GlaxoSmithKline (Ireland) Ltd

Altargo 1% ointment

1 g contains 10 mg retapamulin (1% w/w).

For a full list of excipients, see section 6.1.

Ointment

Smooth, off-white ointment.

Short term treatment of the following superficial skin infections (see section 5.1):

Impetigo.

Infected small lacerations, abrasions, or sutured wounds.

See sections 4.4 and 5.1 for important information regarding the clinical activity of retapamulin against different types of Staphylococcus aureus.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Retapamulin is for cutaneous use only.

Adults (aged 18-65 years), adolescents (aged 12-17 years), infants and children (aged from nine months to 11 years)

A thin layer of ointment should be applied to the affected area twice daily for five days.

The area treated may be covered with sterile bandage or gauze dressing.

Safety and efficacy have not been established in the following:

• Impetiginous lesions >10 in number and exceeding 100 cm2 in total surface area.

• Infected lesions that exceed 10 cm in length or a total surface area >100 cm².

In patients aged less than 18 years the total surface area treated should be no more than 2% of the body surface area.

Patients not showing a clinical response within two to three days should be re-evaluated and alternative therapy should be considered (see section 4.4).

Infants under nine months of age

The safety and efficacy of retapamulin ointment has not been established in paediatric patients less than nine months of age.

Elderly (aged 65 and older)

No dosage adjustment is necessary.

Renal impairment

No dosage adjustment is necessary. See section 5.3.

Hepatic impairment

No dosage adjustment is necessary. See section 5.3.

Known or suspected hypersensitivity to retapamulin or to the excipient.

In the event of a sensitisation or severe local irritation from the use of retapamulin ointment, treatment should be discontinued, the ointment carefully wiped off, and appropriate alternative therapy for the infection instituted.

Retapamulin ointment must be kept away from the eyes and mucous membranes. Epistaxis has been reported with use of Altargo on nasal mucosa.

Care must be taken to avoid ingestion.

Retapamulin should not be used to treat infections known or thought likely to be due to MRSA (see section 5.1).

In clinical studies of secondarily infected open wounds, the efficacy of retapamulin was inadequate in patients with infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The reason for the reduced clinical efficacy observed in these patients is unknown.

Alternative therapy should be considered if there is no improvement or a worsening in the infected area after 2-3 days of treatment.

Retapamulin should not be used to treat abscesses.

Retapamulin ointment contains butylated hydroxytoluene, which may cause local skin reaction (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

As with other antibacterial agents, prolonged use of retapamulin may result in overgrowth of non-susceptible micro-organisms, including fungi.

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

In human liver microsomes, retapamulin was shown to be a strong inhibitor of CYP3A4. However, since plasma concentrations of retapamulin during topical application have been low (see section 5.2), it is not expected that concurrent systemic administration of CYP3A4 substrates will result in clinically important inhibition of their metabolism by retapamulin.

Co-administration of oral ketoconazole 200mg twice daily increased mean retapamulin AUC_(0-24) and C_max by 81% after topical application of retapamulin 1% ointment on the abraded skin of healthy adult males. Nevertheless, the highest plasma concentrations recorded were low (< 10.5 ng/ml in the absence of ketoconazole and < 17 ng/ml in the presence of ketoconazole.

Systemic exposure to retapamulin has been low following topical application of 1% ointment in adult and paediatric patients aged 2 years and older (maximum plasma concentration < 20 ng/mL). Therefore it is not expected that clinically important increases in plasma concentrations of retapamulin will occur in patients aged 2 years and older who are also receiving CYP3A4 inhibitors.

In children aged from 9 months to 2 years it is possible that higher plasma concentrations may occasionally occur during treatment with retapamulin 1% ointment compared to older children and adults. Therefore caution is advised if retapamulin 1% ointment is administered to children in this age group who are also receiving CYP3A4 inhibitors, as further increase in systemic exposure to retapamulin may occur upon CYP3A4 inhibition.

