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Retapamulin Ointment 1%

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Retapamulin is an antibacterial agent. Retapamulin is a semisynthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus). 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, a white to pale-yellow crystalline solid, has a molecular formula of C30H47NO4S, 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.

2. INDICATIONS AND USAGE

Retapamulin is indicated for use in adults and pediatric patients aged 9 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 9 months or older) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of retapamulin and other antibacterial drugs, retapamulin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

3. DOSAGE AND ADMINISTRATION

A thin layer of retapamulin 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 9 months or older) twice daily for 5 days. The treated area may be covered with a sterile bandage or gauze dressing if desired.

4. CONTRAINDICATIONS

None.

5. 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 vitro target-specific cross-resistance with other classes of antibiotics.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in 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 trials in pregnant women. Because animal reproduction studies are not always predictive of human response, retapamulin should be used in pregnancy only when the potential benefits outweigh the potential risk.

6.2 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 retapamulin is administered to a nursing woman. The safe use of retapamulin during breast-feeding has not been established.

6.3 Pediatric Use

The safety and effectiveness of retapamulin in the treatment of impetigo have been established in pediatric patients 9 months to 17 years of age. Use of retapamulin in pediatric patients is supported by evidence from adequate and well-controlled studies of retapamulin in which 588 pediatric patients received at least one dose of retapamulin ointment, 1%. The magnitude of efficacy and the safety profile of retapamulin in pediatric patients 9 months and older were similar to those in adults.

The safety and effectiveness of retapamulin in pediatric patients younger than 9 months of age have not been established. An open-label clinical trial of topical treatment with retapamulin (twice daily for 5 days) was conducted in patients aged 2 to 24 months. Plasma samples were obtained from 79 subjects. In these pediatric subjects, systemic exposure of retapamulin was higher compared with subjects aged 2 to 17 years. Furthermore, a higher proportion of pediatric subjects aged 2 to 9 months had measurable concentrations (>0.5 ng/mL) of retapamulin compared with subjects aged 9 to 24 months [see Pharmacokinetics]. The highest levels were seen in subjects aged 2 to 6 months [see Pharmacokinetics]. The use of retapamulin is not indicated in pediatric patients younger than 9 months.

6.4 Geriatric Use

Of the total number of patients in the adequate and well-controlled studies of retapamulin, 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.

7. WARNINGS AND PRECAUTIONS

7.1 Local Irritation

In the event of sensitization or severe local irritation from retapamulin, usage should be discontinued, the ointment wiped off, and appropriate alternative therapy for the infection instituted.

7.2 Not for Systemic or Mucosal Use

Retapamulin is not intended for ingestion or for oral, intranasal, ophthalmic, or intravaginal use. Retapamulin has not been evaluated for use on mucosal surfaces.

7.3 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 retapamulin 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.

8. ADVERSE REACTIONS

8.1 Clinical Studies Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The safety profile of retapamulin was assessed in 2,115 adult and pediatric subjects ≥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 subjects who used at least one dose of the active control (oral cephalexin), 172 subjects who used an active topical comparator (not available in the US), and 71 subjects 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.

Adults: The adverse events, regardless of attribution, reported in at least 1% of adults (18 years of age and older) who received retapamulin are listed in Table 1.

Table 1. Adverse Events Reported by ≥1% of Adult Patients Treated With Retapamulin in Phase 3 Clinical Studies

Pediatrics: The adverse events, regardless of attribution, reported in at least 1% of pediatric patients aged 9 months to 17 years who received retapamulin are listed in Table 2.

Table 2. Adverse Events Reported by ≥1% in Pediatric Patients Aged 9 Months to 17 Years Treated With Retapamulin in Phase 3 Clinical Studies

Other Adverse Events:

Application site pain, erythema, and contact dermatitis were reported in less than 1% of subjects in clinical trials.

8.2 Postmarketing Experience

In addition to reports in clinical trials, the following events have been identified during postmarketing use of retapamulin. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency orestablish a causal relationship to drug exposure.

General Disorders and Administration Site Conditions: Application site burning.

Immune System Disorders: Hypersensitivity including angioedema.

9. OVERDOSAGE

Overdosage with retapamulin 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 retapamulin.

10. DRUG INTERACTIONS

Co-administration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC0-24 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 retapamulin, retapamulin is unlikely to affect the metabolism of other P450 substrates.

Concomitant administration of retapamulin and CYP3A4 inhibitors, such as ketoconazole, has not been studied in pediatric patients. In pediatric subjects aged 2 to 24 months, systemic exposure of retapamulin was higher compared with subjects aged 2 years and older after topical application [see Pharmacokinetics]. Based on the higher exposure of retapamulin, it is not recommended to coadminister retapamulin with strong CYP3A4 inhibitors in patients younger than 24 months.

The effect of concurrent application of retapamulin and other topical products to the same area of skin has not been studied.

11. PHARMACOKINETICS

Absorption: Systemic exposure following topical application of retapamulin through intact and abraded skin was low.

Plasma samples were obtained from 380 adult patients and 136 pediatric patients (aged 2-17 years) who were receiving topical treatment with retapamulin 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. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: ALTABAX, by GLAXO GRP LTD.

b) Generic drugs: None.

2) How Supplied:

ALTABAX is supplied in 15, and 30 gram tubes.

NDC 0007-5180-22 (15 gram tube)

NDC 0007-5180-25 (30 gram tube)

3) Storage: Store at at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).

Rx only

Rev 01/13