Document
DailyMed Label: Altabax
Title
DailyMed Label: Altabax
Date
2010
Document type
DailyMed Prescription
Name
Altabax
Generic name
retapamulin
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-6096
Product information
NDC: 54868-6096
Description
ALTABAX contains retapamulin, a semisynthetic pleuromutilin antibiotic. The
chemical name of retapamulin is acetic acid, [[(3- exo )-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]thio]-, (3a S ,4 R ,5 S ,6 S ,8 R ,9 R ,9a R ,10 R )-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3a H -cyclopentacycloocten-8-yl ester. Retapamulin, a white to
pale-yellow crystalline solid, has a molecular formula of C 30 H 47 NO 4 S, and a
molecular weight of 517.78. The chemical structure is:
Each gram of ointment for dermatological use contains 10 mg of retapamulin in
white petrolatum.
image of Altabax chemical structure
Indications
ALTABAX is indicated for use in adults and pediatric patients
aged 9 months and older for the topical treatment of impetigo (up to 100 cm 2 in total area in adults or 2% total body surface area in
pediatric patients aged 9 months or older) due to Staphylococcus aureus (methicillin-susceptible isolates
only) or Streptococcus pyogenes
[see Clinical Studies (14)] .
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of ALTABAX and other antibacterial drugs, ALTABAX should
Dosage
A thin layer of ALTABAX should be applied to the affected area (up to 100
cm 2 in total area in adults or 2% total body surface area
in pediatric patients aged 9 months or older) twice daily for 5 days. The
treated area may be covered with a sterile bandage or gauze dressing if desired
[see Patient Counseling Information (17)] .
Dosage forms
10 mg retapamulin/1g of ointment in 5, 10, 15, and 30 gram tubes
Contraindications
None.
Warnings
5.1 Local Irritation In the event of sensitization or severe local irritation from
ALTABAX, usage should be discontinued, the ointment wiped off, and appropriate
alternative therapy for the infection instituted [see
Patient Counseling Information (17)] .
5.2 Not for Systemic or Mucosal Use ALTABAX is not intended for ingestion or for oral, intranasal,
ophthalmic, or intravaginal use. ALTABAX has not been evaluated for use on
mucosal surfaces [see Patient Counseling Information
(17)] .
5.3 Potential for Microbial Overgrowth The use of antibiotics may promote the selection of
nonsusceptible organisms. Should superinfection occur during therapy,
appropriate measures should be taken.
Prescribing ALTABAX in the absence of a proven or strongly suspected
bacterial infection is unlikely to provide benefit to the patient and increases
the risk of the development of drug-resistant bacteria.
Adverse reactions
The safety profile of ALTABAX was assessed in 2,115 adult and
pediatric patients ≥9 months who used at least one dose from a 5-day, twice a
day regimen of retapamulin ointment. Control groups included 819 adult and
pediatric patients who used at least one dose of the active control (oral
cephalexin), 172 patients who used an active topical comparator (not available
in the US), and 71 patients who used placebo.
Drug interactions
Co-administration of oral ketoconazole 200 mg twice daily
increased retapamulin geometric mean AUC (0-24) and C max by 81% after topical application of retapamulin ointment,
1% on the abraded skin of healthy adult males. Due to low systemic exposure to
retapamulin following topical application in patients, dosage adjustments for
retapamulin are unnecessary when co-administered with CYP3A4 inhibitors, such as
ketoconazole. Based on in vitro P450 inhibition studies and the low systemic
exposure observed following topical application of ALTABAX, retapamulin is
unlikely to affect the metabolism of other P450 substrates.
The effect of concurrent application of ALTABAX and other topical products to
the same area of skin has not been studied.
Use in_specific_populations
8.1 Pregnancy
Pregnancy Category B . Effects on
embryo-fetal development were assessed in pregnant rats given 50, 150, or
450 mg/kg/day by oral gavage on days 6 to 17 postcoitus. Maternal toxicity
(decreased body weight gain and food consumption) and developmental toxicity
(decreased fetal body weight and delayed skeletal ossification) were evident at
doses ≥150 mg/kg/day. There were no treatment-related malformations observed in
fetal rats.
Retapamulin was given as a continuous intravenous infusion to pregnant
rabbits at dosages of 2.4, 7.2, or 24 mg/kg/day from day 7 to 19 of gestation.
Maternal toxicity (decreased body weight gain, food consumption, and abortions)
was demonstrated at dosages ≥7.2 mg/kg/day (8-fold the estimated maximum
achievable human exposure, based on AUC, at 7.2 mg/kg/day). There was no
treatment-related effect on embryo-fetal development.
