSA infections were invasive and 77% involved skin and soft tissue, primarily as abscesses. Seventy three percent of MRSA isolates were resistant to prescribed antimicrobial agents. Twenty three percent of patients required hospitalization. This is one of many reports of increased MRSA infections in the hospital and community settings. If this trend continues, tissue cultures may be needed even in cases of “routine” skin and soft tissue infections. Efficacy of the BCG vaccine re-examined. Aronson et al. published long-term follow-up data regarding efficacy of the Bacille Calmette-Guérin (BCG) vaccine.3 BCG is an attenuated strain of Mycobacterium bovis that is used worldwide as a tuberculosis vaccine. Between 1935 and 1938, 3,025 tuberculosis-free American Indian and Alaska Native children and adults aged 1 month to 20 years received either a single intracutaneous dose of BCG vaccine or normal saline as a placebo. Analysis in 1958 showed an 82% reduction in tuberculosis mortality among those that received the BCG vaccine. Follow-up for the period from 1948 to 1998 revealed overall incidence of tuberculosis of 66 and 138 cases per 100,000 person-years in the BCG vaccine and placebo groups, respectively. The estimate of vaccine efficacy is 52%. This study raises the question of vaccination, especially since cases of TB seem to be on the rise. Weekly fluconazole (Diflucan) for recurrent vulvovaginal candidiasis. Sobel et al. examined efficacy of maintenance oral fluconazole for recurrent vulvovaginal candidiasis.4 This double-blind, placebo-controlled study involved immunocompetent women who had at least four documented cases of candidal vulvovaginitis during the previous year. After inducing clinical remission with open-label fluconazole given in three 150-mg doses at 72-hour intervals, 373 female study subjects were randomly assigned to receive treatment with fluconazole (150 mg) or placebo weekly for 6 months. Participants were then followed for 6 months without therapy. At 6 months, 128 of 141 patients (90.8%) receiving fluconazole remained well without a clinical recurrence, as compared with 51 of 142 patients (35.9%) receiving placebo. Symptomatic vulvovaginal candidiasis occurred in 13 of 141 patients receiving fluconazole and 91 of 142 patients receiving placebo (p<0.001). During the 6-month observation period, significantly more episodes of clinical vulvovaginal candidiasis were observed in the fluconazole treatment group patients than in those who had received placebo. At the completion of the 12-month study, 54 of 126 patients in the fluconazole group were clinically cured (42.9%), as compared with 30 of 137 patients who had received placebo (21.9%) (p<0.001). While this study suggests that oral fluconazole is an effective treatment of recurrent vulvovaginal candidiasis, it also suggests the condition tends to recur when prophylactic treatment is discontinued. Acne Update Isotretinoin (Accutane and others) and depression. While the FDA still requires prescribers to ask about depression, yet another study failed to reveal a link between isotretinoin and depression. Chia et al. performed a cohort study to evaluate symptoms of depression in patients with moderate-to-severe acne treated with isotretinoin.5 The investigators used the Center for Epidemiologic Studies Depression Scale (CES-D), a standardized 20-item self-report questionnaire developed by the National Institutes of Mental Health, to assess symptoms of depression in the 101 people who completed the study. Male and female patients between the ages of 12 and 19 years old who presented for treatment of moderate-to-severe inflammatory and cystic acne were included in this prospective cohort study. Participants received isotretinoin at approximately 1 mg/kg per day rounded to the nearest 20 mg or maximal conservative therapy, defined as a topical antibiotic, topical retinoid, and twice-daily administration of an oral antibiotic. Depressive symptoms were assessed at baseline and then again 3 to 4 months after the initiation of isotretinoin therapy or maximal conservative therapy. Seventy five percent of the isotretinoin group and 40% of the conservative treatment group were male. At baseline, the isotretinoin group and the conservative therapy group had similar scores of the CES-D. At follow-up, the prevalence of CES-D scores suggestive of clinically significant depression were 8.2% in the isotretinoin group and 15.4% in the conservative therapy group, a non-significant difference. None of the patients in the isotretinoin group and one patient in the conservative treatment group had suicidal ideations. The 3-month incidence of CES-D scores suggestive of new-onset depression from baseline to follow-up was 4.1% in the isotretinoin group and 3.8% in the conservative therapy group, a difference that was not statistically