Treating Rosacea in the Era of Bacterial Resistance. This presentation is sponsored by Galderma Laboratories, L.P.

Transcription

1 Treating Rosacea in the Era of Bacterial Resistance This presentation is sponsored by Galderma Laboratories, L.P.

2 Lecture Discuss rosacea as an inflammatory condition Assess the psychosocial impact of rosacea Discuss Oracea as a treatment option Consider the impact of antibiotic resistance 2

3 The Prevalence of Rosacea Is Similar to Other Common Disorders in the US 20 Prevalence Million Rosacea Psoriasis Diabetes (Diagnosed) Hepatitis C Asthma <18 yrs diabetes.niddk.nih.gov. aaaai.org/media/statistics. Armstrong GL, et al. Ann Intern Med. 2006;144:

4 The Emotional and Psychological Impact of Rosacea Rosacea can adversely affect your patient s self-image More than 76% of rosacea patients surveyed reported that their condition had lowered their self-esteem and confidence (n=502) Fleischer A. J Drugs Dermatol. 2005;4: National Rosacea Society. Available at: Nicholson K. J Am Acad Dermatol. 2007;57: National Rosacea Society. Available at: 4

5 Rosacea: An Inflammatory Condition?

6 Rosacea Overview Rosacea affects approximately 16 million Americans Only 10% seek conventional medical treatment 76% of rosacea visits are to dermatologists The disorder is often not recognized Often attributed to other conditions such as sunburn or acne Early recognition and treatment are important to prevent progression and permanent changes to the skin Therapeutic regimens should: Address acute symptoms Help patients remain asymptomatic National Rosacea Society. What is rosacea? National Rosacea Society. 14 million Americans urged to face up to rosacea before it gets worse. Del Rosso J. Poster presented at 66th Annual AAD, February Millikan L. Postgrad Med. 1999;105:149-50; Blount BW, et al. Am Fam Physician. 2002; 66: Baldwin HE. J Drugs Dermatol. 2006; 5:

7 Inflammation in Rosacea Evidence supports rosacea being a chronic inflammatory condition Lymphocytes and neutrophils infiltrate the skin Lymphocytes secrete cytokines and inflammatory mediators Neutrophils release factors that produce ongoing damage to the skin Cathelicidins may be dysregulated Buechner SA. Dermatology. 2005; 210: Wise RD. Compr Ther. 2007; 33: Jones D. Cutis. 2004;74(suppl 3):17-20, Baldwin HE. J Drugs Dermatol. 2006;5:

8 Microscopically, Rosacea Shows Inflammation and Vascular Changes Perivascular leukocytic infiltrates (chemotaxis) Vascular and lymphatic abnormalities Elastosis with loss of collagen Absence of pathogenic bacteria Jansen T, et al. J R Soc Med. 1997;90:

9 Summary of Oracea

10 Summary of Oracea Oracea is a once-daily capsule specially formulated with immediate-release 30-mg and delayed-release 10-mg beads to isolate the anti-inflammatory properties of doxycycline Remains below the antimicrobial threshold Clinically demonstrated to be effective and well tolerated for the reduction of inflammatory lesions of rosacea - Equivalent efficacy with fewer GI upsets compared with doxycycline 100 mg - No evidence of bacterial resistance in a 9-month safety study - Most commonly reported adverse events (>2%) were: nasopharyngitis, sinusitis, diarrhea, hypertension, and aspartate aminotransferase increase Oracea (doxycycline USP) capsules 40 mg (prescribing information). Fort Worth, TX: Galderma Laboratories, L.P. Del Rosso JQ, et al. J Am Acad Dermatol. 2007;56: Cazalis J, et al. J Periodontol. 2008;79: Bikowski JB. Pract Dermatol. 2005;June:

11 Oracea vs Doxycycline 100 mg: Study Objective, Design, and Methods Evaluate the safety and efficacy of Oracea vs doxycycline 100 mg for the treatment of moderate to severe papular/pustular rosacea for 16 weeks Both study arms were also treated with topical metronidazole gel 1% Randomized, double-blind, parallel group, multicenter, noninferiority study performed at 7 sites 8 to 40 papules and pustules, 2 nodules with telangiectasia and moderate to severe erythema present at baseline IGA 2 on scale from 0 to 5 Study treatments included Group 1: Doxycycline hyclate 100 mg + metronidazole gel 1% (n=47) Group 2: Oracea 40 mg + metronidazole gel 1% (n=44) Both oral and topical treatments administered once daily for 16 weeks Del Rosso JQ, et al. J Drugs Dermatol. 2008;7:

12 Oracea : Equivalent Decrease in Number of Inflammatory Lesions vs Doxycycline 100 mg 0 Mean Change From Baseline Mean Change in Total Inflammatory Lesion Count P =.61 P =.84 P =.84 Baseline Week 4 Week 8 Week 12 Doxycycline 100 mg (n = 47) Oracea 40 mg (n = 44) P =.51 Week 16 A randomized, multicenter, outpatient, double-blind, active-controlled, noninferiority trial of 91 rosacea patients ( 18 years of age) over 16 weeks. Patients were prospectively randomized to receive daily doses of either 40 mg Oracea or 100 mg doxycycline, each with metronidazole gel, 1%. Del Rosso JQ, et al. J Drugs Dermatol. 2008;7:

