National PBM Drug Monograph

Retapamulin (Altabax^®^)

October 2007

VHA Pharmacy Benefits Management Strategic Healthcare Group and the
Medical Advisory Panel

*The purpose of VACO PBM-SHG drug monographs is to provide a
comprehensive drug review for making formulary decisions.  These
documents will be updated when new data warrant additional formulary
discussion.  Documents will be placed in the Archive section when the
information is deemed to be no longer current.*

**[Executive Summary:]{.underline}**

-   Retapamulin is a semi-synthetic pleuromutilin antibiotic that
    received FDA approval for the topical treatment of impetigo in
    adults and pediatric patients aged 9 months and older.

-   Retapamulin displays potent in vitro activity against Gram-positive
    organisms including *S. aureus*, Coagulase-negative *Staphylococci*,
    and *S. pyogenes*. Retapamulin maintains potent in vitro activity
    against mupirocin--resistant strains of *S. aureus*.

-   In the pivotal, Phase III, randomized, placebo-controlled,
    double-blind clinical trial, retapamulin 1% topically twice daily
    for 5 days was compared to placebo ointment for treatment of
    impetigo in adults and pediatric patients aged 9 months and older.
    Retapamulin was found to be superior to placebo for the treatment of
    impetigo.

-   Retapamulin appears to be well-tolerated with a small percent of
    patients experiencing localized skin irritation at the application
    site.

-   Place in therapy: Retapamulin is an alternative to first-line
    mupirocin for the topical treatment of localized impetigo. Efficacy
    and safety data are not available for intranasal application of
    retapamulin for MRSA decolonization; therefore, this agent should
    not be considered an alternative to mupirocin for MRSA
    decolonization.

**[Introduction]{.underline}**

The purposes of this monograph are to (1) evaluate the available
evidence of safety, efficacy, cost, and other pharmaceutical issues that
would be relevant to evaluating retapamulin for possible addition to the
VA National Formulary; (2) define its role in therapy; and (3) identify
parameters for its rational use in the VA.

# 

**[Pharmacology^1,2^]{.underline}**

Retapamulin is a semi-synthetic derivative of pleuromutilin. It inhibits
bacterial protein synthesis at the elongation phase. Specifically,
retapamulin interacts at the ribosomal protein LS on the 50S subunit of
the bacterial ribosome.

**[Pharmacokinetics]{.underline}**

There is minimal systemic absorption of topically administered
retapamulin. Eighty-two percent of the blood samples collected in
patients with topical retapamulin application to intact skin had
detectable retapamulin concentrations; the Cmax~ss~ was 3.5ng/mL (range
1.2 -- 7.8ng/mL). In comparison, all blood samples collected in patients
with topical retapamulin application to abraded skin had detectable
retapamulin concentrations; the Cmax~ss~ was 9.0ng/mL (range 6.7 --
12.8ng/mL). Retapamulin is 94% bound to human plasma proteins. It
undergoes extensive Phase I hepatic metabolism, primarily via cytochrome
P450 (CYP) 3A4. Other pharmacokinetic parameters (Tmax~ss~, AUC~ss~,
T~1/2~, Vd) and elimination have not been determined.

[]{.mark}

**[Microbiology]{.underline}^1^~,~^3-6^**

Retapamulin displays potent in vitro activity against Gram-positive
organisms including *S. aureus*, Coagulase-negative *Staphylococci*, and
*S. pyogenes*. The in vitro activity of retapamulin against a selected
group of pathogens is provided in Table1. The table presents the minimum
concentration (mcg/mL) of antibiotic required to inhibit growth at 50%
(MIC~50~) of the tested strains and 90% (MIC~90~) of the strains. The
MIC~50~ and MIC~90~ values of retapamulin were not impacted by strains
resistant to methicillin, mupirocin, or erythromycin. Retapamulin
demonstrates bacteriostatic activity against *S. aureus* and *S.
pyogenes* at 1X the MIC value. However, at concentrations of 1,000X the
MIC value, retapamulin shows bactericidal activity.

