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Topical Metronidazole for Rosacea

A. K. Gupta MDa,b, FRCPC, M. Chaudhry, HBScb
aDivision of Dermatology, Department of Medicine, Sunnybrook and
Women’s College Health Sciences Center (Sunnybrook site), and the University of Toronto, Toronto, Ontario, Canada bMediprobe Laboratories Inc., Ontario, Canada

ABSTRACT

Rosacea is relatively common, typically occurring in individuals of Northern European and Celtic origin between 30 and 50 years of age. It is more common in women, but may be more severe in men. Currently there is no cure available for rosacea, but it can be controlled with topical and oral drug therapy. Topical metronidazole 1% cream is approved by the US FDA for the treatment of inflammatory lesions (papules and pustules) and erythema associated with rosacea. This treatment option is effective, safe and well tolerated.

Key Words: management, metronidazole, rosacea

Mechanism of Action

Metronidazole is an imidazole, and is classified as an antiprotozoal and antibacterial agent.1,2 Although this drug has an antimicrobial effect, it is not clear whether the beneficial effects result from direct suppression of skin bacteria.2 The exact mechanism by which topical metronidazole reduces inflammatory lesions and erythema in rosacea is unknown. It is inactive in vitro against Propionibacterium acnes, staphylococci, streptococci, as well as the aerobic and anaerobic skin microflora of rosacea patients.2 In vitro studies suggest that it is inactive against Demodex folliculorum.2 Its anti-inflammatory effect may be due to its antioxidant action.3

Pharmacokinetics

Topical administration of metronidazole results in minimal percutaneous absorption with low systemic bioavailability.1,2,4 The maximum serum concentration after topical application of metronidazole 1% cream is approximately 1% of the value achieved following a single oral dose of metronidazole 250mg.1

Clinical Trials

Metronidazole 1% Cream (Noritate™, Dermik)

Two US multicenter, double-blind, randomized, parallel, placebo (vehicle)-controlled clinical trials established the efficacy of this cream for treating rosacea.5,6 Following a 10-week treatment period, patients in the metronidazole 1% treatment group had significantly fewer numbers of papules plus pustules compared to vehicle (P≤0.03)5 (Table 1). The mean decrease in erythema severity scores from baseline was significantly greater at week 10 for the metronidazole group compared to its vehicle (P< 0.01). The metronidazole group showed significantly greater improvement at week 10 (P< 0.01) when compared to vehicle using Physician’s Global Evaluation Scores. The change from baseline in the overall rosacea severity score was significantly greater (P< 0.01) for the metronidazole group at week 10 than the vehicle group.

In a similar study of 277 adults,6 58% of those receiving Noritate™ once-daily, showed clinical improvement of inflammatory lesions, compared to 30% for the once-daily vehicle group (Table 1). Metronidazole patients achieved a reduction in mean erythema severity scores of 41% at week 10 vs. 19% for the vehicle once-daily group.6 Other studies have confirmed the efficacy of metronidazole 1% cream in the treatment of rosacea.7

Noritate™ is approved in the US for once daily application. The other metronidazole formulations are approved for twice-daily applications. Patient compliance may improve when fewer applications are required.5 Furthermore, once-daily administration may offer a lower total daily drug exposure. The moisturizing cream vehicle may also provide some relief for dry or sensitive skin.

Metronidazole 0.75% Gel (MetroGel®, Galderma)

In a randomized split-face, double-blind, paired comparison trial, 38 patients were treated with 0.75% metronidazole gel.8 Following nine weeks of twice daily application of metronidazole gel to one side of the face and vehicle to the other, there was a mean reduction of 65.1% and 14.9%, respectively, from baseline in total papules and pustules.8 The reduction in erythema scores at week 9 on the metronidazole side was significantly different from scores on the placebo side (P=0.0006).8

Another clinical trial studied 19 patients with severe or recalcitrant rosacea.9 Patients were treated twice daily with MetroGel®, and efficacy was determined based upon the following criteria: inflammatory lesion (papules and pustules) counts, clinical assessment of erythema and edema, and Investigator Global Assessment. The number of inflammatory lesions decreased from a mean of 20 at baseline to 7 at week 8 (P<0.01). Baseline erythema scores were significantly (P≤0.0001) lower at week 8. There was also significant (P<0.0001) improvement in the Investigator Global Assessment scores at week 8 compared to baseline.