significant. Brain imaging of acne patients treated with isotretinoin. Bremner et al. performed magnetic resonance imaging (MRI) and positron emission tomography (PET) scans on 28 patients treated with isotretinoin (13 patients) or oral antibiotics (15 patients).6 Scans were performed before therapy initiation and then again after 4 months of treatment. PET scans showed a decrease in brain metabolism in the orbitofrontal cortex, a finding that is seen in patients with depression, in patients treated with isotretinoin. The greatest decrease in brain metabolism was seen in five patients who developed headaches while treated with isotretinoin. Isotretinoin and Estradiol. Because of the teratogenic effect of isotretinoin, many women of childbearing age choose hormonal oral contraceptive pills (OCPs) as one of two methods of birth control while on isotretinoin. Since both isotretinoin and estradiol are metabolized by the cytochrome P450 (C-P450) system, a potential for drug interaction exists. Hendrix et al. studied 26 healthy women of childbearing age who used OCPs while receiving isotretinoin for treatment of acne.7 The pharmacokinetics of ethinyl estradiol and norethindrone and pharmacodynamic assessments of oral contraceptive effectiveness (concentrations of serum progesterone, luteinizing hormone, and follicle-stimulating hormone) were determined on days 6 and 20 of two separate oral contraceptive cycles, before and during isotretinoin treatment, respectively. The addition of isotretinoin to OCP regimen resulted in small, although statistically significant (p<0.04), decreases in the concentrations of both ethinyl estradiol and norethindrone. Isotretinoin did not cause any statistically significant increases in pharmacodynamic markers. There was no correlation between isotretinoin (or metabolite) levels and OCP levels. One woman in each study phase, one before and one during isotretinoin treatment, had a progesterone elevation consistent with possible ovulation. The authors concluded that small variations in ethinyl estradiol and norethindrone with isotretinoin use did not reduce OCP efficacy but stress that second form of birth control is still needed. Isotretinoin Registry. On August 12, 2005, the FDA approved a program aimed to prevent pregnancies in women of child-bearing age who use isotretinoin for treatment of nodular acne. By Decemberr 30, 2005, wholesalers and pharmacies must be registered and activated in iPledge. Patients can begin registering and qualifying on December 30.8 Propionibacterium acnes genome has been sequenced. Bruggemann et al. were able to sequence the entire genome of P. acnes.9 The genome of the studied strain was found to consist of a single circular chromosome of 2.56 million base pairs with an estimated 2,333 genes. Metabolic reconstruction showed that the genome encodes key components of oxidative phosphorylation and aerobic respiration pathways. Lipase and esterase genes were also identified. Multiple enzymes involved in degrading host tissue, heat-chock proteins and clusters of the porphyrin pathway enzymes were also found. These are believed to be important in the process of colonization and inflammation. Knowledge of P. acnes genome will improve our understanding of the pathogenesis of acne vulgaris. Psoriasis Update Methotrexate and liver biopsies. The American Academy of Dermatology (AAD) guidelines published in 199810 suggest intermittent liver biopsies for patients with psoriasis vulgaris treated with methotrexate. Two studies published in the British Journal of Dermatology suggest that experimental blood tests currently available in Europe may be used in place of invasive liver biopsies in order to assess liver toxicity secondary to methotrexate. Chalmers and colleagues studied the use of serum procollagen III aminopeptide (PIIINP) measurement to determine the need for liver biopsies in 166 patients with psoriasis treated with methotrexate.11 In this multi-center prospective study conducted in the United Kingdom and Ireland between 1998 and 2000, 166 patients were randomized into the AAD guidelines group and 87 into PIIINP level group. Healthcare costs and patient outcomes were examined by the investigators. A sevenfold reduction in the need for liver biopsy was observed in the group whose PIIINP levels were monitored, compared with the control group that used AAD guidelines. Abnormalities of sufficient severity to influence management and warrant liver biopsy were identified in one in five patients biopsied in the PIIINP group compared with one in 16 in the AAD guidelines group. This data suggest that fewer biopsies would be needed if PIIINP was used to monitor for liver toxicity and a higher percentage of these biopsies would show abnormalities sufficient to change management. The authors concluded that PIIINP monitoring would result in