Comparative Absorption of and Miconazole Nitrate

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Comparative Absorption of and Miconazole Nitrate Powered By Docstoc
					                                                                                                                                                                                                                                                                                                                                                                          Lawrence F. Eichenfield, MD1; Elvira M. Gisoldi, MA2
          AAD 2007 Poster 820
                                                                                                                     Comparative Absorption of 0.25% and 2% Miconazole Nitrate Preparations                                                                                                                                                                           1
                                                                                                                                                                                                                                                                                                                                                                       Children’s Hospital and Health Center, San Diego, CA;
                                                                                                                                        in Infants With Diaper Dermatitis                                                                                                                                                                                                            2
                                                                                                                                                                                                                                                                                                                                                                                      Barrier Therapeutics, Princeton, NJ

Introduction                                                                                   Methods                                                                     Results
                                                                                                                                                                                                                                                                                    Evaluation of miconazole absorption                                        • On Day 3, the rash scores were 1.89 ± 0.94 in the 0.25%
• Diaper dermatitis is the most common skin disorder among                                     • This uncontrolled, open-label, noncrossover, clinical pharmacology        • A total of 24 infants (12 male and 12 female) enrolled and                                             • In the 19 infants treated for 7 days with multiple daily applications      miconazole nitrate group and 2.60 ± 1.34 in the 2% miconazole
  infants1,2 and is particularly common between 9 and12 months                                   study evaluated male and female infants between the ages of 1 and           completed the study. Nineteen infants received 0.25% miconazole                                          of 0.25% miconazole nitrate ointment, blood concentrations of              nitrate group
  of age3                                                                                        12 months who had been hospitalized for treatment of systemic               nitrate ointment, and 5 infants received 2% miconazole nitrate                                           miconazole absorbed were nondetectable (<1 ng/mL) in 83%                 • On Day 5, the rash scores were 0.84 ± 0.76 and 1.20 ± 0.84,
• The condition is usually caused by frictional irritation, particularly                         pathology, primarily gastroenteritis, and who had dermatologic              cream. Blood samples were missing for 1 patient in the 0.25%                                             (15 of 18 infants) and at or near the lower limit of detection             respectively; and on Day 7 the scores were 0.32 ± 0.48 and
  when the skin has been overhydrated by occlusive diapers after                                 manifestations consistent with a diagnosis of moderate-to-severe            miconazole nitrate group                                                                                 (3.0 to 3.8 ng/mL) in 17% (3 of 18 infants). Blood samples were            0.40 ± 0.55, respectively
  urination or defecation                                                                        diaper dermatitis. Moderate-to-severe diaper dermatitis was               • At baseline, the severity of the diaper rash for half the subjects                                       missing for 1 infant
• The moist environment under the diaper also makes the skin more                                defined as a rash evaluation score of 2 or higher (Table 1)                 was rated as moderate erythema with or without satellite                                               • In the 5 infants treated with 2% miconazole nitrate cream,
  susceptible to infection with microorganisms, which exacerbate the                                                                                                         papules with maceration and chafing (rash score of 2). One fourth                                        miconazole was nondetectable in 20% (1 infant) and concentrations
  condition and may lead to potentially life-threatening systemic                                  Table 1. Rash Evaluation Scale                                            of the infants (n=6) had severe erythema with papulopustules and                                         of 5.2 to 7.4 ng/mL were noted in 80% (4 infants) (Table 3).There
  candidal infections4-6                                                                                                                                                     maceration (rash score of 3) and one fourth of the infants (n=6)                                         was no correlation between age, sex, weight, or diaper rash scores
• Clinical studies have identified Candida albicans as an important                                 0 = none                                                                 had severe erythema with erosions or ulceration (rash score of 4)                                        with blood concentration
  factor in the evolution of diaper dermatitis2,7,8 (Figure 1)                                      1 = mild erythema with minimal maceration or chafing                   • At baseline, no significant differences were noted in the
                                                    • Typical medical treatments for                2 = moderate erythema with or without satellite papules                  demographics and patient characteristics between treatment
                                                      diaper dermatitis include application                                                                                  groups (Table 2)
                                                                                                                                                                                                                                                                                        Table 3. Distribution of Miconazole Blood
                                                                                                        with maceration or chafing
                                                      of topical antifungal agents and                                                                                                                                                                                                  Levels After 7 Days of Treatment
                                                      steroids2,9                                   3 = severe erythema with papulopustules and maceration                                                                                                                             Miconazole           0.25% Miconazole       2% Miconazole
                                                    • Topical corticosteroids are clinically
                                                                                                                                                                                 Table 2. Patient Demographics and
                                                                                                    4 = severe erythema with erosions or ulceration                                                                                                                                    concentration         nitrate (n=19)         nitrate (n=5)
                                                      effective for inflammation but are                                                                                         Baseline Conditions                                                                                   None detected                15                     1
                                                      easily absorbed by the skin,10,11                                                                                                                        0.25%                                                                   1-4 ng/mL                     3                     0
                                                      which is cause for concern when          • Entry criteria included no known sensitivity to miconazole nitrate                                         Miconazole 2% Miconazole                                                   5-8 ng/mL                     0                     4
                                                      treating infants with dermatitis           or zinc oxide, no active dermatological conditions other than                                                                                                                                                                                                        Figure 2. Mean rash scores for all patients throughout the study.