The efficacy of MetroGel® has been compared to sodium sulfacetamide 10%/sulfur 5% lotion in the treatment of rosacea.10 Fifty-five patients, applying either treatment twice daily, completed the 8-week, investigator-blinded, randomized study. The sodium sulfacetamide/sulfur treatment group experienced a significantly greater improvement than did the metronidazole group at week 8 in overall severity (P< 0.01), reduction in papulopustule score (P< 0.01), and reductions in mean erythema score (P< 0.05).10

Metronidazole 0.75% Lotion (MetroLotion®)

A 12-week clinical study was conducted in 125 patients with moderate-to-severe rosacea comparing metronidazole 0.75% lotion to its vehicle.11 Applications were made twice daily to affected areas. At week 12, MetroLotion® was significantly more effective than vehicle in the mean percent reduction of inflammatory lesions and in the Investigators’ Global Assessment of Improvement. The mean reduction of inflammatory lesion counts from baseline was 55% for MetroLotion® vs. 20% for the vehicle. Definite or marked improvement in the Investigators’ Global Assessment of Improvement occurred in 64% of the patients in the MetroLotion® group compared to 35% in the vehicle group.

Metronidazole 0.75% Cream (MetroCream®)

In a single-center, double-blind, randomized, contralateral, splitface comparison study, the efficacy and safety of topical azelaic acid 20% cream and topical metronidazole 0.75% cream was compared in 37 patients with papulopustular rosacea.12 After 15 weeks of treatment, a significantly higher physician rating of global improvement was achieved with azelaic acid (P=0.05).

Metronidazole 1% Cream with Sunscreens, SPF 15 (Rosasol®)

In a multi-center, randomized, double-blind study, twice daily application of 1% metronidazole cream with sunscreen formulation was compared to sunscreen vehicle in 120 patients with moderateto- severe rosacea.13 After 12 weeks, lesion counts for the Rosasol® group were reduced 70% compared to 23% in the placebo group (P=0.005).13 In addition, 41% of the Rosasol® patients demonstrated improved facial erythema, compared to only 27% with placebo (P=0.02). Facial telangiectasia improved by 17% in the Rosasol® group vs. 4% for the vehicle group (P=0.04).13

Topical Metronidazole Versus Oral Antibiotics

In a randomized, double-blind study, 48 rosacea patients were treated for 2 months with either 1% metronidazole cream applied once daily and placebo tablets, or with 250mg oxytetracycline tablets taken twice daily and placebo (the cream base).14 After 2 months, 1% metronidazole cream was as effective as oral oxytetracycline in reducing erythema and the number of papules and pustules. Improvement occurred in 90% of patients, and there was no significant difference between the two treatments.

In a similar study with 75 patients, metronidazole 1% cream was compared with 250mg oral tetracycline taken twice daily.15 No statistically significant difference was found between the two groups after 8 weeks of treatment. However, tetracycline demonstrated a more rapid onset of effect on papules and pustules compared to the cream, and more patients treated with tetracycline obtained 100% reduction of papules and pustules.15

In a two-month, randomized, double-blind study, 101 patients were treated with either metronidazole 1% cream twice daily and placebo capsules, or placebo cream and oral tetracycline (250mg) three times daily.16 Both metronidazole 1% cream and oral tetracycline significantly reduced (P< 0.05) the mean numbers of papules and pustules by >50% after 1 month of treatment.16

In a double-blind, randomized study, 27 rosacea patients were treated with 0.75% metronidazole gel applied twice daily and placebo capsules, or placebo (gel base) and oxytetracycline capsules (250mg) taken twice daily.17 Following 9 weeks of treatment, both treatment groups showed a reduction of >50% in papule/pustule count in all patients, with 100% clearing in 75% of the topical metronidazole group and 66% of the oxytetracycline group.17 There was no significant difference between the two treatment groups.

Topical Metronidazole and Relapse Rates

Metronidazole 1% cream was applied either once daily or once every second day for 4 months and resulted in significantly fewer relapses than 250mg oxytetracycline taken orally twice daily for two months.18 After 2 months, there was no significant difference between 1% metronidazole cream once daily and oxytetracycline therapy.

A separate study explored whether metronidazole 0.75% gel could prevent relapse of moderate-to-severe rosacea.19 Eightyeight subjects who responded to either systemic tetracycline and topical metronidazole gel were randomized to receive metronidazole 0.75% gel or placebo. Subjects were evaluated monthly for up to 6 months and relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. In the vehicle group, 18 of 43 (42%) subjects experienced relapse, compared to only 9 of 39 (23%) subjects applying the metronidazole gel (P< 0.05).

