Information from Health Canada about retapaumulin (Altargo), a pleuromutilin antibiotic for the treatment of impetigo and skin infections.
On March 19, 2008, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product AltargoTM.
AltargoTM contains the medicinal ingredient retapamulin which is an antibiotic.
AltargoTM is indicated for use in adult and pediatric patients aged 9 months and older for topical treatment of the following uncomplicated bacterial skin and skin structure infections due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes:
Secondarily infected traumatic lesions (small lacerations, abrasions, and sutured wounds)
Retapamulin selectively inhibits bacterial protein synthesis through an interaction at a binding site on the 50S subunit of the bacterial ribosome that differs from that of other antibiotics. Retapamulin is predominantly bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes.
The market authorization was based on quality (chemistry and manufacturing), non-clinical, and clinical information submitted. Four of five pivotal clinical studies submitted were to support the use of AltargoTM for treatment of the indications stated above. Overall, the clinical efficacy and safety evaluation involved 3177 adult and pediatric subjects, of whom 2115 received AltargoTMointment. Clinical response for primary impetigo was 86-99% and for secondarily infected traumatic lesions was 89-90% in the clinically evaluable patients. The most common adverse drug reaction was application site irritation (1%).
AltargoTM (1% retapamulin) is presented as a topical ointment for cutaneous use only. A thin layer of AltargoTMshould be applied to the affected area twice daily for five days. The area treated may be covered with a sterile bandage or gauze dressing if desired. Patients not showing a clinical response within 3-4 days should be re-evaluated. Dosing guidelines are available in the Product Monograph.
AltargoTMis contraindicated for patients with a known or suspected hypersensitivity to AltargoTM or any component of the ointment. AltargoTM should not be ingested. AltargoTM is not for use on mucous membranes or in the eyes. AltargoTMshould be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of AltargoTMare described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of AltargoTMis favourable for the indications stated above.
An excerpt of the Summary Basis of Decision, detailing clinical pharmadynamic and pharmacokinetic aspects of retapamulin, along with recommendations from Health Canada:
3.3 Clinical Basis for Decision
AltargoTM (1.0%, retapamulin) is an antibacterial ointment for cutaneous use only. Retapamulin is predominantly bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes. The pharmacodynamic studies evaluated the potential of retapamulin to induce skin irritation, as well as potential QTc prolongation.
Irritation potential for 0.5%, 1% and 2% retapamulin had been investigated. In the patient population, the skin samples utilized in clinical studies are never 100% intact, thus, non-intact skin. The study conducted on abraded skin (tape-stripped) under fully occlusive dressings considered as a good study models to test irritation potential, allergic contact dermatitis, and exaggerated sensitivity to chemical irritation.
On intact skin, 0.5%, 1%, and 2% retapamulin concentrations were not the primary or cumulative irritants. On abraded skin, retapamulin-, 0.5% and 1% concentrations, were not primary or cumulative irritants. The positive irritant control, 0.1% sodium lauryl sulfate (SLS) was significantly more irritating than all other test products (vehicle control, retapamulin ointment 1%, 0.1% gentamicin and Neopsporin) on abraded skin under full occlusion conditions. The average scores for 2% retapamulin were similar to 0.1% SLS which was used as a positive irritant control on abraded skin under semi-occlusive conditions. Retapamulin 1% ointment had similar irritation scores to marketed products (0.1% gentamicin ointment and Neosporin) after repeat applications on abraded skin.
In the study that evaluated the potential of retapamulin to induce contact sensitization by repeat application to the intact skin of healthy adult subjects, only one subject of 206 demonstrated sensitization to retapamulin 1% and 2% with possible sensitization to retapamulin at 0.5%.
The current new drug submission is for the topical application which has a low systemic absorption. Therefore a thorough QT/QTc prolongation study which includes positive control is not required. In animal pharmacological studies in dog and monkey, no electrocardiogram (ECG) abnormalities, including QTc prolongation were observed at any of the dose level studied. Two clinical Phase I studies are presented where a post-hoc analysis of manually over-read 12-lead ECGs with 103 healthy adult subjects receiving up to seven repeat applications of retapamulin at doses up to and exceeding the maximum proposed clinical dose was completed. The statistical analysis shows that topical application of retapamulin does not cause QT/QTc prolongation.