Retapamulin does not display in vitro activity against most
Gram-Negatives with the exception of respiratory Gram-Negatives. One
study found that retapamulin displays in vitro activity against
*Haemophilus influenzae* (MIC~50~/ MIC~90~ = 0.5/2 mcg/mL; n=27
isolates) and *Moraxella catarrhalis* (MIC~50~/ MIC~90~ = 0.3/0.3
mcg/mL; n=27 isolates). Retapamulin exhibits in vitro activity against
anaerobes often isolated in skin infections (i.e., *Prevotella* spp,
*Porphyromona*s spp., *Fusobacterium* spp, *P. acnes* and anaerobic
Gram-positive cocci); 99% (149/151) of these tested isolates were
inhibited by a retapamulin concentration of ≤2 mcg/mL. Against *B.
fragilis*, the MIC range of retapamulin was 0.25 -- 64 mcg/mL (MIC~50~/
MIC~90~ = 0.25/64 mcg/mL; n=25 isolates).

**Table 1**. In Vitro Activity Profiles of Retapamulin, Mupirocin, and
Bacitracin

  ---------------------- ------------- ------------- ----------- ---------- ------------ ----------
                         Retapamulin                 Mupirocin              Bacitracin   

                         MIC~50~       MIC~90~       MIC~50~     MIC~90~    MIC~50~      MIC~90~

  ***S. aureus***                                                                        

  Methicillin            0.06          0.12          0.25        0.5        \>16         \>16
  susceptible                                                                            

  Methicillin resistant  0.06          0.12          0.25-≤2     32-\>256   \>4-\>16     \>4-\>16

  Mupirocin resistant    0.06          0.12          32          32         \>4-\>16     \>4-\>16

  **CoNS**                                                                               

  Methicillin resistant  ≤0.03         0.06          32          \>256      \>4          \>4

  Mupirocin resistant    ≤0.03         0.06          NR          NR         \>4          \>4

  ***S. pyogenes***                                                                      

  Erythromycin           0.016         0.03          NR          NR         NR           NR
  susceptible                                                                            

  Erythromycin resistant 0.016-≤0.03   0.016-≤0.03   ≤2          ≤2         1            \>4
  ---------------------- ------------- ------------- ----------- ---------- ------------ ----------

NR: not reported

**[FDA Approved Indication^1^]{.underline}**

Retapamulin is indicated for the topical treatment of impetigo due to
*Staphylococcus aureus* (methicillin-susceptible strains) and
*Streptococcus pyogenes* in adults and pediatric patients aged 9 months
and older*.* The affected area may be up to 100cm^2^ in total area in
adults or 2% total body surface area in pediatric patients.

# Current VA National Formulary Alternatives

Current formulary alternatives for topical treatment of impetigo include
mupirocin and bacitracin; however, due to high rates of allergic skin
reactions seen with bacitracin, mupirocin is the preferred agent.

# 

# Dosage and Administration

Retapamulin should be applied with a thin layer to affected area twice
daily for 5 days. The affected area may be up to 100cm^2^ in total area
in adults or 2% total body surface area in pediatric patients.

# 

# Efficacy 

[Treatment of Impetigo^:^ Study TOC 103469^1-2^]{.underline}

This study was the pivotal, Phase III trial utilized to receive the
FDA-approved indication for treatment of impetigo. The trial has not
been published.

In this randomized, placebo-controlled, double-blind clinical trial,
retapamulin 1% topically twice daily for 5 days was compared to placebo
ointment for treatment of impetigo in adults and pediatric patients aged
9 months and older. Randomization occurred in 2:1 for retapamulin to
placebo. All study sites were located outside the US. Inclusion criteria
included 1) diagnosis of primary impetigo 2) infected lesion(s) may be
up to 100cm^2^ in total area (up to 10 lesions) or total body surface
area not exceeding 2% for those \<18 years old 3) total Skin Infection
Rating Score (SIRS) of at least 8. Exclusion criteria included 1)
underlying skin disease or skin trauma with secondary infection 2)
systemic signs and symptoms of infection 3) received oral antibiotic or
topical therapy within 24 hours of study entry.

It was designed to be a superiority study (90% power and one-sided alpha
of 2.5%). Superiority was declared if lower limit of 95% confidence
interval for the treatment difference was greater than zero.

Four populations were evaluated as endpoints. Intent-to-treat clinical
(ITTC) was defined as all randomized patients who took at least one
study drug while clinical per protocol (PPC) represented the subset of
ITTC patients who adhered to the protocol. Intent-to-treat
bacteriological (ITTB) was defined as all randomized patients who took
at least one study drug and had a pathogen identified at study entry
while per protocol bacteriological population (PPB) was defined as
subset of ITTB patients who adhered to the protocol.