Adverse Effects

Adverse effects associated with topical metronidazole therapy are infrequent, but may include transient redness and mild dryness, pruritus, aggravation of rosacea or acne, burning, irritation, and stinging.2 Dermatotoxicity tests have shown no evidence of contact sensitivity, phototoxicity, or photocontact allergenicity reactions.1

Product/Investigator Study n App. Results

Metronidazole 1% Cream: Noritate® (Dermik)
Breneman, et al5

Multicenter, double-blind, randomized, parallel, 1% cream vs. placebo

139

qd for 10 wks

Overall rosacea severity score significantly greater for 1% metronidazole cream group.

Jorizzo, et al6

Multicenter, double-blind, randomized, parallel, 1% cream once daily vs. 1% cream twice daily vs. placebo

277

qd or bid for 10 wks

Using Physician’s Global Assessment Scores the metronidazole qd group rated fair/better improvement (79%) vs. baseline (p<0.01).

Bjerke, et al7

Multicenter, double-blind, randomized, 1% cream vs. placebo

97

bid for 8 wks

Statistically significant difference between regimens for reducing papules plus pustules, erythema, overall assessment.

MetroGel® (Galderma):
Bleicher, et al8

Double-blind, randomized, split-face, paired comparison trial, 0.75% gel vs. vehicle

38

bid for 9 wks

Erythema significantly lower than at baseline and significantly different from placebo group (P=0.006).

Lebwohl, et al10

Controlled, randomized, investigator-blinded, 0.75% gel vs. sodium sulfacetamide 10%/ sulfur 5% lotion

55

bid for 8 wks

Physician’s Global Assessment Scores indicated consistently greater improvement in the sodium sulfacetamide/sulfur treatment group.

Rosasol® (Stiefel)
Tan13

Multi-center, randomized, double-blind, 1% metronidazole + sunscreen vs. sunscreen vehicle

120

bid for 12 wks

Lesion counts showed decrease of 70% (Rosasol) vs. 23% (placebo) (P=0.005). Facial erythema showed 41% (Rosasol) vs. 27% (placebo) group (P=0.02).

Metronidazole vs Oral antibiotics:
Nielsen14

Randomized, double-blind, 1% cream vs. 250mg oral oxytetracycline

48

1% cream: qd Antibiotic: bid for 2 mos

90% of patients showed improvement. No 90% of patients showed improvement. No and oral antibiotics.

Veien, et al15

Randomized, double-blind, 1% cream vs. 250mg oral tetracycline

75

bid for 8 wks

No statistically significant differences found between the two groups.

Schachter, et al16

Multicenter, randomized, double-blind, 1% cream vs. 250mg oral tetracycline vs. vehicle

101

1% cream: bid Antibiotic: bid for 2 mos

Both metronidazole cream and antibiotics significantly reduced mean numbers of papules and pustules by >50% within 1 month of treatment (P<0.05).

Monk, et al17

Randomized, double-blind, 0.75% gel vs. 250mg oral oxytetracycline

27

bid for 9 wks

No statistically significant differences found between treatment groups.

Table 1: Some metronidazole studies in the treatment of rosacea.

Drug Interaction

Oral metronidazole may potentiate the anticoagulant effect of coumarin and warfarin, resulting in prolongation of prothrombin time.1,2 However, given that only minimal concentrations of metronidazole are detectable in plasma following topical application, the likelihood of systemic interactions would be less with topical than with oral administration.

Pregnancy and Lactation

Metronidazole is classified in pregnancy category B. Following oral administration, metronidazole is secreted in breast milk.2 When applied topically, metronidazole blood levels would be substantially lower than following oral administration. The decision of whether to stop nursing or discontinue application of drug will depend upon the risk to the infant and the importance of the drug to the nursing mother. Topical metronidazole should be used during pregnancy only if there is a clear need.

Pediatric Use

The safety and effectiveness of topical metronidazole use in pediatric patients has not been established.2

Dosage and Administration

Following the first 3 weeks of therapy, clinical improvement should be noted, with continuing improvement through 9 weeks of treatment.2 As soon as an acceptable level of response is obtained, the frequency and duration of therapy should be adjusted according to the severity of the disease. Periods of remission may be induced following treatment with metronidazole cream, although no optimum duration of therapy has been established for the treatment of rosacea.2 Long-term therapy may be required as relapse is common following discontinuation of drug treatment. In clinical studies, topical metronidazole therapy for rosacea has been continued for up to 21 weeks.2

Conclusion

Metronidazole should be used as part of an extensive management program. Medical practitioners must educate rosacea patients about how to recognize and avoid trigger factors that can worsen symptoms and interfere with the success of treatment. Multiple studies have demonstrated the therapeutic benefits of topical metronidazole for this condition; furthermore, the agent also helps to prevent relapse. Topical metronidazole therapy may be as effective as oral tetracycline for treating rosacea.14-18

Acknowledgement

We wish to thank J.E. Swan for her contribution to this manuscript.

