Summary Basis of Decision for Altargo ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
AltargoTM
Retapamulin, 0.01, Ointment, Topical
GlaxoSmithKline Inc.
Submission control no: 109037
Date issued: 2008-11-05
Health Products and Food Branch
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Health Canada
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrAltargoMC, Rétapamuline 1 %, topique, GlaxoSmithKline Inc., No de contrôle de la présentation 109037
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02307502
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control No. 109037
Date of Submission:
Date of authorization:
2 Notice of decision
On March 19, 2008, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product Altargo™.
Altargo™ contains the medicinal ingredient retapamulin which is an antibiotic.
Altargo™ 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:
- Primary impetigo
- 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 Altargo™ for treatment of the indications stated above. Overall, the clinical efficacy and safety evaluation involved 3177 adult and pediatric subjects, of whom 2115 received Altargo™ointment. 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%).
Altargo™ (1% retapamulin) is presented as a topical ointment for cutaneous use only. A thin layer of Altargo™should 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.
Altargo™is contraindicated for patients with a known or suspected hypersensitivity to Altargo™ or any component of the ointment. Altargo™ should not be ingested. Altargo™ is not for use on mucous membranes or in the eyes. Altargo™should 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 Altargo™are 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 Altargo™is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Retapamulin, the medicinal ingredient of Altargo™ is an antibiotic. Retapamulin selectively inhibits bacterial protein synthesis through an interaction at a site on the 50S subunit on the bacterial ribosome that differs from that of other antibiotics. Retapamulin is predominantly bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes. Retapamulin demonstrates no in vitro target-specific cross-resistance with other classes of antibiotics.
Manufacturing Process and Process Controls
Retapamulin is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet ICH requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of retapamulin is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of retapamulin.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated and long-term testing show that retapamulin is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
Altargo™ (retapamulin) 1% topical ointment is off-white, smooth ointment, contained in three sizes of aluminium tubes, 5 g, 10 g, 15g, and 500 mg sachets. The milled active ingredient (retapamulin) is blended in white soft paraffin, Ph Eur. The ointment is available in aluminium tubes with a white cap, and also in unit sachets constructed from aluminum foil laminate. Each gram of Altargo™ contains 10 mg of retapamulin (1% w/w) and the following non-medicinal ingredients: white soft paraffin containing butylated hydroxytoluene (BHT).
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of retapamulin with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Altargo™, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization, and discussion on the effect of formulation change on the safety and/or efficacy of Altargo™. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Manufacturing Process and Process Controls
Altargo™ topical ointment will be manufactured by Glaxo Wellcome Operations in the United Kingdom. The ointment is manufactured by heating white soft paraffin to which the drug substance is added, blended, cooled and filled into the container/closure system. White soft paraffin is the only non-medicinal ingredient and contains the antioxidant BHT. Levels of BHT in the formulation are considered to be within acceptable limits. There is no schedule B compendial monograph available for topical products containing retapamulin therefore the sponsor is claiming a professed standard for the drug product.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Altargo™ is tested to verify that the appearance, identity, content uniformity, content of retapamulin, minimum fill, drug-related impurities content, and microbial limit test are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
The validation process is considered to be complete. Validation reports were submitted for in-process and release testing of the drug product, and no anomalies were present. The results for all of the batches were within the proposed specification limits.
Stability
The results of long-term stability demonstrate the acceptable chemical and physical stability of product filled into aluminium tubes when stored at or below 25°C for up to 24 months. No significant changes were observed in the description, retapamulin content, or in drug related impurities.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. None of the components in the Altargo™ topical ointment are of human or animal origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Altargo™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
To assess the effects of retapamulin on major organ systems and to detect any potential adverse effects, an in vitro hERG assay and a battery of in vivo cardiovascular, respiratory, renal, and gastrointestinal safety pharmacology studies were conducted in the mice, rats, dogs or monkeys at doses up to 450 mg/kg.
