Drug Criteria & Outcomes: Retapamulin (Altabax) Formulary Evaluation
September 1, 2007
Drug Criteria & Outcomes
Retapamulin (Altabax™) Formulary Evaluation
By Sarita Bhat, Pharm.D. Candidate, Auburn (AL) University
Brand Name (Manufacturer): Albatax™
GlaxoSmithKline)
Generic Name: Retapamulin
FDA Approved Indication:
- Retapamulin: For adults and pediatric patients aged nine months and older for impetigo (up to 100 cm2 of total area in adults or 2% total body surface area in pediatric patients) due to methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes.
- Mupirocin: Treatment of impetigo or secondary infected traumatic skin lesions due to Staphylococcus aureus and Streptococcus pyogenes.
Dose:
- Retapamulin: Applied twice daily for five days; 1% ointment (5g, 10g, 15g)
- Mupirocin: Applied three times daily; 2% ointment (22g)
- Retapamulin: Apply a thin layer of ointment to affected area twice daily for five days; do not use on abraded skin or open wounds; treated area may be covered by a sterile bandage or gauze if desired; use for the full time recommended by health care provider even if symptoms have improved.
- Mupirocin: Apply thin film to affected area three times daily; wash hands before and after application; avoid getting into eyes.
Storage:
- Retapamulin: Store between 59°-86°F
- Mupirocin: Store below 77°F; do not freeze, and store away from heat, light, and moisture.Mechanism of Action:
- Retapamulin: Binds to unique protein L3 site of 50S subunit of the ribosome; inhibits bacterial protein synthesis by inhibiting peptidyl transfer and blocking P-site interactions.
- Mupirocin: Selective binding to isoleucyl-tRNA synthetase which stops the inclusion of isoleucine in the bacterial protein.
Pharmacokinetics:
Retapamulin:
- Absorption: low; increased when applied to skin with abrasions
- Distribution: 94% plasma protein bound with protein binding independent of concentration
- Metabolism: hepatic via CYP3A4; heavily metabolized by oxygenation and N-demethylation
- Elimination: not investigated due to low systemic absorption.
Mupirocin:
- Absorption: through outer skin layer; systemic absorption is minimal through intact skin
- Metabolism: 3% converts to monic acid (inactive)
- Elimination: renal
Microbiology:
- Retapamulin: In vitro studies show lower values for methicillin-resistant S. aureus (MRSA), but not enough clinical evidence exists for the FDA to grant approval for the use of retapamulin in treating MRSA. Further well-controlled clinical studies are needed to ensure its place in the treatment of MRSA.
- Mupirocin: Yes; FDA approval for treatment of MRSA with overall susceptibility rate of 77%.
Pregnancy/Lactation Category:
- Retapamulin and Mupirocin: B: both have not shown teratogenicity in animal studies; should be avoided in pregnancy unless benefit outweighs the risk
- Data is inconclusive on lactation risk; thus infant risk cannot be ruled out
- Retapamulin: Headache, pyrexia, pruritis, eczema, diarrhea, nausea, application site irritation and pruritis, nasopharyngitis, application site erythema, contact dermatitis, increased creatinine phosphokinase
- Mupirocin: Dermatitis, dry skin, erythema, hives, pruritus, rash, ulcerative stomatitis, burning, edema, pain, stinging, tenderness, secondary wound infection
Contraindications:
- Retapamulin: none
- Mupirocin: Hypersensitivity to mupirocin or any components of its formulation. Not for treatment of pressure sores
Precautions/Warnings:
- Retapamulin: Discontinue and wipe off ointment if either sensitization or severe local irritation occurs. Inappropriate use may promote the growth of resistant organisms. For external use only.
- Mupirocin: Possibly toxic amounts of polyethylene glycol may be absorbed through skin that is not intact, such as in patients with burns and open wounds. Prolonged use may promote the growth of resistant organisms. For external use only.
Interactions:
- Retapamulin: Oral ketoconazole increases mean AUC and Cmax in healthy adult males with abraded skin. Dosage adjustments for Altabax™are not necessary when given with CYP3A4 inhibitors due to low systemic absorption of Altabax™.
- Mupirocin: none
Black Box Warnings:
- Retapamulin: none
- Mupirocin: none
Overdose:
- Altabax™: No overdosing has been reported; treat any signs and symptoms of overdose or accidental ingestion using good clinical practice
- Mupirocin: Overdose is rare
Costs:
| Altabax™1% ointment | 15g | $68.00 |
| 10g | $55.62 | |
| 5g | $32.82 | |
| Bactroban® nasal ointment 1g | $6.07 | |
| Bactroban® 2% ointment 22g | $38.08 | |
| Mupirocin 2% ointment 22g | $10.30 | |
Potential for Medication Errors:
- Retapamulin (Altabax™):
- Look alike/sound alike drugs: Retaplase, Alteplase
- Administration: avoid applying to abraded skin or open wounds Mupirocin (Bactroban®)
- Look alike/sound alike drugs: bacitracin, baclofen
Monitoring Parameters:
- Renal: none
- Hepatic: none
- Other: resolution of signs and symptoms of infection
Clinical Trial Summary:
Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1% wt/wt) twice daily for five days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis: Results of a randomized controlled trial. J Am Acad Dermatol. 2006; 55: 1003-1013.
Objective:
To determine clinical safety and efficacy of topical retapamulin ointment 1% versus oral cephalexin for the treatment of SID.
Study Design and Population:
5 randomized 2:1 retapamulin: cephalexin trials with 3 non-inferiority trials against oral cephalexin, 1 non-inferiority trial against topical fusidic acid ointment for impetigo treatment, and 1 superiority trial against placebo.