See section 5.2 regarding plasma concentrations of retapamulin observed in patients in different age groups.

Pregnancy

No clinical data on exposed pregnancies are available. Animal studies have shown reproductive toxicity after oral administration and are insufficient with respect to effects on parturition and fetal/postnatal development (see Section 5.3).

Retapamulin ointment should only be used in pregnancy when topical antibacterial therapy is clearly indicated and the use of retapamulin is considered to be preferable to administration of a systemic antibacterial agent.

Lactation

It is unknown whether retapamulin is excreted in human breast milk. Minimal systemic exposure is observed in adults, therefore exposure of the breast-feeding infant is likely to be negligible. The excretion of retapamulin in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Altargo should be made taking into account the benefit of breast-feeding to the child and the benefit of Altargo therapy to the woman.

No studies on the effects on the ability to drive and use machines have been performed. Altargo is administered topically and is unlikely to have an effect on the ability to drive or use machines.

In clinical studies in which 2150 patients with superficial skin infections applied Altargo, the most commonly reported adverse reaction was application site irritation, which affected approximately 1% of patients.

The following convention has been used for the classification of frequency:

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Any signs or symptoms of overdose, either topically or by accidental ingestion, should be treated symptomatically.

No specific antidote is known.

Pharmacotherapeutic group: Dermatologicals ATC code: D06AX13

Mode of action

Retapamulin is a semi-synthetic derivative of the compound pleuromutilin, which is isolated through fermentation from Clitopilus passeckerianus (formerly Pleurotus passeckerianus).

Retapamulin selectively inhibits bacterial protein synthesis by interacting at a unique site on the 50S subunit of the bacterial ribosome that is distinct from the binding sites of other non-pleuromutilin antibacterial agents that interact with the ribosome.

Data indicate that the binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase centre. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, partially block P-site interactions, and prevent normal formation of active 50S ribosomal subunits. Therefore the pleuromutilins appear to inhibit bacterial protein synthesis by multiple mechanisms.

Retapamulin is predominantly bacteriostatic against S. aureus and S. pyogenes.

Mechanism of Resistance

Due to its distinct mode of action, target specific cross-resistance with other classes of antibacterial agents is rare.

In vitro, three mechanisms have been identified which reduce susceptibility to retapamulin. One involves mutations in ribosomal protein L3, the second is a non-specific efflux mechanism (ABC transporter vgaAv). This non-target specific efflux mechanism has also been demonstrated to reduce the in vitro activity of streptogramin A.

Susceptibility to pleuromutilins can also be affected by the Cfr rRNA methyltransferase, which confers cross-resistance to phenicols, lincosamides and streptogramin A in staphylococci.

Retapamulin MICs of 2-64 µg/ml have been reported for clinical isolates of S. aureus possessing either the efflux or cfr resistance mechanisms described above. For S. aureus isolates with laboratory-generated mutations in ribosomal protein L3, retapamulin MICs were 0.25-4 µg/ml. While the S. aureus epidemiological cut off value for retapamulin is 0.5 µg/ml, the clinical significance of isolates with elevated retapamulin MICs is unknown due to the potential for high local concentrations (20,000 µg/ml) of retapamulin on the skin.

No development of resistance was observed during treatment with retapamulin in the clinical study programme and all clinical isolates were inhibited by retapamulin concentrations of <2μg/ml.

Antibacterial spectrum

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infection is questionable.

^$ In vitro, retapamulin was equally active against methicillin-susceptible and methicillin-resistant strains of S. aureus. However, see section 4.4 and below regarding clinical efficacy against MRSA. Retapamulin should not be used to treat infections known or thought likely to be due to MRSA.

* Activity has been satisfactorily demonstrated in clinical studies

Information from clinical trials

Very few MRSA were isolated in studies in impetigo and all were clinical successes (100%: 8/8).