In light of the statistical limitations, pharmacokinetic/pharmacodynamic analyses were presented as an alternative approach to assess the potential QT effects of retapamulin. The pharmacokinetic/pharmacodynamic analyses of the ECG data showed no correlation between QTcF, QTcB, or QT absolute values or maximum change from baseline with retapamulin plasma concentration, or Cmax.
To support the efficacy of retapamulin, the dose and duration of the drug were evaluated via in vivo animal model studies. A mouse suture wound model showed statistical significance in the efficacy of 1% Retapamulin ointment, when dosed for ≥4 days, against susceptible and resistant strains of Staphylococcus aureus (methicillin-resistant Staphylococcus aureu), and Streptococcus pyogenes, when compared to placebo and non-treated controls.
In vitro profile of isolates was determined in multiple studies. Retapamulin showed MIC50 (minimum inhibitory concentration at 50%), MIC90 (minimum inhibitory concentration at 90%) and MIC range values of ≤0.12, ≤0.25, 0.004-64 ug/mL, respectively, against a total of 5537 isolates of Staphylococcus aureus. Only one Staphylococcus aureus isolate reported a MIC value for retapamulin of ≥ 2ug/mL (64 ug/mL). Against a total of 3538 isolates tested in multiple studies, retapamulin inhibited all isolates of Streptococcus pyogenes at ≤0.25 μg/mL. Retapamulin demonstrated good in vitro activity against Coagulase-negative staphylococci, Streptococcus agalactiae and viridans streptococci with MIC90 value of ≤0.25 ug/mL, ≤0.06 ug/mL, and ≤0.5 ug/mL, respectively. Retapamulin demonstrated poor in vitro activity against the enterococcal isolates tested with a MIC90 value of 128 μg/mL against both Enterococcus faecalis and Enterococcus faecium. Retapamulin also demonstrated poor in vitro activity, against Bacillus species with MIC90 values of ≤128 μg/mL, but was active in vitro against Propionibacterium species with MIC90 values of ≤ 1 μg/mL. Enterobactericeae and Pseudomonas aeruginosa are inherently resistant to retapamulin.
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Pharmacokinetic studies had been conducted in both intact and abraded skin models in healthy subjects. The uncomplicated skin and soft tissue infections would represent “non-intact” skin and therefore testing on the abraded skin is appropriate. The results of the study indicated that there was a higher systemic exposure from abraded skin applications when compared to intact skin applications. The highest systemic exposure in the abraded skin cohorts was a Cmax of 22 ng/mL and AUC of 238 ng.h/mL. This was well below the steady state, Cmax of 124 ng/mL and AUC of 739 ng.h/mL at the no observed adverse effect level for oral administration in monkeys (50 mg/kg/day).
Pharmacokinetic data were not available for adult patients with impetigo. However, the pharmacokinetic data collected from patients with secondarily infected traumatic lesions would be expected to represent the worst-case scenario for systemic exposure to retapamulin. In secondarily infected traumatic lesions, the entire epidermis is compromised so that there is no epidermal barrier to drug penetration, whereas in impetigo some degree of epidermal layers may still be present, although somewhat disrupted due to inflammation. Therefore, systemic exposure of retapamulin may be higher in patients with secondarily infected traumatic lesions as compared with impetigo.
In the Phase III studies, a single pharmacokinetic sample was collected from the pediatric population (2-17 yrs). The small number of samples with measurable retapamulin concentration (only 9 out of 136 plasma samples) ranging 0.54-18.47 ng/mL indicated low systemic absorption following topical administration. The minimal systemic exposures in pediatric patients were comparable to those in adult patients. Therefore, systemic exposure of retapamulin does not pose any safety concerns for pediatric patients.
Tissue distribution of retapamulin was not investigated in humans. Pre-clinical studies indicate that the drug-related material was rapidly and widely distributed into the peripheral tissues. The passage of retapamulin across the blood brain barrier was limited. The drug-related material associated with the melanin-containing tissues declined slowly with time. The drug was approximately 94% bound to plasma proteins.