References

  1. Metronidazole cream 1% (Noritate™, Dermik). Physicians’ Desk Reference. Medical Economics Company, Inc., Montvale, NJ, USA. (2000) pp. 954-955.
  2. McEvoy GK (Editor). Metronidazole. AHFS Drug Information 2001®. Bethesda:American Society of Health-System Pharmacists, Inc., pp. 3389- 3395 (2001).
  3. Miyachi Y, Imamura S, Niwa Y. Anti-oxidant action of metronidazole: a possible mechanism of action in rosacea. Br J Dermatol 114(2):231-4 (1986 Feb).
  4. Aronson IK, Rumsfield JA, West DP, Alexander J, Fischer JH, Paloucek FP. Evaluation of topical metronidazole gel in acne rosacea. Drug Intell Clin Pharm 21(4):346-51 (1987 Apr).
  5. Breneman DL, Stewart D, Hevia O, Drake LA. A double-blind, multicenter clinical trial comparing efficacy of once-daily metronidazole 1 percent cream to vehicle in patients with rosacea. Cutis 61(1):44-47 (1998 Jan).
  6. Jorizzo JL, Lebwohl M, Tobey RE. The efficacy of metronidazole 1% cream once daily compared with metronidazole 1% cream twice daily and their vehicles in rosacea: A double-blind clinical trial. J Am Acad Dermatol 39(3):502-4 (1998 Sep).
  7. Bjerke JR, Nyfors A, Austad J, et al. Metronidazole (Elyzol) 1% cream vs placebo cream in the treatment of rosacea. Clin Trials 1989;26:187-194.
  8. Bleicher PA, Charles JH, Sober AJ. Topical metronidazole therapy for rosacea. Arch Dermatol 123(5):609-14 (1987 May).
  9. Lowe NJ, Henderson T, Millikan LE, Smith S, Turk K, Parker F. Topical metronidazole for severe and recalcitrant rosacea: a prospective open trial. Cutis 43(3):283-6 (1989 Mar).
  10. Lebwohl MG, Medansky RS, Russo CL, Plott RT, The comparative efficacy of sodium sulfacetamide 10%/sulfur 5% (Sulfacet-R®) lotion and metronidazole 0.75% (MetroGel®) in the treatment of rosacea. J Geriatr Dermatol 3(5):183-5 (1995).
  11. Metronidazole lotion 0.75% (Metrolotion™). Physicians’ Desk Reference. Medical Economics Company, Inc., Montvale, NJ, USA, pp. 1106-1107 (2000).
  12. Maddin S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 40(6 Pt 1):961-965 (1999 Jun).
  13. Tan JK. A new formulation containing sunscreen (SPF 15) and 1% metronidazole (Rosasol® Cream) in the treatment of rosacea. Skin Therapy Lett 6(8):1-2 (2001 May).
  14. Nielsen PG. A double-blind study of 1% metronidazole cream versus systemic oxytetracycline therapy for rosacea. Br J Dermatol 109(1):63-5 (1983 Jul).
  15. Veien NK, Christiansen JV, Hjorth N, Schmidt H. Topical metronidazole in the treatment of rosacea. Cutis 38(3):209-10 (1986 Sep).
  16. Schachter D, Schachter RK, Long B, et al. Comparison of metronidazole 1% cream versus oral tetracycline in patients with rosacea. Drug Invest 1991;3(4):220-224.
  17. Monk BE, Logan RA, Cook J, et al. Topical metronidazole in the treatment of rosacea. J Dermatol Treat 1991;2:91-93.
  18. Nielsen PG. The relapse rate for rosacea after treatment with either oral tetracycline or metronidazole cream. Br J Dermatol 109(1):122 (1983 Jul).
  19. Dahl MV, Katz HI, Krueger GG, et al. Topical metronidazole maintains remissions of rosacea. Arch Dermatol 134(6):679-83 (1998 Jun).

In this issue:

  1. Topical Metronidazole for Rosacea
  2. Treatments Of Choice For Bullous Pemphigoid
  3. Update on Drugs and Drug News - January 2002