Altargo - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gram of ointment contains 10 mg retapamulin (1% w/w).

Excipient(s) with known effect:

Each gram of ointment contains up to 20 micrograms of butylated hydroxytoluene (E321).

Ointment.

Smooth, off-white ointment.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Short term treatment of the following superficial skin infections in adults, adolescents, infants and children (aged from nine months) (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 medicinal products.

4.2 Posology

Posology

Adults (aged 18–65years), 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).

Special populations

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.

Paediatric population

The safety and efficacy of retapamulin ointment in infants less than nine months of age has not been established. Currently available data are described in section 5.2, but no recommendation on a posology can be made.

Method of administration

Retapamulin is for cutaneous use only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Sensitisation or severe loc ai 'rritation

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.

Eyes and mucous membranes

Ret apamulin ointment must be kept away from the eyes and mucous membranes. Epistaxis has been

with use of Altargo on nasal mucosa.

igestion

Care must be taken to avoid ingestion.

Re-evaluation of treatment

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

Prolonged use and overgrowth of non-susceptible micro-organisms

Prolonged use of retapamulin may result in overgrowth of non-susceptible micro-organisms, including fungi. If super-infection with a non-susceptible organism is suspected, treatment should be guided by clinical and microbiological assessments.

Abscesses

Retapamulin should not be used to treat abscesses.

Methicillin-resistant Staphylococcus aureus (MRSA)

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 MRSA. The reason for the reduced clinical effica these patients is unknown.

Butylated hydroxytoluene

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

4.5 Interaction with other medicinal products and other forms of interaction

The effect of concurrent application of retapamulin and other topical medicinal 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 Cmax by 81% after topical application of retapamulin 10 mg/g 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 10 mg/g 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.

Paed iatric population

In children aged from 9 months to 2 years it is possible that higher plasma concentrations may occasionally occur during treatment with retapamulin 10 mg/g ointment compared to older children and adults. Therefore caution is advised if retapamulin 10 mg/g 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.

4.6 Fertility, pregnancy and lactation

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 medicinal product.

Breast-feeding

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.

Fertility

There are no data on the effects of retapamulin on human fertility. No treatment-related effects on male or female fertility have been shown in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Altargo has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Summary of the safety profile

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.

Tabulated list of adv erse reactions

The following convention has been used for the classification of frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Paediatric population

Frequency, type and severity of adverse reactions in the paediatric population are the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is importa allows continued monitoring of the benefit/risk balance of the medicinal product. Hea?hca."e professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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

No specific antidote is known.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, Antibiotics for topical use. ATC code: D06AX13

Mechanism 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 ^g/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 laboratorygenerated mutations in ribosomal protein L3, retapamulin MICs were 0.25–4 ^g/ml. While the S. aureus epidemiological cut off value for retapamulin is 0.5 ^g/ml, the clinical significance of isolates with elevated retapamulin MICs is unknown due to the potential for high local concentrations (20,000 ^g/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 <2 ^g/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,

$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

5.2 Pharmacokinetic properties

Single plasma samples were obtained from 516 adult and paediatric patients who received topical treatment with retapamulin 10 mg/g 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 10 mg/g ointment on 200 cm2 of abraded skin (Cmax= 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.

Biotransformation

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 populations

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

5.3 Preclinical safety data

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 embryofetal 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

White soft paraffin

Butylated hydroxytoluene (E321)

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Unopened tube and sachet: 2 years.

In-use tube: 7 days.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

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

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

7. MARKETING AUTHORISATION HOLDER

Glaxo Group Ltd

980 Great West Road

BrentfordMiddlesex TW8 9GS

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S )

EU/1/07/390/001

EU/1/07/390/002

EU/1/07/390/003

EU/1/07/390/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24 May 2007

Date of latest renewal: 20 April 2012