In the human hepatocyte incubation studies, retapamulin was extensively metabolized. The main routes of metabolism were mono-oxygenation and di-oxygenation of the parent drug. The oxidative metabolism in human liver microsomes was primarily mediated by CYP3A4 with minor contributions from CYP2C8 and CYP2D6. An in vitro study assessed the metabolism of retapamulin in skin. Most of the drug-related compound was the parent drug. Only very low amounts of three mono-oxygenated metabolites were generated in the skin. Retapamulin metabolism in humans was investigated using qualitative methodologies. Two minor mono-oxygenated metabolites were detected in plasma of healthy adult subjects when retapamulin was applied on abraded skin but not on intact skin. Metabolic profiles were similar in urine from subjects with topical application of drug on intact or abraded skin. The parent drug, two N-demethylated metabolites, and numerous products of mono-oxygenation as well as further oxidation products were present in urine samples.
The oxidative metabolism of retapamulin was primarily mediated by CYP3A4, with minor contributions from CYP2C8 and CYP2D6. Retapamulin was also shown to be a P-glycoprotein substrate. One clinical drug interaction study tested the effect of co-administration of oral ketoconazole, a potent CYP3A4 and P-glycoprotein inhibitor, on the pharmacokinetics of retapamulin after topical application of 1% retapamulin. An approximate 80% increase in retapamulin plasma AUC(0-24) and Cmax was observed with co-administration of oral ketoconazole with topical application of 1% retapamulin. Other CYP3A4 and P-glycoprotein inhibitors would be expected to interact with retapamulin to a similar degree. The systemic exposures to retapamulin in most patients with secondarily infected traumatic lesions and other uncomplicated bacterial skin infections were non-measureable (i.e., less than the lower limit of qualification 0.5 ng/mL) and the maximum systemic exposure was 18.5 ng/mL. As systemic exposure is low, no dosing modification is recommended when co-administered with CYP3A4 inhibitors, such as ketoconazole.
In human liver microsomes, retapamulin was a potent inhibitor of CYP3A4 when midazolam, nifedipine and atrovastatin were used as substrates. In vitro, retapamulin was shown to be a P-glycoprotein substrate and inhibited P-glycoprotein transport of digoxin with an IC50 of 28.2 μM or 14601.3 ng/mL. The maximum individual systemic exposure in humans following topical application of 1% retapamulin is about 10-fold lower than the lowest Ki (dissociation constant of an inhibitor) for CYP3A4 inhibition by retapamulin and 660-fold lower than the IC50 for P-glycoprotein inhibition by retapamulin. Therefore, topical application of 1% retapamulin is unlikely to cause clinically relevant CYP3A4 inhibition in patients. As 1% retapamulin applied topically is not expected to affect the metabolism of other CYP substrates or the disposition of other P-glycoprotein substrates, no clinical drug interaction studies on the effect of retapamulin on other co-administered, systemically bioavailable drugs were performed.
The elimination of retapamulin in humans has not been investigated due to very low systemic exposure following topical administration. In pre-clinical studies, retapamulin was rapidly eliminated primarily via metabolism and excretion of drug related material in the bile.
No pharmacokinetic studies were performed in subjects with hepatic impairment. As the systemic exposures to retapamulin are predominantly non-measurable in patients, dosage adjustment is not required in hepatic impairment. Also there were no pharmacokinetic studies performed in subjects with renal impairment. As renal elimination plays a minor role, dosage adjustments would not be required for subjects with renal impairment.