Endpoints

-   Primary efficacy endpoint (considered by the FDA)

    -   Clinical response defined as success or failure at follow-up (9
        days after treatment) in ITTC population; success defined as
        absence of treated lesion or improvement that no further
        antibiotic is necessary

-   Secondary efficacy endpoint:

    -   Clinical response at end of therapy (2 days after treatment) in
        ITTC, PPC, PPB, and ITTB population

    -   Clinical response at follow-up in PPC, PPB, and ITTB

    -   Microbiological response at follow-up in ITTB and PPB population

    -   Microbiological response at end of therapy in ITTB and PPB
        population

    -   Clinical response at end of therapy and follow-up in patients
        who isolated MRSA

Of the 210 patients in the ITTC, 139 patients were administered
retapamulin and 71 patients were administered placebo. The demographic
were similar between retapamulin-treated and placebo-treated groups.
Seventy-eight percent of enrolled patients were \< 13 years old. The
placebo group had a higher rate of premature withdrawn compared to
retapamulin group (44% vs 12%); this appears to be related to higher
rates of lack of efficacy (25% vs 4%, respectively) and disease
progression (13% vs 2%, respectively). Overall, 81.3% in
retapamulin-treated and 84.5% placebo-treated patients were diagnosed
with non-bullous impetigo at baseline.

Clinical success at end therapy and follow-up with retapamulin was
superior to treatment with placebo in ITTC, PPC, PPB and ITTB
populations (Table 2). Clinical success by baseline pathogen with
retapamulin was also superior to treatment with placebo (Table 3). Of
note, MRSA was not isolated in any of the patient's baseline cultures.

**Table 2. Efficacy Endpoints**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **        | **95% CI  |
|                                 | pamulin** | Placebo** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Clinical Success Rates at End |           |           |           |
| of Therapy**                    |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC                            | 119/139   | 37/71     | 20.5,     |
|                                 |           |           | 46.5      |
|                                 | (85.6%)   | (52.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPC                             | 111/124   | 33/62     | 22.8,     |
|                                 |           |           | 49.8      |
|                                 | (89.5%)   | (53.2%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 101/114   | 28/57     | 25.2,     |
|                                 |           |           | 53.7      |
|                                 | (88.6%)   | (49.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPB                             | 96/107    | 26/52     | 25.0,     |
|                                 |           |           | 54.5      |
|                                 | (89.7%)   | (50.0%)   |           |
+---------------------------------+-----------+-----------+-----------+
| **Clinical Success Rates at     |           |           |           |
| Follow-up**                     |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC\*                          | 105/139   | 28/71     | 22.7,     |
|                                 |           |           | 49.5      |
|                                 | (75.5%)   | (39.4%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPC                             | 98/119    | 25/58     | 24.8,     |
|                                 |           |           | 53.7      |
|                                 | (82.4%)   | (43.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 91/114    | 18/48     | 31.4,     |
|                                 |           |           | 62.2      |
|                                 | (79.8%)   | (37.5%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPB                             | 86/102    | 25/58     | 24.8,     |
|                                 |           |           | 53.7      |
|                                 | (84.3%)   | (43.1%)   |           |
+---------------------------------+-----------+-----------+-----------+

\*Primary efficacy endpoint; ITTC: clinical intent to treat population;
PPC: clinical per protocol population; ITTB: bacteriological intent to
treat population; PPB: bacteriological per protocol population

**Table 3. Clinical Response in ITTC Population**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **        | **95% CI  |
|                                 | pamulin** | Placebo** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at End of       |           |           |           |
| Therapy**                       |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 79/88     | 25/48     | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (89.8%)   | (52.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 29/32     | 3/7       | NA        |
|                                 |           |           |           |
|                                 | (90.6%)   | (42.9%)   |           |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at Follow Up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 71/84     | 19/44     | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (84.5%)   | (43.2%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 29/32     | 2/6       | NA        |
|                                 |           |           |           |
|                                 | (90.6%)   | (33.3%)   |           |
+---------------------------------+-----------+-----------+-----------+

NA=not available

Localized impetigo can sometimes be considered self-limiting disease as
demonstrated by success rates of 30-40% in placebo arm at follow-up;
however, placebo arm had higher rates of premature withdrawal secondary
to lack of efficacy. According to the FDA product review, the study
results were "statistically robust" despite the small sample size.
Several limitations were also identified. First, the bacteriological
samples were obtained by cotton swabs rather than more sterile
techniques (i.e., needle biopsy, curettage). Secondly, the protocol did
not require sampling of the pus or exudates. In conclusion, retapamulin
was found to be superior to placebo for the treatment of impetigo.