In studies in impetigo and in two studies of secondarily infected open wounds (SIOW), clinical success rates were high for retapamulin in patients with mupirocin-resistant S. aureus (100%: 11/11) or fusidic acid-resistant S. aureus (96.7%: 29/30). However, in the two studies that enrolled patients with SIOW the efficacy of retapamulin in infections due to MRSA was inadequate (75.7%). No differences were observed in the in vitro activity of retapamulin versus S. aureus whether the isolates were susceptible or resistant to methicillin.

The explanation for lower clinical efficacy against MRSA in SIOW is unclear and it may have been influenced by the presence of a particular MRSA clone. In the case of treatment failure associated with S. aureus, the presence of strains possessing additional virulence factors (such as Panton-Valentine Leukocidin) should be considered.

Clinical Success Rates at Follow up for SIOW patients with S. aureus

CI: confidence interval. Exact CI is calculated using the F-distribution method.

^$: the response rate for MRSA due to PVL+ MRSA was 8/13 (62%)

A multicentre, randomised, double-blind, study compared the efficacy of retapamulin ointment to placebo ointment for the treatment of SIOW. The study failed to meet the primary end point which was the clinical success rate at follow-up (day 12 – 14) for subjects in the Intent to Treat Clinical population (see Table below).

Clinical Response at Follow-up (day 12-14), by Analysis population

However, when adjusted for baseline wound characteristics including pathogen, wound size and severity, the clinical success rate of retapamulin was superior to placebo for the primary efficacy endpoint (p=0.0336). Lesions of subjects treated with retapamulin healed more quickly by the End of therapy visit (day 7-9), with a reduction in size of the lesions by 77.3% compared to 43.5% for placebo treated subjects. However by the Follow-up visit this difference was less pronounced, (88.6% vs, 81% for retapamulin and placebo treated subjects respectively).

In the Intent to Treat Bacteriological evaluable population, the clinical success rate of retapamulin (76.4%: 139/182) was statistically superior to that of placebo (64.3%; 54/84). This difference was primarily due to the higher success rate observed in retapamulin-treated subjects with infections caused by S. aureus in comparison to placebo treated subjects (see Table below). However, retapamulin showed no advantage over placebo in subjects with SIOW due to S. pyogenes.

Clinical Success rates at Follow-up for Intent to Treat Bacteriological Evaluable SIOW subjects with S. aureus and S. pyogenes

Absorption

Healthy adults

In a study conducted in healthy adult subjects, 1% retapamulin ointment was applied daily to intact and to abraded skin under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact skin was very low. The geometric mean C_max value in plasma after application to 200 cm² of abraded skin was 9.75 ng/ml on day 1 and 8.79 ng/ml on day 7, and the maximum individual systemic exposure (C_max) recorded was 22.1 ng/ml.

Patients from the age of 2 years

Single plasma samples were obtained from 516 adult and paediatric patients who received topical treatment with retapamulin 1% ointment twice daily for 5 days for the treatment of secondarily infected traumatic lesions. Sampling occurred pre-dose for adult subjects on days 3 or 4, and between 0-12 hours after the last application for paediatric subjects on days 3 or 4. The majority of samples (89%) were below the lower limit of quantitation (0.5 ng/ml). Of the samples that had measurable concentrations 90% had retapamulin concentrations less than 2.5 ng/ml. The maximum measured plasma concentration of retapamulin was 10.7 ng/ml in adults and 18.5 ng/ml in paediatric patients (aged 2-17 years).

Patients aged from 2 months to 24 months

Single plasma samples were obtained approximately 4-8 hours after the first application on days 3 or 4 from patients aged from 2 months to 2 years with impetigo or with secondarily infected traumatic lesions or dermatoses (note that retapamulin is not indicated for use in secondarily infected dermatoses). Retapamulin concentrations were measurable in 46% (36/79) of samples (range 0.52 to 177.3 ng/ml) but the majority of these samples (27/36; 75%) contained < 5.0 ng/ml.