There are no adequate and well-controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, ALTABAX
should be used in pregnancy only when the potential benefits outweigh the
potential risk.
8.3 Nursing Mothers It is not known whether retapamulin is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when
ALTABAX is administered to a nursing woman. The safe use of retapamulin during
breast-feeding has not been established.
8.4 Pediatric Use The safety and effectiveness of ALTABAX in the treatment of
impetigo have been established in pediatric patients 9 months to 17 years of
age. Use of ALTABAX in pediatric patients is supported by evidence from adequate
and well-controlled studies of ALTABAX in which 588 pediatric patients received
at least one dose of retapamulin ointment, 1% [see Adverse
Reactions (6), Clinical Studies (14)]. The magnitude of efficacy and the
safety profile of ALTABAX in pediatric patients 9 months and older were similar
to those in adults.
The safety and effectiveness of ALTABAX in pediatric patients younger than
9 months of age have not been established.
8.5 Geriatric Use Of the total number of patients in the adequate and
well-controlled studies of ALTABAX, 234 patients were 65 years of age and older,
of whom 114 patients were 75 years of age and older. No overall differences in
effectiveness or safety were observed between these patients and younger adult
patients.
How supplied
ALTABAX is supplied in 15 gram
tubes.
NDC 54868-6096-0 (15 gram tube)
Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).
Clinical pharmacology
12.1 Mechanism of Action ALTABAX is an antibacterial agent [see
Clinical Pharmacology (12.4)] .
12.2 Pharmacodynamics In post-hoc analyses of manually over-read 12-lead ECGs from
healthy subjects (N = 103), no significant effects on QT/QTc intervals were
observed after topical application of retapamulin ointment on intact and abraded
skin. Due to the low systemic exposure to retapamulin with topical application,
QT prolongation in patients is unlikely [see Clinical
Pharmacology (12.3)] .
12.3 Pharmacokinetics
Absorption
In a study of healthy adult subjects, retapamulin ointment, 1%
was applied once daily to intact skin (800 cm 2 surface
area) and to abraded skin (200 cm 2 surface area) under
occlusion for up to 7 days. Systemic exposure following topical application of
retapamulin through intact and abraded skin was low. Three percent of blood
samples obtained on Day 1 after topical application to intact skin had
measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL);
thus C max values on Day 1 could not be determined.
Eighty-two percent of blood samples obtained on Day 7 after topical application
to intact skin and 97% and 100% of blood samples obtained after topical
application to abraded skin on Days 1 and 7, respectively, had measurable
retapamulin concentrations. The median C max value in
plasma after application to 800 cm 2 of intact skin was
3.5 ng/mL on Day 7 (range 1.2 to 7.8 ng/mL). The median C max value in plasma after application to 200 cm 2 of abraded skin was 11.7 ng/mL on Day 1 (range 5.6 to 22.1
ng/mL) and 9.0 ng/mL on Day 7 (range 6.7 to 12.8 ng/mL).
Plasma samples were obtained from 380 adult patients and 136 pediatric
patients (aged 2-17 years) who were receiving topical treatment with ALTABAX
topically twice daily. Eleven percent had measurable retapamulin concentrations
(lower limit of quantitation 0.5 ng/mL), of which the median concentration was
0.8 ng/mL. The maximum measured retapamulin concentration in adults was
10.7 ng/mL and in pediatric patients was 18.5 ng/mL.
Distribution
Retapamulin is approximately 94% bound to human plasma proteins,
and the protein binding is independent of concentration. The apparent volume of
distribution of retapamulin has not been determined in humans.
Metabolism
In vitro studies with human hepatocytes showed that the main
routes of metabolism were mono-oxygenation and di-oxygenation. In vitro studies
with human liver microsomes demonstrated that retapamulin is extensively
metabolized to numerous metabolites, of which the predominant routes of
metabolism were mono-oxygenation and N-demethylation. The major enzyme
responsible for metabolism of retapamulin in human liver microsomes was
cytochrome P450 3A4 (CYP3A4).
Elimination
Retapamulin elimination in humans has not been investigated due
to low systemic exposure after topical application.
12.4 Microbiology Retapamulin is a semisynthetic derivative of the compound
pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus ). In vitro activity of retapamulin
against isolates of Staphylococcus aureus as well as
Streptococcus pyogenes has been demonstrated.
Antimicrobial Mechanism of
Action
Retapamulin selectively inhibits bacterial protein synthesis by
interacting at a site on the 50S subunit of the bacterial ribosome through an
interaction that is different from that of other antibiotics. This binding site
involves ribosomal protein L3 and is in the region of the ribosomal P site and
peptidyl transferase center. By virtue of binding to this site, pleuromutilins
inhibit peptidyl transfer, block P-site interactions, and prevent the normal
formation of active 50S ribosomal subunits. Retapamulin is bacteriostatic
against Staphylococcus aureus and Streptococcus pyogenes at the retapamulin in vitro minimum
inhibitory concentration (MIC) for these organisms. At concentrations 1,000x the
in vitro MIC, retapamulin is bactericidal against these same organisms.