[Treatment of Impetigo^:^ Study TOC 100224^2^]{.underline}

This study supported the efficacy of retapamulin for the treatment of
impetigo. The comparator agent, sodium fusidate, is not approved in the
US, therefore, the FDA did not utilize this study as a pivotal trial for
treatment of impetigo. The trial has not been published.

In this randomized, multi-center, single-blind clinical trial,
retapamulin 1% topically twice daily for 5 days was compared to sodium
fusidate topically three times daily for 7 days for treatment of
impetigo in adults and pediatric patients aged 9 months and older.
Randomization occurred in 2:1 for retapamulin to placebo. All study
sites were located outside the US. This study was designed to be a
non-inferiority study.

Endpoints

-   Primary efficacy endpoint (considered by the FDA)

    -   Clinical response defined as success or failure at follow-up
        (day 14 for both treatment groups)

-   Secondary efficacy endpoint:

    -   Clinical response at end of therapy

    -   Clinical response at Day 7

    -   Clinical response at Day 9

    -   Microbiological response at end of therapy in ITTB and PPB
        population

    -   Microbiological response at follow-up in ITTB and PPB population

    -   Clinical response at end of therapy and follow-up in patients
        who isolated MRSA

There were 517 patients as part of ITTC population. The demographics
were similar between retapamulin-treated and sodium fusidate-treated
groups with the exception of age (mean 14.4 vs 7 years old,
respectively). Overall, 78.3% in retapamulin-treated and 79.7% sodium
fusidate-treated patients were diagnosed with non-bullous impetigo at
baseline.

Clinical success at follow-up was similar between the
retapamulin-treated and sodium fusidate-treated patients (Table 5) while
clinical success at end of therapy was statistically higher in
retapamulin-treated patients in 3 out of the 4 analyzed populations.
Clinical success rate for retapamulin-treated patients with *S*.
*aureus* was 96.6% (199/206) compared to 92.2% (83/90) for sodium
fusidate-treated patients. Refer to Table 6 for pathogen specific
clinical success rates.

**Table 5**. Efficacy Endpoints

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Sodium  | **95% CI  |
|                                 | pamulin** | F         | (%)**     |
|                                 |           | usidate** |           |
+---------------------------------+-----------+-----------+-----------+
| **Clinical Success Rates at End |           |           |           |
| of Therapy**                    |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC                            | 327/345   | 155/172   | -0.4, 9.7 |
|                                 |           |           |           |
|                                 | (94.8%)   | (90.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPC                             | 314/317   | 141/150   | 1.1, 9.0  |
|                                 |           |           |           |
|                                 | (99.1%)   | (94.0%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 250/263   | 116/131   | 1.4, 11.0 |
|                                 |           |           |           |
|                                 | (95.1%)   | (88.5%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPB                             | 240/242   | 106/114   | 0.5, 12.6 |
|                                 |           |           |           |
|                                 | (99.2%)   | (93.0%)   |           |
+---------------------------------+-----------+-----------+-----------+
| **Clinical Success Rates at     |           |           |           |
| Follow-up**                     |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC\*                          | 310/345   | 150/172   | -3.3, 8.6 |
|                                 |           |           |           |
|                                 | (89.9%)   | (87.2%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPC                             | 297/308   | 134/143   | -1.8, 7.2 |
|                                 |           |           |           |
|                                 | (96.4%)   | (93.7%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 237/263   | 111/131   | -1.8,     |
|                                 |           |           | 12.5      |
|                                 | (90.1%)   | (84.7%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPB                             | 227/235   | 99/107    | -1.4, 9.6 |
|                                 |           |           |           |
|                                 | (96.6%)   | (92.5%)   |           |
+---------------------------------+-----------+-----------+-----------+

\*Primary efficacy endpoint

**Table 6**. Clinical Response in PPC Population

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Sodium  | **95% CI  |
|                                 | pamulin** | F         | (%)**     |
|                                 |           | usidate** |           |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at End of       |           |           |           |
| Therapy**                       |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 201/203   | 88/95     | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (99.0%)   | (92.6%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 8/8       | 2/2       | NA        |
| (methicillin-resistant)         |           |           |           |
|                                 | (100%)    | (100%)    |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 90/92     | 32/36     | NA        |
|                                 |           |           |           |
|                                 | (97.8%)   | (88.9%)   |           |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at Follow Up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 191/198   | 81/88     | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (96.5%)   | (92.0%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 8/8       | 2/2       | NA        |
| (methicillin-resistant)         |           |           |           |
|                                 | (100%)    | (100%)    |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 87/91     | 31/36     | NA        |
|                                 |           |           |           |
|                                 | (95.6%)   | (86.1%)   |           |
+---------------------------------+-----------+-----------+-----------+

NA=not available

The FDA identified several limitations is this trial. First, the study
was only single blinded (evaluator blinded) because of the different
dosing intervals and length of therapy for the two agents. Secondly,
higher success rates were seen in the retapamulin arm in this trial
compared to Study 103469. This may be related to the single-blind nature
of the study as well. In conclusion, clinical success rates at follow-up
were similar for retapamulin-treated and sodium fusidate-treated
patients.

