ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 6.1 Clinical Studies ExperienceThe safety profile of ALTABAX was assessed in 2,115 adult and pediatric patients >=9 months who used at least one dose from 5-day, twice 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.Adverse events rated by investigators as drug-related occurred in 5.5% (116/2,115) of patients treated with retapamulin ointment, 6.6% (54/819) of patients receiving cephalexin, and 2.8% (2/71) of patients receiving placebo. The most common drug-related adverse events (>=1% of patients) were application site irritation (1.4%) in the retapamulin group, diarrhea (1.7%) in the cephalexin group, and application site pruritus (1.4%) and application site paresthesia (1.4%) in the placebo group.Because clinical studies are conducted under varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide basis for identifying the adverse events that appear to be related to drug use and for approximating rates.AdultsThe adverse events, regardless of attribution, reported in at least 1% of adults (18 years of age and older) who received ALTABAX are listed in Table 1.Table 1. Adverse Events Reported by Greater Than or Equal To 1% of Adult Patients Treated With ALTABAX in Phase Clinical StudiesAdverse EventALTABAXN 1,527%CephalexinN 698%Headache2.02.0Application site irritation1.6Less than 1.0Diarrhea1.42.3Nausea1.21.9Nasopharyngitis1.2Less than 1.0Creatinine phosphokinase increasedLess than 1.01.0PediatricsThe adverse events, regardless of attribution, reported in at least 1% of pediatric patients aged months to 17 years who received ALTABAX are listed in Table 2.Table 2. Adverse Events Reported by Greater Than or Equal To 1% in Pediatric Patients Aged Months to 17 Years Treated With ALTABAX in Phase Clinical StudiesAdverse EventALTABAXN 588%CephalexinN 121%PlaceboN 64%Application site pruritus1.900Diarrhea1.75.00Nasopharyngitis1.51.70Pruritus1.51.01.6Eczema1.000Headache1.21.70Pyrexia1.2Less than 1.01.6 Other Adverse EventsApplication site pain, erythema, and contact dermatitis were reported in less than 1% of patients in clinical studies.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of ActionALTABAX is an antibacterial agent [see Clinical Pharmacology (12.4)].12.2 PharmacodynamicsIn 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 PharmacokineticsAbsorptionIn study of healthy adult subjects, retapamulin ointment, 1% was applied once daily to intact skin (800 cm2 surface area) and to abraded skin (200 cm2 surface area) under occlusion for up to days. Systemic exposure following topical application of retapamulin through intact and abraded skin was low. Three percent of blood samples obtained on Day after topical application to intact skin had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL); thus Cmax values on Day could not be determined. Eighty-two percent of blood samples obtained on Day after topical application to intact skin and 97% and 100% of blood samples obtained after topical application to abraded skin on Days and 7, respectively, had measurable retapamulin concentrations. The median Cmax value in plasma after application to 800 cm2 of intact skin was 3.5 ng/mL on Day (range 1.2 to 7.8 ng/mL). The median Cmax value in plasma after application to 200 cm2 of abraded skin was 11.7 ng/mL on Day (range 5.6 to 22.1 ng/mL) and 9.0 ng/mL on Day (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.DistributionRetapamulin 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.MetabolismIn 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).EliminationRetapamulin elimination in humans has not been investigated due to low systemic exposure after topical application.12.4 MicrobiologyRetapamulin is 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 ActionRetapamulin selectively inhibits bacterial protein synthesis by interacting at 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 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 RetapamulinIn vitro, 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 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 clinical program. The clinical significance of these findings is not known.OtherBased 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 BacteriaStaphylococcus aureus (methicillin-susceptible isolates only)Streptococcus pyogenesSusceptibility TestingThe 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 TechniquesDilution TechniquesQuantitative 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 standardized procedure.1,2 Standardized procedures are based on dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of retapamulin powder.Diffusion TechniquesQuantitative 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 mcg of retapamulin to test the susceptibility of microorganisms to retapamulin.Susceptibility Test Interpretive CriteriaIn 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 TestingIn 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 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 RetapamulinMicroorganismMIC Range (mcg/mL)Disk Diffusion Zone Diameter (mm)Staphylococcus aureus ATCC 292130.06-0.25NAStaphylococcus aureus ATCC 25923NA23-30Streptococcus pneumoniae ATCC 496190.06-0.5a 13-19b 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. ALTABAX was evaluated in placebo-controlled study that enrolled adult and pediatric patients months of age and older for treatment of impetigo up to 100 cm2 in total area (up to 10 lesions) or total body surface area not exceeding 2%. The majority of patients enrolled (164/210, 78%) were under the age of 13. The study was double-blind, randomized, multi-center, parallel-group comparison of the safety of ALTABAX and placebo ointment, both applied twice daily for days. The study was randomized ALTABAX to 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 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 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 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 PopulationAnalysis PopulationALTABAXPlaceboDifference in Success Rates (%)95% CI (%)n/NSuccess Rate (%)n/NSuccess Rate (%)End of TherapyPPC111/12489.533/6253.236.3(22.8, 49.8)ITTC119/13985.637/7152.133.5(20.5, 46.5)PPB96/10789.726/5250.039.7(25.0, 54.5)ITTB101/11488.628/5749.139.5(25.2, 53.7)Follow-Up PPC98/11982.425/5843.139.2(24.8, 53.7)ITTC105/13975.528/7139.436.1(22.7, 49.5)PPB86/10284.318/4837.546.8(31.4, 62.2)ITTB91/11479.819/5733.346.5(32.2, 60.8)n number with clinical success outcome, = 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 PopulationThe 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)PathogenALTABAXPlacebon/NSuccess Rate (%)n/NSuccess Rate (%)End of TherapyStaphylococcus aureus (Methicillin-susceptible)79/8889.825/4852.1Streptococcus pyogenes 29/3290.63/742.9Follow-UpStaphylococcus aureus (Methicillin-susceptible)71/8484.519/4443.2Streptococcus pyogenes 29/3290.62/633.3n/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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.