Retapamulin demonstrates no in vitrotarget-specific cross-resistance with other
classes of antibiotics.
Mechanisms of Decreased
Susceptibility to Retapamulin
In vitro, 2 mechanisms that cause reduced susceptibility to
retapamulin have been identified, specifically, mutations in ribosomal protein
L3 or the presence of an efflux mechanism. Decreased susceptibility of S. aureus to retapamulin (highest retapamulin MIC was
2 mcg/mL) develops slowly in vitro via multistep mutations in L3 after serial
passage in sub-inhibitory concentrations of retapamulin. There was no apparent
treatment-associated reduction in susceptibility to retapamulin in the Phase 3
clinical program. The clinical significance of these findings is not
known.
Other
Based on in vitro broth microdilution susceptibility testing, no
differences were observed in susceptibility of S. aureus to retapamulin whether the isolates were
methicillin-resistant or methicillin-susceptible. Retapamulin susceptibility did
not correlate with clinical success rates in patients with methicillin-resistant
S.aureus . The reason for this is not known but may
have been influenced by the presence of particular strains of S. aureus possessing certain virulence factors, such as
Panton-Valentine Leukocidin (PVL). In the case of treatment failure associated
with S. aureus (regardless of methicillin
susceptibility), the presence of strains possessing additional virulence factors
(such as PVL) should be considered.
Retapamulin has been shown to be active against the following microorganisms,
both in vitro and in clinical trials [see Indications and
Usage (1)] .
Aerobic and Facultative Gram-Positive Bacteria
Staphylococcus aureus
(methicillin-susceptible isolates only)
Streptococcus pyogenes
Susceptibility Testing
The clinical microbiology laboratory should provide cumulative
results of the in vitro susceptibility test results for antimicrobial drugs used
in local hospitals and practice areas to the physician as periodic reports that
describe the susceptibility profile of nosocomial and community-acquired
pathogens. These reports should aid the physician in selecting the most
effective antimicrobial.
Susceptibility Testing Techniques
Dilution Techniques
Quantitative methods can be used to determine the minimum
inhibitory concentration (MIC) of retapamulin that will inhibit the growth of
the bacteria being tested. The MIC provides an estimate of the susceptibility of
bacteria to retapamulin. The MIC should be determined using a standardized
procedure. 1,2 Standardized procedures are based on a
dilution method (broth or agar) or equivalent with standardized inoculum
concentrations and standardized concentrations of retapamulin powder.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters
also provide reproducible estimates of the susceptibility of bacteria to
antimicrobial compounds. One such standardized procedure requires the use of
standardized inoculum concentrations. 2,3 This procedure
uses paper disks impregnated with 2 mcg of retapamulin to test the
susceptibility of microorganisms to retapamulin.
Susceptibility Test Interpretive Criteria In vitro susceptibility test interpretive criteria for
retapamulin have not been determined for this topical antimicrobial. The
relation of the in vitro MIC and/or disk diffusion susceptibility test results
to clinical efficacy of retapamulin against the bacteria tested should be
monitored.
Quality Control Parameters for Susceptibility
Testing In vitro susceptibility test quality control parameters were
developed for retapamulin so that laboratories that test the susceptibility of
bacterial isolates to retapamulin can determine if the susceptibility test is
performing correctly. Standardized dilution techniques and diffusion methods
require the use of laboratory control microorganisms to monitor the technical
aspects of the laboratory procedures. Standard retapamulin powder should provide
the following MIC and a 2 mcg retapamulin disk should produce the following zone
diameters with the indicated quality control strains in Table 3.
Table 3. Acceptable Quality Control Ranges for Retapamulin
Microorganism
MIC Range
(mcg/mL)
Disk Diffusion
Zone Diameter (mm)
Staphylococcus aureus ATCC 29213
0.06-0.25
NA
Staphylococcus aureus ATCC 25923
NA
23-30
Streptococcus pneumoniae ATCC 49619
0.06-0.5 a
13-19 b
NA = Not applicable.
a This quality control range is applicable using
cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
b This quality control limit is applicable using
Mueller-Hinton agar with 5% sheep blood.
Nonclinical toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility Long-term studies in animals to evaluate carcinogenic potential
have not been conducted with retapamulin.