Among the children aged from 9 months to 2 years plasma concentrations of retapamulin were measurable in 32% (16/50) of samples. A single retapamulin concentration (95.1 ng/ml) exceeded the highest concentration observed in patients aged 2-17 years (18.5 ng/ml). This plasma concentration was observed in a child with a secondary infected dermatosis, for which retapamulin is not indicated for use.

Retapamulin is not recommended for use in children aged less than 9 months. In children aged from 2 months to 9 months plasma concentrations of retapamulin were measurable in 69% (20/29) of samples. Four plasma retapamulin concentrations (26.9, 80.3, 174.3, and 177.3 ng/ml) exceeded the highest concentration observed in patients aged 2-17 years (18.5 ng/ml).

Distribution

Due to the very low systemic exposures, tissue distribution of retapamulin has not been investigated in humans.

In vitro, retapamulin was shown to be a P-glycoprotein (Pgp) substrate and inhibitor.

However, the maximum individual systemic exposure in humans following topical application of 1% ointment on 200 cm² of abraded skin (C_max= 22 ng/ml; AUC_(0-24) = 238 ng.h/ml) was 660-fold lower than the retapamulin IC₅₀ for Pgp inhibition.

Retapamulin is approximately 94% bound to human plasma proteins.

Metabolism

The in vitro oxidative metabolism of retapamulin in human liver microsomes was primarily mediated by CYP3A4 with minor contributions from CYP2C8 and CYP2D6 (see section 4.5).

Elimination

Retapamulin elimination in humans has not been investigated.

Special Patient Populations

No pharmacokinetic data are available in children aged less than 2 years, or in patients with renal or hepatic impairment. However, due to the low systemic plasma levels that have been observed, no safety problems are foreseen.

Repeated-dose toxicity

In 14-day (50, 150 or 450 mg/kg) oral toxicity studies in rats there was evidence of adaptive hepatic and thyroid changes. Neither of these findings is of clinical relevance.

In monkeys dosed orally (50, 150 or 450 mg/kg) for 14 days there was dose-related emesis.

Carcinogenesis, mutagenesis, reproductive toxicity

Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.

There was no evidence of 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 for chromosomal effects in a rat micronucleus test.

There was no evidence of impaired fertility in male or female rats at oral doses of 50, 150, or 450 mg/kg/day, resulting in exposure margins of up to 5-times the highest human estimated exposure (topical application to 200 cm² abraded skin: AUC 238 ng.h/ml).

In an embryotoxicity study in rats, developmental toxicity (decreased fetal body weight and delayed skeletal ossification) and maternal toxicity were observed at oral doses of 150 mg/kg/day (corresponding to 3 times the human estimated exposure (see above). There were no treatment-related malformations in rats.

Retapamulin was given as a continuous intravenous infusion to pregnant rabbits from day 7 to day 19 of gestation. Maternal toxicity was demonstrated at dosages of 7.2 mg/kg/day corresponding to 8 times the estimated human exposure (see above). There was no treatment-related effect on embryo-fetal development.

No studies to evaluate effects of retapamulin on pre-/postnatal development were performed. However, there were no systemic effects on juvenile rats with topical application of retapamulin ointment.

White soft paraffin.

Butylated hydroxytoluene

Not applicable.

Unopened: 2 years.

In-use: 7 days.

Do not store above 25°C.

0.5 g aluminium foil sachet. Carton of 12 sachets.

5 g, 10 g and 15 g aluminium tubes with a plastic screw cap. Carton of 1 tube.

Not all pack sizes may be marketed.

Any remaining ointment at the end of treatment should be discarded.

Any unused product or waste material should be disposed of in accordance with local requirements.

Glaxo Group Ltd

Glaxo Wellcome House

Berkeley Avenue

Greenford

Middlesex UB6 0NN

United Kingdom

EU/1/07/390/001

EU/1/07/390/002

EU/1/07/390/003

EU/1/07/390/004

24/05/2007

April 2011

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.ema.europa.eu/.