significant cost savings. Maurice et al. examined data available from a clinical series of 38 patients on methotrexate who had undergone a total of 70 liver biopsies and 306 PIIINP assays.12 PIIINP assays were consistently normal throughout the study period in 17 of the 38 (45%) patients. Eight of the 70 (11%) biopsies showed fibrosis. Four of the five patients with abnormal liver biopsies had normal liver function tests throughout and the fifth patient had a slight alanine aminotransferase elevation. The patients with abnormal liver biopsies had a median lifetime cumulative dose of methotrexate of 5960 mg, compared with a median cumulative dose of 2740 mg for the whole cohort. Patients with consistently normal PIIINP levels did not have a single abnormal liver biopsy. All patients with abnormal liver biopsies had abnormal PIIINP results on more than half of the assays. Fifty percent of patients with biopsies without fibrosis had at least one abnormal associated PIIINP assay. Two patients with non-alcoholic steatohepatitis, which manifests a pattern of fibrosis not scored under the Roenigk classification, had persistently and substantially elevated PIIINP levels. The authors concluded that monitoring PIIINP levels will result in fewer liver biopsies. More studies are needed to evaluate the accuracy with which PIIINP can predict hepatic fibrosis in patients on methotrexate, but these studies seem promising. The AAD guidelines should be followed until more data are available. Biologics update. Biologic therapies continued to dominate psoriasis literature in the past year. With three products already FDA approved for treatment of moderate-to-severe psoriasis vulgaris (alefacept [Amevive], efalizumab [Raptiva] and etanercept [Enbrel]) and two more products awaiting approval (infliximab [Remicade] and adalimumab [Humira]), we can expect more data. Gribetz and colleagues performed a randomized, single-center study comparing the safety and efficacy of a standard FDA-approved 12-week course of alefacept versus an extended 16-week course in 20 patients with chronic plaque psoriasis.13 In each group, 60% of patients achieved PASI 50 any time between weeks 12 and 24. The mean percentage change from week 12 PASI score was higher and continued to increase through week 24 in the patients who received a 16-week course of alefacept, when compared to the patients who received 12 weeks of alefacept (p<0.05). Adverse events were similar between the two groups and comparable with those observed in Phase II and III clinical studies of alefacept. Leonardi et al. examined an extended course of efalizumab for treatment of psoriasis. In this Phase III, randomized, double-blind trial, 498 patients received subcutaneous 1 or 2 mg/kg/wk efalizumab or placebo for 12 weeks.14 Efalizumab-treated patients who achieved <75% PASI improvement were re-randomized to a second 12-week course of treatment. After 12 weeks of treatment, 39% and 27% of efalizumab-treated patients (1 and 2 mg/kg, respectively) achieved PASI-75 (vs. 2% placebo; p<0.001, both dose groups). At week 24, an additional 20% of efalizumab-treated patients (13% from the 2mg/kg/wk group) achieved PASI-75 (vs. placebo 7%, p=0.018). A new warning was placed in the efalizumab package insert this year. Two reports of immune-mediated hemolytic anemia were observed in clinical trials. Hemolytic anemia was diagnosed 4 to 6 months after starting efalizumab with hemoglobin levels decreasing to 6 and 7 g/dl. Additional cases were reported in the postmarketing setting.15 Safety and efficacy of a 24-week course of efalizumab was also examined by Menter and colleagues.16 In this Phase III, randomized, double-blind, parallel-group, placebo-controlled 12-week study followed by a 12-week open-label study, 556 patients were initially randomized to receive 1 mg/kg of efalizumab weekly or placebo subcutaneously. At week 13, all patients were eligible to enter the open-label, 12-week extended treatment phase to receive 12 weekly doses of 1 mg/kg of subcutaneous efalizumab and 516 patients elected to do so. Although the second 12-week period was open label, investigators remained blinded to the initial treatment assignment. At week 12, 26.6% of efalizumab-treated patients achieved PASI 75 and 58.5% achieved PASI 50. After 24 weeks of continuous efalizumab therapy, 43.8% of patients achieved PASI 75 and 66.6% achieved PASI 50. Papp et al. examined safety and efficacy of etanercept in a 24-week, double-blind, placebo-controlled, multicenter study.17 Five hundred and eighty-three patients with psoriasis involving at least 10% body surface area from the United States, Canada and Western Europe were enrolled in this study. The subjects were randomized to receive subcutaneous injection of etanercept twice weekly (b.i.w.) at a dose of 50 mg or 25 mg, or placebo b.i.w. in a double-blind