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3.3.4 Clinical Efficacy
Four pivotal Phase III studies were submitted to support the use of retapamulin ointment, 1% (AltargoTM) for treatment of impetigo and secondarily infected traumatic lesions. There were two studies for primary impetigo; one a comparator study versus topical sodium fusidate ointment (Study TOC100224, n= 514) and the other a placebo-controlled study (Study TOC103469, n= 210). The other two studies were for secondarily infected traumatic lesions. They were similar in design and compared AltargoTM to oral cephalexin (Study 030A, n= 988 and Study 030B, n= 916). In addition, single pharmacokinetic plasma samples were collected in the secondarily infected traumatic lesions studies from the first 500 enrolled adult subjects and all enrolled pediatric subjects in order to assess exposure to AltargoTM during topical treatment under the proposed conditions of clinical use. Cohorts studied were subjects with uncomplicated skin and skin structure infections suitable to topical treatment and which had a high likelihood of infection with staphylococci or streptococci. Cohorts included both adult and pediatric subjects (≥9 months of age). Patients received AltargoTMointment topically twice daily for five days.
In the Study TOC103469, the primary efficacy endpoint was met and retapamulin ointment was demonstrated to be superior (85.6%) over placebo ointment (52.1%), in the treatment of primary impetigo based on clinical response at End of Therapy in the intent to treat clinical population. Retapamulin ointment was effective against the key pathogens associated with primary impetigo Staphylococcus aureus (methicillin-susceptible isolates) (88.4% versus 52.9% success rate), and Streptococcus pyogenes (88.2% versus 37.5% success rate). The microbiological success rates by pathogen for the intent to treat bacteriology populations were similar to corresponding clinical success rates at the End of Therapy. Generally, there was a good correlation between clinical and microbiological responses at both the End of Therapy and Follow Up. A higher percentage of subjects in the placebo group were withdrawn due to lack of efficacy, and disease progression.
In study TOC100224, the primary efficacy endpoint was met and retapamulin ointment was demonstrated to be non-inferior (99.1%) to sodium fusidate ointment applied three times a day for seven days (94.0%) based on clinical response at End of Therapy in per protocol clinical population. Retapamulin ointment was effective against the key pathogens associated with primary impetigo Staphylococcus aureus (methicillin-susceptible isolates) (99.0% versus 92.6% success rate), and Streptococcus pyogenes (97.8% versus 88.9% success rate). The microbiological success rates by pathogen for the per protocol bacteriology population were similar to the corresponding clinical success rates at End of Therapy. Staphylococcus aureus was the most frequently isolated pathogen in the primary impetigo studies, comprising 63.8%-77.3% of the isolates.
Secondarily Infected Traumatic Lesions
In Study SB275833/030A, the primary efficacy endpoint was met and retapamulin ointment was demonstrated to be non-inferior (88.7%) to oral cephalexin (91.9%) based on clinical response at Follow Up in the per protocol clinical population. Retapamulin ointment was effective against the key pathogens associated with secondarily infected traumatic lesions Staphylococcus aureus (methicillin-susceptible isolates) (91.1% versus 91.0% success rate), and Streptococcus pyogenes (89.7% versus 88.9% success rate). In Study SB275833/030B, the primary efficacy endpoint was met and retapamulin ointment was demonstrated to be non-inferior (90.4%) to oral cephalexin (92.0%) based on clinical response at Follow Up in the per protocol clinical population. Retapamulin ointment was effective against the key pathogens associated with secondarily infected traumatic lesions Staphylococcus aureus (methicillin-susceptible isolates) (93.4% versus 91.2% success rate), and Streptococcus pyogenes (96.6% versus 100.0% success rate).
In the combined Study SB275833/030A and SB275833/030B, retapamulin ointment was effective against the key pathogens associated with secondarily infected traumatic lesions Staphylococcus aureus (methicillin-susceptible isolates) (92.2.4% versus 91.1% success rate), but not for Streptococcus pyogenes (92.6% versus 94.1% success rate). Pathogens were generally isolated with similar frequencies across the treatment group in the studies. Staphylococcus aureus was the most frequently isolated pathogen, compromised 57.0-61.5% of isolates.