[Treatment of Secondarily Infected Dermatitis^7^]{.underline}

In this randomized, double-blind, double-dummy clinical trial,
retapamulin 1% topically twice daily for 5 days was compared to
cephalexin 500mg orally twice daily (or cephalexin suspension 12.5mg/kg
twice daily for age \<13 years old) for 10 days in adults and pediatric
patients aged 9 months and older. Randomization occurred in 2:1 for
retapamulin to cephalexin. Inclusion criteria included 1) atopic
dermatitis, psoriasis, or allergic contact dermatitis 2) secondary
infection 3) size of infected lesion may be up to 100cm^2^ in total area
in adults or 2% total body surface area in pediatric patients 4) ranked
at least minimal severity by the skin infection rating scale.

Endpoints

-   Primary efficacy endpoint:

    -   Clinical response defined as success or failure at follow-up (7
        -- 9 days after therapy)

-   Secondary efficacy endpoint:

    -   Clinical response at end of therapy

    -   Microbiological response at follow-up (7 -- 9 days after
        therapy)

    -   Microbiological response at end of therapy

Of the 546 patients in the ITTC population, 363 patient received
retapamulin and 183 received cephalexin. Demographics and results of
microbiology culture(s) were similar among the retapamulin-and
cephalexin-treated patients. The mean age was 33.7 and 34.8 years old,
respectively. Overall, approximately 23% of patients were \<18 years old
and 62% men. The most common inflammatory skin disease was atopic
dermatitis followed by allergic contact dermatitis and psoriasis.
Approximately 60% (327/546) of patients had ≥ 1 organism obtained at
baseline. As expected, *S. aureus* and *S. pyogenes* accounted for 80%
of the pathogens. Of the 277 MRSA, only 8 were resistant to methicillin.

Clinical success rates at follow-up were similar in patients treated
with retapamulin topically for 5 days compared with cephalexin orally
for 10 days (Table 7). The authors state that more retapamulin-treated
patients were categorized as "unable to determine" secondary to missing
their clinic visits. Microbiologic success rates at follow-up were 86.7%
and 92.5% among retapamulin-treated and cephalexin-treated patients,
respectively (Table 8). []{.mark}

**Table 7. Efficacy Endpoint in ITTC Population**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Cep     | **95% CI  |
|                                 | pamulin** | halexin** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Success rates at End of       | []{.mark} | []{.mark} | []{.mark} |
| Therapy**                       |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC                            | 335/363   | 168/183   | NR        |
|                                 | (92.3%)   | (91.8%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 198/212   | 105/115   | NR        |
|                                 |           |           |           |
|                                 | (93.4%)   | (91.3%)   |           |
+---------------------------------+-----------+-----------+-----------+
| **Success rates at Follow-up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC\*                          | 301/363   | 158/183   | -9.7,2.9  |
|                                 | (82.9%)   | (86.3%)   |           |
+---------------------------------+-----------+-----------+-----------+
| ITTB                            | 177/212   | 101/115   | NR        |
|                                 |           |           |           |
|                                 | (83.5%)   | (87.8%)   |           |
+---------------------------------+-----------+-----------+-----------+

\*Primary efficacy endpoint; NR = not reported

**Table 8. Microbiologic Response at Follow-up by Baseline Pathogen**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Cep     | **95% CI  |
|                                 | pamulin** | halexin** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at Follow Up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 138/154   | 78/84     | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (89.6%)   | (92.9%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 5/5       | 2/2       | NA        |
| (methicillin-resistant)         |           |           |           |
|                                 | (100%)    | (100%)    |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 32/33     | 13/14     | NA        |
|                                 |           |           |           |
|                                 | (97%)     | (92.9%)   |           |
+---------------------------------+-----------+-----------+-----------+

NA=not available

Overall, adverse events were reported 22% (79/363) in
retapamulin-treated and 22% (40/183) in cephalexin-treated patients.
Nasopharyngitis was reported 3% in both treatment arms while other
frequently reported adverse events were headache (2%) in retapamulin and
diarrhea (3%) in cephalexin group. Investigators only attributed the
following adverse events to retapamulin administration: application site
irritation (1%, n=4 patients), application site pruritus (1%, n=4
patients), and application site pain (\<1%, n=4 patients). In
comparison, investigators attributed only diarrhea and abdominal pain as
adverse events related to cephalexin therapy.