In an in vitro hERG assay using cloned hERG potassium channels expressed in HEK293 cells, retapamulin inhibited hERG tail current by 10.7%, 59.7%, and 96.2% at 1, 10 and 100 μM, respectively. There were no effects of retapamulin on in vivo cardiovascular or ECG parameters, including QTc, in dogs or monkeys following intravenous doses of up to 3 mg/kg.
In rats, a small transient increase in blood pressure and a minor transient decrease in respiratory rate with a selective increase in expiratory time occurred at 450 mg/kg when administered orally. An increased heart rate at doses ≥150 mg/kg was also observed. The effect on respiratory function was not due to airway obstruction as there were no changes in total pulmonary resistance.
The intravenous doses of 10 mg/kg and 30 mg/kg were associated with vomiting, trembling, increased heart rate, and increased blood pressure (30 mg/kg only) in the dog, and decreased blood pressure and body temperature, seizures, and death in the monkey.
The renal safety pharmacology studies in rats indicated an increased water intake with an associated increase in urine output and reduction in urine osmolarity at 450 mg/kg. There was no evidence of a direct effect on renal excretory function at doses ≤450 mg/kg.
In isolated guinea pig ileum segments, retapamulin (>10 ug/mL) caused decreases in the contractile response to various agonists but had no effect on contraction at 1 ug/mL. In mice, an oral dose of ≥150 mg/kg retapamulin produced a significant decrease in intestinal motility. In studies evaluating the neuropharmacological effects of retapamulin in mice, a dose of 450 mg/kg resulted in analgesia and a decrease in spontaneous motor activity but did not show anticonvulsant or proconvulsant activity or change barbiturate-induced sleep-time. The decrease in spontaneous motor activity in mice with retapamulin was dose-dependent with minimal effect at the 50 mg/kg dose level. The systemic exposure resulting from topical application of retapamulin ointment, 1%, in a clinical setting was very low. In two Phase III studies, the majority (89%) of the plasma samples were non-measureable for retapamulin. In those samples with measurable concentrations, the range of plasma retapamulin concentration after administration was 0.52-18.5 ng/mL; therefore the findings described above are unlikely to be of clinical significance.
Several studies have been performed with retapamulin to investigate its activity on a range of tissues and organ systems both in vitro and in vivo. Screening studies against a broad range of enzymes, receptors and ion channels indicates that retapamulin had minimal activity at most common drug target sites. The only exception is that retapamulin did inhibit radioligand binding at the muscarinic M1 receptor with an IC50 (50% inhibitory constant) of 131 nM (67.8 ng/mL), however, this concentration is well above the plasma concentration achieved with topical application in the clinical studies.
3.2.2 Pharmacokinetics
Absorption
The pharmacokinetics of retapamulin following topical application was investigated in non-clinical species. Generally, the plasma levels of the study drug were either not quantifiable or very low. In a 14-day dermal irritation study in rabbits, plasma concentrations of retapamulin were frequently below the level of quantification with intact skin sites. When retapamulin was applied to abraded skin, the systemic exposure was generally increased with increasing dose. With repeated topical application, the concentration maximum (Cmax) and the area under the curve (AUC) were higher on Day-14 as compared to Day-1, which was in contrast to the results of oral administration. It is possible that systemic levels achieved following topical application may be too low to stimulate the liver microsomal enzymes. In neonatal rats, following topical application to intact skin sites, retapamulin was not detected on post-natal Day-13 and only sporadically detected on post-natal Day-51.
Metabolism
The metabolism of retapamulin was investigated in vivo following a single oral administration of [14C] retapamulin at 50 mg/kg to rats (male and female) and monkeys (male and female). The principal radiolabelled components in rat plasma were retapamulin and mono-oxygenation products of retapamulin. The majority of radiolabelled components in rat bile and feces were numerous mono-oxygenation products. In monkeys, the parent compound was present in plasma at relatively low concentrations. The principal circulating components consisted primarily of mono-oxygenation products, glucuronides of mono-oxygenation products and glucuronides of mono-oxygenated and demethylated products. The principal radiolabelled components in urine and feces were mono-oxygenation products. Retapamulin was extensively metabolized in both species.