                                                                                                                                                                               Variable                    nitrate (n=19) nitrate (n=5) Overall
                                                      because the skin is more permeable         diaper rash, and no known allergy or sensitivity to skin care                 Sex                                                                                                  • All infants treated with multiple applications of miconazole nitrate
                                                      than adult skin10                          toiletry products                                                              Male                                   9                            3                     12          had blood concentrations below 8 ng/mL. Of the 7 infants who had
                                                    • Infants may absorb proportionately       • Participants were to remain hospitalized throughout the 7-day                  Female                                10                            2                     12          detectable levels of miconazole nitrate, 3 in the 0.25% treatment
    Figure 1. Presentation of
    diaper dermatitis complicated
                                                      greater quantities of topical              trial period                                                                  Age (months)                                                                                           group had blood concentrations of 3.0, 3.5, and 3.8 ng/mL, and 4
    by candidiasis.
                                                      medication than adults, and tests        • Blood samples (0.5 mL of whole blood) for analysis of absorption                                                                                                                     in the 2% treatment group had blood concentrations of 5.2, 6.6,          • Seven days of multiple daily applications resulted in blood
                                                                                                                                                                                1-6                                   10                            3                     13
    Photograph courtesy of Linda De Raeve, MD, VUB,   have shown the potential for topical       of miconazole nitrate were collected prior to treatment on Day 0                                                                                                                     6.8, and 7.4 ng/mL (Table 4)                                               concentrations of <8 ng/mL in all patients, and nondetectable
    Brussels, Belgium, 2004.
                                                      corticosteroids to cause                   and at the completion of treatment on Day 7, after the routine                 7-12                                   9                            2                     11
                                                                                                                                                                                                                                                                                                                                                                 levels in most of the 0.25% miconazole group
  suppression of the hypothalamic-pituitary axis with possible                                   blood testing for the underlying gastroenteritis                               Mean ± SD                        7.16 ± 4.21                   5.8 ± 4.08             6.87 ± 4.13
                                                                                                                                                                                                                                                                                        Table 4. Miconazole Blood Concentrations                               • The results of this study demonstrate the safety of 0.25%
  impairment of growth.10,11 Moreover, many of these products are                              • 2% miconazole cream was tested in 5 of the 24 patients enrolled                Range                                1-12                         1-10                   1-12
                                                                                                                                                                                                                                                                                                                                                                 miconazole nitrate ointment in the treatment of moderate-to-
  not approved by the US Food and Drug Administration for use on                               • The test medications were applied sparingly at each diaper change             Body weight (kg)                                                                                         in the 7 Infants With Detectable Levels                                  severe diaper dermatitis
  infants as young as 4 weeks2,12                                                                and after bathing at least 5 times per day for 7 days to the clinically        Mean ± SD                        6.41 ± 2.76                  4.96 ± 1.97             6.10 ± 2.64      Formulation                         Miconazole blood
• When C. albicans infection complicates diaper dermatitis, a topical                            affected area                                                                  Range                             2.8 - 10.5                    2.8 - 7.1             2.8 - 10.5       concentration                     concentration (ng/mL)
  antifungal is warranted9,13                                                                  • Treatment of the affected area was to continue, even if symptoms
• The antifungal agent, miconazole nitrate, has been shown to be                                 of diaper dermatitis were no longer visible
                                                                                                                                                                               Severity of
                                                                                                                                                                                                                                                                                       0.25%                                         3.0                       References
                                                                                                                                                                                                                                                                                       0.25%                                         3.5                       1. Ward DB, Fleischer AB Jr, Feldman SR, Krowchuk DP. Arch Pediatr Adolesc Med. 2000;
  effective against C. albicans14,15                                                           • Use of other topical or systemic antifungal therapy or                        diaper rash* (n)
                                                                                                                                                                                                                                                                                       0.25%                                         3.8                          154:943-946.
• A 2% miconazole nitrate cream successfully treated Candida skin                                corticosteroid treatment was not permitted. Only medications                   Score of 2                            10                            2                     12                                                                                   2. Shin HT. Dermatol Ther. 2005;18:124-135.
  infections in the diaper area of premature and term infants as well                            already administered on admission to the study were permitted,                                                                                                                        2%                                            5.2                       3. Jordan WE, Lawson KD, Berg RW, Franxman JJ, Marrer AM. Pediatr Dermatol. 1986;3:198-207.