Inclusion:
- Underlying atopic dermatitis
- One or more signs or symptoms of secondary infection (i.e. sudden exacerbation of underlying dermatosis, crusting, weeping, small superficial pustules, purulent discharge)
- SID had to be suitable for topical or oral antimicrobial therapy
- Size of lesion less than 100 cm2 or less than or equal to 2% of body surface for patients under 18 years of age
- Severity of lesion had to be of at least minimal severity based on a skin infection rating scale
- Women of childbearing potential had to have a negative urine pregnancy test before inclusion
Exclusion:
- Patients for whom the causative agent was not Staphylococcus aureus or Streptococcus pyogenes.
- Patients who had demonstrated previous hypersensitivity to beta-lactam antimicrobials or to retapamulin.
- Patients who had received systemic and/or topical antibacterials within 72 hours of starting the study, or had received systemic corticosteroid dose of more than 10 mg/d, or renal tubular secretion inhibitors.
- Patients with chronic ulcerative lesion, systemic signs and symptoms of infection, required surgical intervention for SID, or any underlying life threatening condition.
- Patients who had used an investigational drug within 30 days before starting the study.
- Patients who had previous enrolled in a study involving retapamulin.
- Patients who were pregnant, breast-feeding, planning a pregnancy, or not using an accepted method of contraception.
Treatment Regimen:
- All patients received either retapamulin
ointment 1% twice daily for five days and oral Cephalexin placebo twice daily for 10 days, or retapamulin placebo ointment and oral Cephalexin as two 250 mg capsules twice daily for 10 days - Follow up period of 17-19 days
Results:
| Clinical success rates (%) with retapamulin: | |||
| Age | SITL | SID | Impetigo |
| 9 mos - <2 yrs | 50 | 93 | 95 |
| 2 - <6 yrs | 95 | 89 | 88 |
| 6 - <13 yrs | 98 | 90 | 95 |
| 13 - <18 yrs | 93 | 100 | 94 |
| 18 - <65 yrs | 90 | 91 | 91 |
| >65 yrs | 91 | 91 | 94 |
| Clinical success rates (%) with other drugs: | |||
| Age | Cephalexin for SITL | Fusidic Acid for Impetigo | Placebo for Impetigo |
| 9 mos - <2 yrs | N/A | 92 | 33 |
| 2 - <6 yrs | 92 | 93 | 33 |
| 6 - <13 yrs | 100 | 89 | 68 |
| 13 - <18 yrs | 89 | 79 | 50 |
| 18 - <65 yrs | 91 | 91 | 71 |
| >65 yrs | 89 | 100 | N/A |
Study endpoint:
- Primary end point was clinical response (success or failure) at follow-up (Day 7-9 after retapamulin and Day 12-14 after cephalexin).
- Secondary end point included response at the end of therapy and microbiologic responses (elimination of baseline pathogen without infection with a new pathogen) at follow-up and end of therapy.
Results:
Treatment with retapamulin ointment 1% was as effective as oral cephalexin as seen by 85.9% efficacy in the retapamulin group and 89.7% efficacy in the cephalexin group in the PPC population. This was a non-inferiority trial with 90% power to detect a greater than 10% difference in treatment, and the treatment difference was -3.8%, which is within 10%.
Authors' Conclusions:
- Both topical Retapamulin and oral Cephalexin were equally efficacious and equally well tolerated with similar safety profiles, based on efficacy data.
Clinical Trial Summary:
Rittenhouse S, Biswas S, Broskey J et al. Selection of Retapamulin, A Novel Pleuromutilin for Topical Use. Antimicrob Agents Ch. 2006; 50: 3882-3885.
This trial compared the in vitro activity of retapamulin to that of other commonly used topical antibiotics, showing MIC and MBC values for various antibiotics against several different strains of Staphylococcus and Streptococcus. MBC's were lower for retapamulin when directly compared with mupirocin against the same bacterial isolates in vitro. Retapamulin had the lowest MIC90 in most of the isolates studied. The authors concluded that retapamulin retains excellent in vitro activity against some isolates that are currently known to be resistant to commonly used antibiotics such as mupirocin, beta-lactams, macrolides, and quinolones, but they looked at very few isolates of these resistant strains.
Recommendations:
Since the cost of retapamulin is much higher than that of generic mupirocin, it would be best to use Mupirocin when appropriate for impetigo and other skin infections caused by susceptible strains of Staphylococcus aureus and Streptococcus pyogenes. Retapamulin is not indicated for coverage of methicillin-resistant Staphylococcus aureus, and mupirocin is indicated for this purpose. Although the in vitro studies with retapamulin showed promise, the published clinical data has not proven that retapamulin is superior to the current treatment options available for gram-positive skin infections. It is recommended that retapamulin currently be restricted on the institutional formulary. Some institutions may want to classify the drug as non-formulary, where use is strongly discouraged. Alternatively, retapamulin could be classified as formulary status, but restricted to a small group of specialty physicians such as infectious disease and dermatology, where for unusual cases a specialty practitioner desires to use the new drug.
Selected References
- Altabax™ package insert [database on the internet]. Rockville (MD): U.S. Food and Drug Administration. [cited 2007 May 7]. Available from: www.fda.gov
- Bactroban® package insert [database on the internet]. Rockville (MD): U.S. Food and Drug Administration. [cited 2007 May 7]. Available from: www.fda.gov.
- Baddour MM, Abuelkheir MM, Fatani AJ. Trends in antibiotic susceptibility patterns and epidemiology of MRSA isolates from several hospitals in Riyadh, Saudi Arabia. Ann Clin Microbiol Antimicrob. 2006;5(30).
- Data on File. Clinical Study Report. GlaxoSmithKline. Research Triangle Park, North Carolina. 2005.
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