Altabax

Dosage Forms And Strengths

10 mg retapamulin per 1g of ointment in 15- and 30- gram tubes

Storage And Handling

ALTABAX is supplied in 15-gram and 30-gram tubes.

NDC 16110-518-15 (15-gram tube)
NDC 16110-518-30 (30-gram tube)

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

Manufactured by: GlaxoSmithKline, Barnard Castle, County Durham, DL12 8DT, United Kingdom. Manufactured for: Aqua Pharmaceuticals, an Almirall Company, Exton, PA 19341. Revised: Apr 2015

ALTABAX® 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 . Safety in patients younger than 9 months has not been established.

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

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

None.

Sections or subsections omitted from the full prescribing information are not listed.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

Not For Systemic Or Mucosal Use

ALTABAX is not intended for ingestion or for oral, intranasal, ophthalmic, or intravaginal use. The efficacy and safety of ALTABAX on mucosal surfaces have not been established. Epistaxis has been reported with the use of ALTABAX on nasal mucosa.

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.

Nonclinical Toxicology

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 per kg per day orally.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Effects on embryo-fetal development were assessed in pregnant rats given 50, 150, or 450 mg per kg per 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 greater than or equal to 150 mg per kg per 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 per kg per day from Day 7 to 19 of gestation. Maternal toxicity (decreased body weight gain, food consumption, and abortions) was demonstrated at dosages greater than or equal to 7.2 mg per kg per day (8-fold the estimated maximum achievable human exposure, based on AUC, at 7.2 mg per kg per 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, ALTABAX should be used in pregnancy only when the potential benefits outweigh the potential risk.

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 breastfeeding has not been established.

Pediatric Use

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

The safety and effectiveness of ALTABAX in pediatric patients younger than 9 months have not been established. An open-label clinical trial of topical treatment with ALTABAX (twice daily for 5 days) was conducted in subjects 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 (greater than 0.5 ng per mL) of retapamulin compared with subjects aged 9 to 24 months. The highest levels were seen in subjects aged 2 to 6 months. The use of retapamulin is not indicated in pediatric patients younger than 9 months.

Geriatric Use

Of the total number of subjects in the adequate and well-controlled trials of ALTABAX, 234 subjects were aged 65 years and older, of whom 114 subjects were aged 75 years and older. No overall differences in effectiveness or safety were observed between these subjects and younger adult subjects.

SIDE EFFECTS

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 ALTABAX was assessed in 2,115 adult and pediatric subjects 9 months and older 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 subjects treated with retapamulin ointment, 6.6% (54/819) of subjects receiving cephalexin, and 2.8% (2/71) of subjects receiving placebo. The most common drug-related adverse events (greater than or equal to 1% of subjects) 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 (aged 18 years and older) who received ALTABAX or comparator are presented in Table 1.

Table 1: Adverse Events Reported by ≥1% of Adult Subjects Treated with ALTABAX or Comparator in Phase 3 Clinical Trials

Pediatrics

The adverse events, regardless of attribution, reported in at least 1% of pediatric subjects aged 9 months to 17 years who received ALTABAX are presented in Table 2.

Table 2: Adverse Events Reported by ≥1% in Pediatric Subjects Aged 9 Months to 17 Years Treated with ALTABAX in Phase 3 Clinical Trials

Other Adverse Events

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

Postmarketing Experience

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

General Disorders And Administration Site Conditions

Application site burning.

Immune System Disorders

Hypersensitivity including angioedema.

DRUG INTERACTIONS

Coadministration 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 adults and pediatric patients aged 2 years and older, dosage adjustments for retapamulin are unnecessary in these patients when coadministered 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.

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. Based on the higher exposure of retapamulin, it is not recommended to coadminister ALTABAX with strong CYP3A4 inhibitors in patients younger than 24 months.

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

Pregnancy Category B

Effects on embryo-fetal development were assessed in pregnant rats given 50, 150, or 450 mg per kg per 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 greater than or equal to 150 mg per kg per 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 per kg per day from Day 7 to 19 of gestation. Maternal toxicity (decreased body weight gain, food consumption, and abortions) was demonstrated at dosages greater than or equal to 7.2 mg per kg per day (8-fold the estimated maximum achievable human exposure, based on AUC, at 7.2 mg per kg per 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, ALTABAX should be used in pregnancy only when the potential benefits outweigh the potential risk.

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 ALTABAX was assessed in 2,115 adult and pediatric subjects 9 months and older 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 subjects treated with retapamulin ointment, 6.6% (54/819) of subjects receiving cephalexin, and 2.8% (2/71) of subjects receiving placebo. The most common drug-related adverse events (greater than or equal to 1% of subjects) 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 (aged 18 years and older) who received ALTABAX or comparator are presented in Table 1.

Table 1: Adverse Events Reported by ≥1% of Adult Subjects Treated with ALTABAX or Comparator in Phase 3 Clinical Trials

Pediatrics

The adverse events, regardless of attribution, reported in at least 1% of pediatric subjects aged 9 months to 17 years who received ALTABAX are presented in Table 2.

Table 2: Adverse Events Reported by ≥1% in Pediatric Subjects Aged 9 Months to 17 Years Treated with ALTABAX in Phase 3 Clinical Trials

Other Adverse Events

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

Postmarketing Experience

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

General Disorders And Administration Site Conditions

Application site burning.

Immune System Disorders

Hypersensitivity including angioedema.

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.

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.

Absorption

In a trial 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 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 per mL); thus Cmax 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 Cmax value in plasma after application to 800 cm² of intact skin was 3.5 ng per mL on Day 7 (range: 1.2 to 7.8 ng per mL). The median Cmax value in plasma after application to 200 cm of abraded skin was 11.7 ng per mL on Day 1 (range: 5.6 to 22.1 ng per mL) and 9.0 ng per mL on Day 7 (range: 6.7 to 12.8 ng per mL).

Plasma samples were obtained from 380 adult subjects and 136 pediatric subjects (aged 2 to 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 per mL), of which the median concentration was 0.8 ng per mL. The maximum measured retapamulin concentration in adults was 10.7 ng per mL and in pediatric subjects (aged 2 to 17 years) was 18.5 ng per mL.

A single plasma sample was obtained from 79 pediatric subjects (aged 2 to 24 months) who were receiving topical treatment with ALTABAX twice daily. Forty-six percent had measurable retapamulin concentrations greater than 0.5 ng per mL) compared with 7% in pediatric subjects aged 2 to 17 years. A higher proportion (69%) of pediatric subjects aged 2 to 9 months had measurable concentrations of retapamulin compared with subjects aged 9 to 24 months (32%). Among pediatric subjects aged 2 to 9 months (n = 29), 4 subjects had retapamulin concentrations that were higher (greater than or equal to 26.9 ng per mL) than the maximum concentration observed in pediatric subjects aged 2 to 17 years (18.5 ng per mL). Among pediatric subjects aged 9 to 24 months (n = 50), 1 subject had a retapamulin concentration that was higher (95.1 ng per mL) than the maximum level observed in pediatric subjects aged 2 to 17 years.

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 monooxygenation 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.