Retapamulin showed no genotoxicity when evaluated in vitro for gene mutation
and/or chromosomal effects in the mouse lymphoma cell assay, in cultured human
peripheral blood lymphocytes, or when evaluated in vivo in a rat micronucleus
test.
No evidence of impaired fertility was found in male or female rats given
retapamulin 50, 150, or 450 mg/kg/day orally.
Clinical studies
ALTABAX was evaluated in a placebo-controlled study that enrolled
adult and pediatric patients 9 months of age and older for treatment of impetigo
up to 100 cm 2 in total area (up to 10 lesions) or a total
body surface area not exceeding 2%. The majority of patients enrolled (164/210,
78%) were under the age of 13. The study was a double-blind, randomized,
multi-center, parallel-group comparison of the safety of ALTABAX and placebo
ointment, both applied twice daily for 5 days. The study was randomized 2
ALTABAX to 1 placebo patient. Patients with underlying skin disease (e.g.,
preexisting eczematous dermatitis) or skin trauma, with clinical evidence of
secondary infection were excluded from these studies. In addition, patients with
any systemic signs and symptoms of infection (such as fever) were excluded from
the study. Clinical success was defined as the absence of treated lesions, or
treated lesions had become dry without crusts with or without erythema compared
to baseline, or had improved (defined as a decline in the size of the affected
area, number of lesions or both) such that no further antimicrobial therapy was
required. The intent-to-treat clinical (ITTC) population consisted of all
randomized patients who took at least 1 dose of study medication. The clinical
per protocol (PPC) population included all ITTC patients who satisfied the
inclusion/exclusion criteria and subsequently adhered to the protocol. The
intent-to-treat bacteriological (ITTB) population consisted of all randomized
patients who took at least one dose of study medication and had a pathogen
identified at study entry. The bacteriological per protocol (PPB) population
included all ITTB patients who satisfied the inclusion/exclusion criteria and
subsequently adhered to the protocol.
The following table describes the results for clinical response at end of
therapy (2 days after treatment) and follow-up (9 days after treatment), by
analysis population:
Table 4. Clinical Response at End of Therapy and at Follow-Up by
Analysis Population
Analysis Population
ALTABAX
Placebo
Difference in Success Rates (%)
95%
CI (%)
n/N
Success Rate
(%)
n/N
Success Rate
(%)
End of
Therapy
PPC
111/124
89.5
33/62
53.2
36.3
(22.8, 49.8)
ITTC
119/139
85.6
37/71
52.1
33.5
(20.5, 46.5)
PPB
96/107
89.7
26/52
50.0
39.7
(25.0, 54.5)
ITTB
101/114
88.6
28/57
49.1
39.5
(25.2, 53.7)
Follow-Up
PPC
98/119
82.4
25/58
43.1
39.2
(24.8, 53.7)
ITTC
105/139
75.5
28/71
39.4
36.1
(22.7, 49.5)
PPB
86/102
84.3
18/48
37.5
46.8
(31.4, 62.2)
ITTB
91/114
79.8
19/57
33.3
46.5
(32.2,
60.8)
n = number with clinical success outcome, N = number in analysis population,
PPC = Clinical Per Protocol Population, ITTC = Clinical Intent to Treat
Population, PPB = Bacteriological Per Protocol Population, ITTB =
Bacteriological Intent to Treat Population
The following table describes the clinical success at end of therapy and
follow-up by baseline pathogen:
Table 5. Clinical Response at End of Therapy and Follow-Up for Patients
With Staphylococcus aureus and Streptococcus pyogenes at Baseline in the Per
Protocol Bacteriological Population (PPB)
Pathogen
ALTABAX
Placebo
n/N
Success Rate
(%)
n/N
Success Rate
(%)
End of
Therapy
Staphylococcus aureus (Methicillin-susceptible)
79/88
89.8
25/48
52.1
Streptococcus pyogenes
29/32
90.6
3/7
42.9
Follow-Up
Staphylococcus aureus (Methicillin-susceptible)
71/84
84.5
19/44
43.2
Streptococcus pyogenes
29/32
90.6
2/6
33.3
n/N = number of clinical successes/number of pathogens isolated at
baseline.
Examination of age and gender subgroups did not identify differences in
response to ALTABAX among these groups. The majority of patients entered into
this study were classified as White/Caucasian or of Asian heritage; when
response rates by racial subgroups were viewed across studies, differences in
response to ALTABAX were not identified.
Package label
ALTABAX TM
(retapamulin ointment), 1%
15 grams (Net Wt.)
R x only
image of Altabax 1% Ointment package label for 15 grams
3 organizations
1 product
Product
AltabaxOrganization
Rebel Distributors Corp.Organization
Almirall, LLCOrganization
Physicians Total Care, Inc.