In conclusion, retapamulin was found to be noninferior to cephalexin in
the primary efficacy endpoint for treatment of secondary infected
dermatitis. The FDA did not grant approval for the indication of
secondary infected dermatitis.

[Empiric Treatment of Secondarily Infected Traumatic Lesions of the
Skin^8^]{.underline}

In two randomized, double-blind, double-dummy clinical trials,
retapamulin 1% topically twice daily for 5 days was compared to
cephalexin 500mg orally twice daily for 10 days in adults and pediatric
patients aged 9 months and older. Randomization occurred in 2:1 for
retapamulin to cephalexin. Inclusion criteria included 1) secondarily
infected traumatic lesions of skin (e.g., laceration, sutured wound,
abrasion) 2) infected area ≤10cm in length and surrounding erythema ≤2cm
3) size of lesion may be up to 100cm^2^ in total area 4) ranked at least
minimal score of 8 by the skin infection rating scale.

Endpoints

-   Primary efficacy endpoint:

    -   Clinical success: resolution or improvement of the signs and
        symptoms of infection at follow-up in PPC; no further
        antimicrobial therapy is necessary.

-   Secondary efficacy endpoint:

    -   Microbiologic success: eradication of pathogen(s) from lesion at
        follow-up

Of the 1904 patients in the ITTC population, 1268 received retapamulin
and 636 received cephalexin. Demographics and results of microbiology
culture(s) were similar among the retapamulin-treated and
cephalexin-treated patients. The mean age was 40.6 and 40.8 years old in
PPC population, respectively. Overall, 55% were men. Approximately 50%
(954/1904) of patients in ITTC population had ≥ 1 organism obtained at
baseline. Of all the pathogens, *S. aureus* was isolated most frequently
(59.8% in retapamulin and 58.1% in cephalexin arms).

Clinical success rates were similar in patients treated with retapamulin
topically for 5 days compared with cephalexin orally for 10 days (Refer
to Table 9). Among patients infected with *S. aureus*, clinical success
rates (PPC population at follow-up) were 89.2% (365/409) in the
retapamulin-treated and 90.8% (157/173) in cephalexin-treated patients
(Table 10). However, clinical success was only 68.6% (35/51) in
retapamulin-treated patients with MRSA compared to 88.5% (23/26) in
cephalexin-treated patients with MRSA (p=0.092).

**Table 9. Efficacy Endpoints**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Cep     | **95% CI  |
|                                 | pamulin** | halexin** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Success rates at Follow-up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| ITTC                            | 1094/1268 | 545/636   | NR        |
|                                 |           |           |           |
|                                 | (86.3%)   | (85.7%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPC\*                           | 1013/1132 | 468/509   | -5.4, 0.5 |
|                                 |           |           |           |
|                                 | (89.5%)   | (91.9%)   |           |
+---------------------------------+-----------+-----------+-----------+
| PPB                             | 505/566   | 230/255   | NR        |
|                                 |           |           |           |
|                                 | (89.2%)   | (90.2%)   |           |
+---------------------------------+-----------+-----------+-----------+

\*Primary efficacy endpoint; NR=not reported

**Table 10. Microbiologic Response by Baseline Pathogen in PPC
Population**

+---------------------------------+-----------+-----------+-----------+
|                                 | **Reta    | **Cep     | **95% CI  |
|                                 | pamulin** | halexin** | (%)**     |
+---------------------------------+-----------+-----------+-----------+
| **Success Rates at Follow Up**  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 330/358   | 133/146   | NA        |
| (methicillin-susceptible)       |           |           |           |
|                                 | (92.2%)   | (91.1%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. aureus*                     | 35/51\`   | 23/26     | NA        |
| (methicillin-resistant)         |           |           |           |
|                                 | (68.6%)   | (88.5%)   |           |
+---------------------------------+-----------+-----------+-----------+
| *S. pyogenes*                   | 63/68     | 32/34     | NA        |
|                                 |           |           |           |
|                                 | (92.6%)   | (94.1%)   |           |
+---------------------------------+-----------+-----------+-----------+

NA=not available

Overall, adverse event(s) were reported 22.8% (289/1268) in
retapamulin-treated and 26.9% (171/636) in cephalexin-treated patients.
Treated-related adverse events was 5.3% (67/1268) and 7.7% (49/636),
respectively. In patients treated with retapamulin, the most frequent
treated-related adverse event was application site irritation (1.3%,
17/1268). In comparison, diarrhea (1.9%, 12/636) and nausea (1.6%,
10/636) were the most frequently reported treated-related adverse in
cephalexin group.