fashion for the first 12 weeks of the study. During the second 12 weeks, all patients received etanercept 25 mg b.i.w. At week 12, 49% of patients in the etanercept 50 mg b.i.w., 34% in the etanercept 25 mg b.i.w., and 3% in the placebo group, respectively, achieved PASI 75 (p<0.0001 for each etanercept group compared with placebo). At week 24, PASI 75 was achieved by 54% of patients who initially received 50 mg b.i.w., 45% of patients who initially received 25 mg b.i.w., and 28% of patients who initially received placebo followed by etanercept 25 mg b.i.w. Wolfe and Michaud used the National Data Bank for Rheumatic Diseases with data from a cancer database to compile data from 18,752 patients with rheumatoid arthritis (RA) to examine lymphoma risk in patients treated with anti-tumor necrosis factor (TNF) agents and methotrexate.18 All patients with RA had an increased risk of lymphoma, standardized incidence ratio (SIR) 1.9. The authors found that anti-TNF agents increased the risk of lymphoma: SIR for all biological treatments was 2.9, SIR for infliximab (alone or with etanercept) was 2.6, and SIR for etanercept (alone or with infliximab) was 3.8. SIR for methotrexate was 1.7. While psoriasis patients may not have the same risks, further studies are needed to accurately assess the risk of lymphoma in patients treated with anti-TNF agents. Biological treatments have given us a wide variety of treatment options to treat psoriasis. While the efficacy of biological treatments is quite high, more safety studies are needed so that we can better inform our patients regarding the risks and benefits. Melanoma Update According to data from the Centers for Disease Control, approximately 59,580 new cases of melanoma were diagnosed in 2004.19 More research is needed to improve our understanding, early detection and treatment of this malignancy. Histopathology update. Two important studies published in the last year examined histopathologic features of melanoma. Barnhill and colleagues examined mitotic rate (MR) of melanomas in a review of 650 consecutive cases of invasive melanoma from the Connecticut cancer registry.20 Seventeen clinical and histopathologic factors were evaluated, including Breslow depth, ulceration and MR. In a multivariate-regression analysis, tumor thickness in millimeters, moderate or high MR, and solar elastosis were independent prognostic factors. The authors suggest that MR can be used as a histologic prognostic criteria for patients with melanoma. Dyson and colleagues examined 100 consecutive cases of melanoma and compared Breslow depth of the initial two slides with Breslow depth of five additional deeper slides from the entire tissue block.21 Review of the additional slides from level sectioning revealed a greater maximum tumor thickness than was evident from the original slide in 43% of the cases. In 10 of these cases, the new maximum tumor thickness measurements changed the surgical management of the patients — nine patients were reclassified from melanoma in situ to invasive melanoma. Excisional biopsies had the lowest percentage change (25%) and shave biopsies had the greatest percentage change (54%). Breslow thickness and incisional biopsy of melanoma. Karimipour et al. prospectively followed 250 patients whose melanoma was initially diagnosed by a partial incisional biopsy that removed one-half of the original lesion.22 Mean Breslow thickness increased from 0.66 mm in the original incisional biopsy to a mean Breslow depth of 1.07 mm as determined by the complete excision. In 21% of patients, increase in Breslow depth resulted in upstaging and sentinel lymph node biopsy. Melanoma excision margins revisited. Thomas et al. examined loco-regional recurrence, recurrence and death of patients with melanoma after undergoing an excision with 1-cm margins versus 3-cm margins.23 A total of 900 patients with melanoma greater than 2 mm in depth on the trunk or extremities were randomly assigned to a margin of excision of 1 cm (453 patients) and 3 cm (447 patients). Median follow-up was 60 months. There were 168 loco-regional recurrences (defined as being within 2 cm of the original excision site) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins. There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins. Both of these results were statistically significant. However, overall survival was similar in the two groups. This study raises the question of whether wider surgical margins are necessary, especially in cosmetically sensitive areas. Tanning Bed Addiction Feldman and colleagues sought to determine if there was a physiologic reinforcing effect of ultraviolet (UV) exposure that may contribute to tanning behavior.24 A total of 14 healthy adult volunteers who used tanning beds on a regular basis were exposed to identical UV and non-UV tanning beds on Mondays