DESCRIPTION SECTION.

11 DESCRIPTION. ALTABAX contains retapamulin, semisynthetic pleuromutilin antibiotic. The chemical name of retapamulin is acetic acid, [[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]thio]-, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester. Retapamulin, white to pale-yellow crystalline solid, has molecular formula of C30H47NO4S, and 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. thin layer of ALTABAX should be applied to the affected area (up to 100 cm2 in total area in adults or 2% total body surface area in pediatric patients aged months or older) twice daily for days. The treated area may be covered with sterile bandage or gauze dressing if desired [see Patient Counseling Information (17)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 10 mg retapamulin/1g of ointment in 5, 10, 15, and 30 gram tubes.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmax 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ALTABAX is supplied in 10 gram tubes.NDC 21695-644-10 (10 gram tube)Store at 25C (77F) with excursions permitted to 15-30C (59-86F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ALTABAX is indicated for use in adults and pediatric patients aged months and older for the topical treatment of impetigo (up to 100 cm2 in total area in adults or 2% total body surface area in pediatric patients aged 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Patients using ALTABAX and/or their guardians should receive the following information and instructions: Use ALTABAX as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.ALTABAX is for external use only. Do not swallow ALTABAX or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area. The treated area may be covered by sterile bandage or gauze dressing, if desired. This may also be helpful for infants and young children who accidentally touch or lick the lesion site. bandage will protect the treated area and avoid accidental transfer of ointment to the eyes or other areas. Use the medication for the full time recommended by the healthcare practitioner, even though symptoms may have improved. Notify the healthcare practitioner if there is no improvement in symptoms within to days after starting use of ALTABAX. ALTABAX may cause reactions at the site of application of the ointment. Inform the healthcare practitioner if the area of application worsens in irritation, redness, itching, burning, swelling, blistering, or oozing. ALTABAX is registered trademark of GlaxoSmithKline.GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2009, GlaxoSmithKline. All rights reserved.Repackaged by:Rebel Distributors Corp.Thousand Oaks, CA 91320. ALTABAX is for external use only. Do not swallow ALTABAX or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area. The treated area may be covered by sterile bandage or gauze dressing, if desired. This may also be helpful for infants and young children who accidentally touch or lick the lesion site. bandage will protect the treated area and avoid accidental transfer of ointment to the eyes or other areas. Use the medication for the full time recommended by the healthcare practitioner, even though symptoms may have improved. Notify the healthcare practitioner if there is no improvement in symptoms within to days after starting use of ALTABAX. ALTABAX may cause reactions at the site of application of the ointment. Inform the healthcare practitioner if the area of application worsens in irritation, redness, itching, burning, swelling, blistering, or oozing.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityLong-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 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage with ALTABAX has not been reported. Any signs or symptoms of overdose, either topically or by accidental ingestion, should be treated symptomatically consistent with good clinical practice.There is no known antidote for overdoses of ALTABAX.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. ALTABAXTM (retapamulin ointment), 1%10 grams (Net Wt.) Rx only. Altabax 1%.

REFERENCES SECTION.

15 REFERENCES. Clinical and Laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard. CLSI Document M7-A7. CLSI, Wayne, PA, Jan. 2006. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing 17th Informational Standard. M100-S17. CLSI, Wayne, PA, Jan. 2007. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard. CLSI Document M2-A9. CLSI, Wayne, PA, Jan. 2006.. Clinical and Laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard. CLSI Document M7-A7. CLSI, Wayne, PA, Jan. 2006. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing 17th Informational Standard. M100-S17. CLSI, Wayne, PA, Jan. 2007. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests. Approved Standard. CLSI Document M2-A9. CLSI, Wayne, PA, Jan. 2006.

SPL UNCLASSIFIED SECTION.

FULL PRESCRIBING INFORMATION.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 PregnancyPregnancy 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 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 continuous intravenous infusion to pregnant rabbits at dosages of 2.4, 7.2, or 24 mg/kg/day from day 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 MothersIt 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 nursing woman. The safe use of retapamulin during breast-feeding has not been established.8.4 Pediatric UseThe safety and effectiveness of ALTABAX in the treatment of impetigo have been established in pediatric patients 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 months and older were similar to those in adults.The safety and effectiveness of ALTABAX in pediatric patients younger than months of age have not been established.8.5 Geriatric UseOf 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 5.1 Local IrritationIn 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 UseALTABAX 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 OvergrowthThe 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 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.