Overall Efficacy Conclusion
The data presented in the pivotal studies (TOC1003469, TOC100224, SB275833/030A and SB275833/030B) were adequate to support the Sponsor’s claims of efficacy of AltargoTM (retapamulin) 1% Ointment in the treatment of uncomplicated bacterial skin and skin structure infections in adult and pediatric (≥9 months of age) populations: primary impetigo; and, secondarily infected traumatic lesions (small laceration, abrasions and sutured wounds) caused by the pathogens Staphylococcus aureus (methicillin-susceptible isolates) and Streptococcus pyogenes. For the proposed indication of secondarily infected traumatic lesions, there were very limited data for the cohort ≥9 months to < 2 years of age (2 subjects enrolled). Efficacy data were limited to primary impetigo to <10 lesions and up to 100 cm2 in total surface area or < 2% of body surface area in pediatric patients and to secondarily infected traumatic lesions <10 cm in length or 100 cm2 in total surface area. AltargoTM is not recommended for the treatment of uncomplicated bacterial skin and skin structure infections with methicillin-resistant Staphylococcus aureus or secondarily infected traumatic lesions with abscess.
3.3.5 Clinical Safety
The safety data was combined from the Phase III studies, with a total of 3177 study subjects (adult and pediatric patients). Of these subjects, 2115 subjects were exposed to AltargoTM, 819 subjects were exposed to an active oral comparator (cephalexin); 172 subjects were exposed to an active topical comparator (sodium fusidate ointment 2%), and 71 subjects were exposed to placebo ointment.
The safety data did not identify any major safety concerns for the topical use of AltargoTM ointment 1% in the five-day twice a day treatment for uncomplicated bacterial skin and skin structure infections: primary impetigo and secondarily infected traumatic lesions, in adult and pediatric populations.
The frequency of drug- related adverse events was low with AltargoTM (5%), and no drug-related events were reported as serious. The most frequent drug-related adverse event was application site irritation (≥ 1%). The incidence of discontinuation due to drug-related adverse events was low (0.2%) and included application site irritation, pain, pruritus and contact dermatitis. AltargoTM was not evaluated for use on mucosal membranes or in eyes, thus caution should be taken against ingestion and use of the ointment in eyes or on mucosal surfaces. AltargoTM contains a preservative, butylated hydroxytoluene, which may cause a local skin reaction or irritation to the eyes and mucosal membranes. Given minimal systemic absorption and high renal clearance, adverse systemic effects/drug interactions are not expected under the recommended conditions of use.
There were very limited data (safety and efficacy) for the secondarily infected traumatic lesions indication for the cohort ≥ 9 months to < 2 years of age; however, there were safety data in this cohort for the other proposed indications using the same treatment regimen, scientific rationale, and non-clinical studies which indicated similar adverse event profiles in adult and pediatric populations.
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3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
AltargoTM (retapamulin) ointment, 1%, is an antibacterial agent from a new molecular class and has a unique mechanism of action. Data showed evidence of clinical efficacy, microbiological efficacy, and the adverse event(s) profile to be similar in adult and pediatric (≥9 months of age) populations for topical treatment of primary impetigo and secondarily infected traumatic lesions (of limited size) caused by susceptible organisms Staphylococcus aureus (methicillin-susceptible isolates) and Streptococcus pyogenes. The pharmacokinetic data indicated minimal systemic absorption and rapid clearance. As a result, there is no need for dosage adjustments based on age or the use of concomitant medication. AltargoTM shows no target-specific cross-resistance to the other classes of antibiotics. Topical treatment may allow subjects to decrease the use of systemic oral agents and thus avoid the accompanying systemic side effects and concomitant antibiotic resistance concerns. The efficacy of AltargoTM is neither dependent on nor compromised by dressing-type.
The frequency of adverse events was low with AltargoTM. Drug-related site reactions were non-serious and resolved with removal or discontinuation of ointment. AltargoTM should not be ingested or used in eyes or on mucosal surfaces. AltargoTM contains a preservative, butylated hydroxytoluene, which may cause a local skin reaction or irritation to the eyes and mucosal membranes.
AltargoTM is considered to be effective and was well tolerated. The benefit and risk profile for AltargoTMis considered positive.
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of AltargoTM is favourable for adult and pediatric patients aged 9 months and older for the topical treatment of the following uncomplicated skin and skin structure infections due to Staphylococcus aureus (methicillin-susceptible isolates) and Streptococcus pyogenes: primary impetigo and secondarily infected traumatic lesions (small lacerations, abrasions, sutured wounds of limited size).