                                                                                                                                                                                Score of 3                             5                            1                     6
                                                                                                                                                                                                                                                                                                                                                               4. Randolph S. RN. 2002;65(3):41-44.
  as children16,17                                                                               except those necessary for emergency reasons                                   Score of 4                             4                            2                     6            2%                                            6.6
                                                                                                                                                                                                                                                                                                                                                               5. Passeron T, Desruelles F, Gari-Toussaint M, Dageville C, Lacour JP. Pediatr Dermatol. 2004;
• Miconazole nitrate 0.25%/15% zinc oxide/81.35% white                                         • Clinical evaluations of the diaper rash (if present) continued on                                                                                                                     2%                                            6.8                          21:260-261.
                                                                                                                                                                             *Rating scale:
  petrolatum ointment is the only product indicated and specifically                             treatment Days 1, 3, 5, and 7. On Day 7, another physical                   0=No lesions                                                                                              2%                                            7.4
                                                                                                                                                                                                                                                                                                                                                               6. Rowen JL,Tate JM, Nordoff N, Passarell L, McGinnis MR. J Clin Microbiol. 1999;37:3735-3737.
                                                                                                                                                                                                                                                                                                                                                               7. Rebora A, Leyden JJ. Br J Dermatol. 1981;105:551-555.
  formulated for diaper dermatitis complicated by candidiasis in                                 examination was conducted, and another blood sample was drawn               1=Light erythema with minimal maceration or desquamation
                                                                                                                                                                                                                                                                                                                                                               8. Weston WL, Lane AT,Weston JA. Pediatrics. 1980;66:532-536.
                                                                                                                                                                             2=Moderate erythema with or without satellite papules with maceration and desquamation
  immunocompetent patients 4 weeks and older18                                                   for analysis                                                                3=Severe erythema with papulopustules and maceration                                                   • No adverse events were reported for any infant in either                 9. Spraker MK, Gisoldi EM, Siegfried EC, et al. Cutis. 2006;77:113-130.
• Prior to this study, absorption of miconazole nitrate through                                • The primary outcome measures were the evaluation of miconazole              4=Severe erythema with erosions or ulceration                                                                                                                                    10. West DP,Worobec S, Solomon LM. J Invest Dermatol. 1981;76:147-150.
                                                                                                                                                                                                                                                                                      treatment group                                                         11. Munro DD. Dermatologica. 1976;152(suppl 1):173-180.
  inflamed skin of infants with diaper dermatitis had not been                                   absorption and the clinical evaluation                                                                                                                                                                                                                       12. [No authors listed]. Nurse Pract. 2006;31:62.
  evaluated                                                                                    • The patients' clinical response to therapy was indicated by the rash      • Infants had initially been admitted to the hospital for treatment                                      Clinical evaluation
                                                                                                                                                                                                                                                                                                                                                              13. Janniger CK,Thomas I. Cutis. 1993;52:153-155.
                                                                                                                                                                                                                                                                                                                                                              14. Drouhet E, Dupont B. Arzneimittelforschung. 1992;42:705-711.
                                                                                                 evaluation score obtained on treatment Days 0, 1,3, 5, and 7                of gastrointestinal conditions and all had diaper dermatitis                                           • Rash scores at baseline were 2.68 ± 0.82 in the 0.25% miconazole        15. Hawser S, Islam K. J Antimicrob Chemother. 1999;43:411-413.
                                                                                               • Any adverse events were assessed and recorded on Days 1, 3, 5,              secondary to systemic pathology.The most common additional                                               nitrate group and 3.00 ± 1.00 in the 2% miconazole nitrate group        16. Vanheule R, Adriaensen K, De Hauwere R,Van Cutsem J, De Crée J. Castellania. 1974;2:91-92.

Objective                                                                                        and 7. Participants were to be withdrawn from the study if adverse          diagnoses on enrollment included diarrhea (n=9); intestinal                                              (Figure 2)
                                                                                                                                                                                                                                                                                                                                                              17. MacKie RM, Scott E. Practitioner. 1979;222:124-126.
                                                                                                                                                                                                                                                                                                                                                              18. Vusion [package insert]. Princeton, NJ: Barrier Therapeutics; 2006.
                                                                                                 reactions developed or the parent or legal guardian wished to               symptoms, including amoebic dysentery and acute viral                                                  • At each evaluation, mean rash scores for all infants in the 0.25%
• To determine the absorption of 0.25% miconazole nitrate ointment                               withdraw the patient from the study.                                        gastroenteritis (n=7); dehydration (n=7); or malnutrition (n=3).
  through the skin of infants with moderate-to-severe diaper                                                                                                                                                                                                                          miconazole nitrate group were slightly lower than mean scores in
                                                                                               • Patients who were treated with miconazole nitrate for less than             Some infants had multiple diagnoses                                                                      the 2% miconazole nitrate group
  dermatitis after multiple applications                                                         7 days were considered not evaluable
                                                                                                                                                                                                                                                                                                                                                              This study was performed at the Hospital General Vasco de Quiroga in Morelia, Michoacan, Mexico.
                                                                                                                                                                                                                                                                                                                                                                                     This poster was sponsored by Barrier Therapeutics.

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