In conclusion, retapamulin was found to be noninferior to cephalexin in
the primary efficacy endpoint for treatment of secondary infected
traumatic lesions of the skin. The FDA did not grant approval for the
indication of secondary infected dermatitis.

**[Adverse Events (Safety Data)]{.underline}**

A total of 2115 adults and pediatric patients were administered at least
one dose of the retapamulin regimen (application twice daily for 5
days). The incidence of treatment-related clinical adverse events was
5.5% (116/2115) for retapamulin-treated, 6.6% (54/819) for
cephalexin-treated and 2.8% (2/71) for placebo-treated patients (Refer
to Table 11 and 12).

**Table 11. Adverse Events Reported by ≥1% of Adults**

  -------------------------- ---------------------- ----------------------
  **Adverse Event**          **Retapamulin          **Cephalexin (n=698)**
                             (n=1527)**             

  Headache                   2.0%                   2.0%

  Application site           1.6%                   \<1.0%
  irritation                                        

  Diarrhea                   1.4%                   2.3%

  Nausea                     1.2%                   1.9%

  Nasopharyngitis            1.2%                   \<1.0%

  Creatinine phosphokinase   \<1.0%                 1.0
  increased                                         
  -------------------------- ---------------------- ----------------------

**Table 12. Adverse Events Reported** by ≥1% of Pediatrics Patients

  ------------------------- --------------- --------------- ---------------
  **Adverse Event**         **Retapamulin   **Cephalexin    **Placebo
                            (n=588)**       (n=121)**       (n=64)**

  Application site          1.9%            0%              0%
  irritation                                                

  Diarrhea                  1.7%            5.0%            0%

  Nasopharyngitis           1.5%            1.7%            0%

  Pruritus                  1.5%            1.0%            1.6%

  Eczema                    1.0%            0%              0%

  Headache                  1.2%            1.7%            0%

  Pyrexia                   1.2%            \<1.0%          1.6%
  ------------------------- --------------- --------------- ---------------

**[Contraindications/precautions]{.underline}**^1^

**Contraindications**

-   None

**Warnings and Precautions**

-   Local Irritation: Retapamulin should be discontinued if severe local
    irritation occurs in a patient. The ointment should be removed from
    the skin and replaced with an alternative agent.

-   Not for Systemic or Mucosal Use: Retapamulin should be not be
    administered via the following routes: oral, intranasal, ophthalmic
    or intravaginal.

-   Potential for Microbial Overgrowth: The administration of antibiotic
    such as retapamulin may lead to the selection or development of drug
    resistant organisms. Retapamulin should only be utilized in proven
    or strongly suspected bacterial infections.

**Pregnancy/Nursing Mothers**

-   Pregnancy category B.

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-   It is not known if retapamulin is excreted in human breast milk.

# 

# 

# 

# 

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

# 

[LA/SA for trade name Altabax]{.underline}

Aldara topical cream, aldex D oral suspension, alrex ophthalmic
suspension, altafed oral syrup, altalube ophthalmic ointment, altazine
ophthalmic solution, altace capsule, altinac topical cream, clobex
topical lotion, allermax tablet, alphatrex topical gel, eurax topical
cream, lidex topical ointment, lotemax ophthalmic suspension/drops,
mentax topical cream, taclonex topical ointment.

[LA/SA for generic name retapamulin]{.underline}

Rapamune tablet, remodulin injectable solution, renamin w/o electrolytes
injection, ethamolin injection, renamin intravenous solution,
repaglinide tablet, retin-a micro topical gel

# Drug-Drug Interactions^1,\ 2^

Due to the low systemic absorption of topically administered
retapumulin, no clinically significant drug-drug interactions have been
identified.