13 Side Effect Profile of Oracea

14 Oracea Is Clinically Demonstrated to be Well Tolerated Adverse Event* Oracea (n=269) n (%) Placebo (n=268) n (%) Nasopharyngitis 13 (4.8) 9 (3.3) Diarrhea 12 (4.4) 7 (2.6) Headache 12 (4.4) 16 (5.9) Upper respiratory tract infection 9 (3.3) 20 (7.4) Hypertension 8 (2.9) 2 (0.7) Sinusitis 7 (2.6) 2 (0.7) AST 6 (2.2) 2 (0.7) Abdominal pain, upper 5 (1.8) 1 (0.3) Fungal infection 5 (1.8) 1 (0.3) Influenza 5 (1.8) 3 (1.1) Nausea 5 (1.8) 8 (2.9) *Reported adverse events not necessarily determined to be probably or possibly related to study drug. There were no cases of vaginal candidiasis or photosensitivity in the active-treatment arm. Del Rosso J et al. J Am Acad Dermatol. 2007;56: Pivotal Clinical Studies. Data on File Galderma Laboratories, L.P. 14

15 Antibiotic Resistance Review

16 Antibiotic Resistance: An Issue of Concern for All Antibiotics are widely used by dermatologists for inflammatory disorders and cutaneous infections Dermatologists write 8-9 million oral antibiotic Rx per year 3-4 million topical antibiotic Rx per year Emergence of bacterial strains which are more resistant to commonly used antibiotics MRSA Macrolide-resistant staphylococci and streptococci Fewer new antibiotics being developed Del Rosso JQ, et al. Dermatol Ther. 2009;22:

17 Microbiologic Considerations With Oral Antibiotics Use associated with increasing prevalence of antimicrobial drug resistance Antibiotic selection pressure Genetic mechanisms Alteration of normal flora presents risk for superimposed infections Vaginal candidiasis Levy SB. Sci Am. 1998;278:

18 Oracea s Formulation Isolates the Anti- Inflammatory properties of Doxycycline Oracea steady-state plasma concentrations remain below the antimicrobial threshold, whereas doxycycline 50 mg does not Plasma Concentration (ng/ml) *16 healthy adult subjects in the Oracea arm measured at 7 days; mean weight, 75 kg Doxycycline 50 mg exceeds antimicrobial threshold Fowler Jr JF. Expert Rev Dermatol. 2007;2:

19 This study examined the efficacy and safety of Oracea versus placebo in patients with periodontal disease. A total of 266 patients underwent scaling and root planting and were randomized to adjunctive therapy with Oracea or placebo for 9 months. [Preshaw p 444 para 2] Microbiologic outcomes were evaluated in 70 patients (34 in the Oracea group and 36 in the placebo group). [p 447 para 3] Bacterial samples were cultured and tested for resistance to doxycycline at a concentration of 4 µg/ml. At baseline, there was an imbalance between the 2 groups in the proportion of patients with doxycycline-resistant bacteria. Resistant bacteria were identified in 12.69% of patients in the Oracea group and 3.95% in the placebo group at baseline. [p 447 para 3] Preshaw PM, Novak MJ, Mellonig J, et al. Modified-release subantimicrobial dose doxycycline enhances scaling and root planting in subjects with periodontal disease. J Periodontol. 2008;79:

20 Oracea : No Increased Reports of Antimicrobial Resistance Over 9 Months N=70 Mean percent of recovered flora resistant to doxycycline (4 µg/ml) for each treatment Oracea (n=34) Placebo (n=36) Mean Std Dev Mean Std Dev Baseline Months Change from Baseline to 9 Months Change over 9 months was equivalent between active and placebo groups Preshaw PM, et al. J Periodontol. 2008;79: (5.09% and 5.38%) 20

21 Oracea Long-Term (9-months) Safety Study Results Microbial flora remained stable in both groups Susceptibility of studied bacteria to 6 commonly used antibiotics, including doxycycline, remained unchanged in the active group The baseline to end point assessment of the development of doxycycline-resistant strains was equivalent between the anti-inflammatory dose doxycycline and placebo groups Consistent with natural selection and no antibiotic effect Preshaw PM, et al. J Periodontol. 2008;79:

22 Oracea Important Safety Information Indication: ORACEA is indicated for the treatment of only inflammatory lesions (papules and pustules) of rosacea in adult patients. Adverse Events: In controlled clinical studies, the most commonly reported adverse events (>2%) in patients treated with ORACEA were nasopharyngitis, sinusitis, diarrhea, hypertension and aspartate aminotransferase increase. Warnings/Precautions: ORACEA should not be used to treat or prevent infections. ORACEA should not be taken by patients who have a known hypersensitivity to doxycycline or other tetracyclines. ORACEA should not be taken during pregnancy, by nursing mothers, or during tooth development (up to the age of 8 years). Although photosensitivity was not observed in clinical trials, ORACEA patients should minimize or avoid exposure to natural or artificial sunlight. The efficacy of ORACEA treatment beyond 16 weeks and safety beyond 9 months have not been established. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit or call FDA 1088.