and Wednesdays for 6 weeks. On Fridays participants had access to both. Participants were asked to rate the tanning bed and their mood on a 1-to-9 scale. Twelve participants chose additional tanning exposure on Fridays — 11 chose the UV bed. Of the total 41 Friday tanning sessions, 39 (95%) were in the UV bed and two in the non-UV bed. A statistically significant more relaxed and less tense mood was reported after UV exposure than after non-UV exposure. The biological basis for this is unclear. The authors suggest that endorphins released during UV exposure may be responsible for tanning bed addiction. While behavioral addiction may play a role in tanning bed use, more studies are needed to show that tanning beds are habit forming and to elucidate the biological basis of this possible addiction. Oral Lichen Planus, Human Immunodeficiency Virus and Hepatitis C virus. While multiple reports exist in the literature to suggest an association between oral lichen planus (OLP) and hepatitis C virus (HCV) infection,25-28 two recent studies failed to show a connection. Campisi et al. examined oral mucosa in 178 anti-HCV-positive adults from two cohorts: 104 human immunodeficiency virus (HIV) negative patients and 74 patients with HIV coinfection.29 The overall prevalence of OLP was 2.8% (5 of 178). Exclusion of the HIV-coinfected cases brought the prevalence of OLP up to 4.8% (5 of 104). All cases of OLP presented with a reticular pattern. Laeijendecker and colleagues prospectively examined two cohorts of patients, 100 with OLP and 100 control patients with psoriasis vulgaris.30 All patients were screened for liver enzyme levels, including total bilirubin, aspartate aminotransferase, alanine aminotransferase, Gamma-glutamyl transpeptidase and alkaline phosphatase, as well as HCV with a third-generation enzyme-linked immunosorbent assay. There was no serologic evidence of antibodies against HCV in either group. Therefore, it appears that routine serologic testing for HCV is unwarranted in patients with OLP in North America. Atopic Dermatitis Update Tacrolimus ointment (Protopic) vs. pimecrolimus cream (Elidel). Paller et al. conducted a multi-center, randomized, investigator-blinded study comparing efficacy of tacrolimus ointment 0.03% or 0.1% and pimecrolimus 1% cream.31 A total of 1,065 patients were randomized to receive tacrolimus ointment (531 subjects) or pimecrolimus (534) cream. Pediatric patients with mild disease received tacrolimus 0.3% ointment or pimecrolimus 1% cream. Pediatric and adult patients with mild-to-severe disease received tacrolimus 0.1% ointment or pimecrolimus 1% cream. Eczema Area Severity Index (EASI) and Investigator Global Atopic Dermatitis Assessment (IGADA) were used to evaluate the patients in the study. Based on the EASI, tacrolimus ointment was more effective than pimecrolimus cream at the end of this 6-week study in adults (54.1% vs. 34.9%, respectively; p<0.0001), in children with moderate-to-severe disease (67.2% vs. 56.4%, respectively; p=0.04), in the combined analysis (52.8% vs. 39.1%, respectively; p<0.0001), and at week 1 in children with mild disease (39.2% vs. 31.2%, respectively; p=0.04). Based on the IGADA, tacrolimus had greater improvement in percentage of total body surface area affected and in itch scores, with a faster onset of action. Incidence of local application site reactions was similar and more pimecrolimus-treated patients than tacrolimus-treated patients withdrew from the studies because of a lack of efficacy. This study suggests that tacrolimus is more efficacious than pimecrolimus and that both medications are tolerated well. FDA focus on tacrolimus and pimecrolimus. The post-rofecoxib (Vioxx) FDA re-evaluated the safety of tacrolimus ointment and pimecrolimus cream and issued a public health advisory to inform healthcare providers and patients about a potential cancer risk. According to the FDA, the health advisory is based on “information from animal studies, case reports in a small number of patients, and how these drugs work”.32 A total of 11 lymphoma cases (6 cases of cutaneous T-cell lymphoma) have been reported in the 1.7 million U.S. patients treated with tacrolimus. Despite this, the FDA issued recommendations for these agents including:32 • Use only as second-line agents for short-term and intermittent treatment of atopic dermatitis in patients unresponsive to or intolerant of other treatments. • Avoid use in children younger than 2 years of age because the effect on the developing immune system is not known. • Use only for short periods of time, not continuously, since the long-term safety is unknown. • Do not use on children and adults with a weakened or compromised immune system. • Use the minimum amount needed to control the patient’s symptoms. In animals, increasing the dose resulted in higher rates of cancer.