-   In vitro studies have shown that retapamulin is substrate of
    cytochrome P450 (3A4 \> 2C8, 2D6). The co-administration of
    ketoconazole, a known inhibitor of CYP3A4, and retapamulin resulted
    in an increase in the C~max~ and AUC of retapamulin by 77% and 88%,
    respectively. But, due to the minimal systemic absorption of
    retapamulin, these elevated C~max~ and AUC were still within the
    range seen in previous pharmacokinetic studies. Therefore, no dosage
    adjustment is recommended when retapamulin is co-administered with
    ketoconazole or other CYP3A4 inhibitors.

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-   In vitro studies have shown that retapamulin is an inhibitor
    cytochrome P450 3A4. But, it does not inhibit other cytochrome P450
    isoenzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D26).

-   Retapamulin is a substrate and inhibitor of P-glycoprotein mediated
    transport.

**[Acquisition Costs]{.underline}**

Table 13. Cost for Topical Antibiotics

+--------------------------------------------+-------------------------+
| **Drug**                                   | **Cost**                |
+--------------------------------------------+-------------------------+
| Retapamulin 1% ointment topical            | \$24.50 (5 gram)        |
|                                            |                         |
|                                            | \$41.53 (10 gram)       |
|                                            |                         |
|                                            | \$50.78 (15 gram)       |
+--------------------------------------------+-------------------------+
| Bacitracin 500 unit/gram, ointment topical | \$1.36 (30 gram)        |
+--------------------------------------------+-------------------------+
| Mupirocin 2% ointment topical              | \$5.55 (22 gram)        |
+--------------------------------------------+-------------------------+
| Mupirocin 2% ointment nasal                | \$36.02 (1 gram)        |
+--------------------------------------------+-------------------------+

**[Conclusions]{.underline}** []{.mark}

# Retapamulin is the first agent in the class of pleuromutilins approved for human use. Retapamulin displays potent in vitro activity against *S*. *aureus* and *S*. *pyogenes*. It received FDA-approved for topical treatment of impetigo. Head-to-head trials of retapamulin and mupirocin for treatment of impetigo have not been conducted; however, both agents have shown high success rates in Phase III trials. Mupirocin should still be utilized first-line for topical treatment of localized impetigo while retapamulin should be considered second-line. Although retapamulin has in vitro activity against mupirocin-resistant *S. aureus*, susceptibility testing does not routinely evaluate for mupirocin resistance in the clinical microbiology laboratory. Thus, clinicians will not be able to target retapamulin use for impetigo caused by mupirocin-resistant *S. aureus*. Lastly, retapamulin has not been evaluated for intranasal application for MRSA decolonization; therefore, it should not be administered for decolonization of nares including patients colonized with mupirocin-resistant strains of *S. aureus*.

# 

# Recommendations

# Retapamulin is only approved for the topical administration of impetigo, which primarily occurs in childhood. It should be considered a second-line topical agent for localized impetigo while mupirocin should be employed first-line. Efficacy and safety data are not available for intranasal application of retapamulin for MRSA decolonization; therefore, this agent should not be considered an alternative to mupirocin for MRSA decolonization.

# 

# References:

1.  Package insert

2.  FDA dossier

3.  Rittenhouse S, Biswas S, Broskey J, et al. Selection of retapamulin,
    a novel pleuromutilin for topical use. Antimicrob Agents Chemother.
    2006;50:3882-5.

4.  Jones RN, Fritsche TR, Sader HS, Ross JE. Activity of retapamulin
    (SB-275833), a novel pleuromutilin, against selected resistant
    gram-positive cocci. Antimicrob Agents Chemother. 2006;50:1727-30.

5.  Pankuch GA, Lin G, Hoellman DB, et al. Activity of retapamulin
    against Streptococcus pyogenes and Staphylococcus aureus evaluated
    by agar dilution, microdilution, E-test, and disk diffusion
    methodologies. Antimicrob Agents Chemother. 200650:1727-30.

6.  Odou MF, Muller C, Calvet L, Dubreuil L. In vitro activity against
    anaerobes of retapamulin, a new topical antibiotic for treatment of
    skin infections. J Antimicrob Chemother 2007;59:646

7.  Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapaumulin
    ointment (1%, wt/wt) twice daily for 5 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;55:1003-13.

8.  Free A, Roth E, Delassandro M, et al. Retapamulin ointment twice
    daily for 5 days vs oral cephalexin twice daily for 10 days for
    empiric treatment of secondarily infected traumatic lesions of the
    skin. SKINmed 2006;5:224-232.

Prepared 10/07 Contact person: Melinda Neuhauser, PharmD