The hepatocytes of multiple species had been investigated for the metabolism of retapamulin in vitro studies. The results indicated that retapamulin is metabolized extensively. In preliminary in vitro studies, retapamulin disappeared very rapidly in incubations with monkey or human liver microsomes in the presence of NADPH, and was undetectable at 5 minutes. The main routes of metabolism observed in human hepatocytes were mono-oxygenation and di-oxygenation of the parent drug. Mono- and di-oxygenation in combination with N-demethylation were also observed. The routes of metabolism in the rat, mouse, female rabbit, dog, and monkey hepatocytes were generally qualitatively similar to those observed in human hepatocytes. Each primary human metabolite of retapamulin was detected in the hepatocyte incubations of at least one of the non-clinical species used in the toxicology. Studies conducted to examine the involvement of various human cytochromes P450 isoenzymes in the metabolism of [14C] retapamulin indicates that oxidative metabolism is primarily mediated by CYP3A4 with minor contributions from CYP2C8 and CYP2D6.
Distribution
The tissue distribution of retapamulin had been determined by using quantitative whole body autoradiography in male pigmented Long Evans rats. Drug-related material was rapidly and widely distributed into peripheral tissues with the highest concentration observed in most tissues at the earliest sampling time of 0.5 hours post-dose.
Concentrations of radioactivity in the central nervous system, except meninges, were very low and were not quantifiable beyond 0.5 hours post-dose. This suggested that passage of retapamulin across the blood brain barrier is limited. In general, the radioactivity concentrations in most tissues declined with time, but at 7 days post-dose, notable tissue concentrations were observed in the uveal tract of the eye, skin, and pituitary gland. The drug-related material associated with the melanin-containing tissues declined slowly with time; however, appreciable concentrations were still present at 35 days post-dose in the uveal tract of the eye and in sporadically localized areas of skin.
Excretion
In rats and monkeys, the elimination of drug-related material was rapid with the majority of the recovered radioactivity excreted within 48 hours. The average total recovery of administered dose was >92% for both rat and monkeys. The amount of radioactivity remaining in the carcasses at termination of the collection period (72 or 96 hours) was very low and indicates the lack of significant retention of radioactivity in the body. Excretion of retapamulin-related material was predominantly by secretion in the bile. Biliary secretion accounted for approximately 70% of the administered dose in the bile duct-cannulated rats. In both male and female rats the predominant route of excretion was the faces.
Elimination of [14C] retapamulin was found to occur primarily via metabolism. In rats, unchanged parent compound accounted for less than 1% of the dose in urine and was not detected in feces or bile. In monkeys, unchanged parent compound was not detected in the urine and accounted for less than 3% of the dose in feces.
Drug Interaction
Retapamulin was found to be a substrate of human P-glycoprotein over expressed in confluent monolayers of Madin-Darby canine kidney type II cells. Retapamulin also inhibited P-glycoprotein-mediated transport of digoxin in these cells with an IC50 of 28.2 ± 8.5 μM. The drug submission is for the topical administration of retapamulin. The systemic concentration of retapamulin detected in plasma following dermal application is very low. Therefore, the risk of P-glycoprotein-mediated drug-drug interactions with retapamulin in humans is considered to be very low.
In human liver microsomes, retapamulin is an inhibitor of CYP3A4 when midazolam, nifedipine and atrovastatin were used as substrates. Given the very low plasma concentrations of retapamulin observed following dermal application to humans, the risk for clinically significant P450-mediated drug interactions due to inhibition of CYP3A4 is low.
3.2.3 Toxicology
A comprehensive toxicological evaluation was performed to support the clinical use of Altargo™ for treatment of impetigo, and secondarily infected traumatic lesions. Most studies were performed using the free base of retapamulin which is the form proposed for human use. The oral route of administration was used to provide higher systemic exposure than that obtained with topical applications in order to evaluate potential target organ toxicities. The monkey was chosen as the non-rodent species due to similarities in metabolite profile and intrinsic clearance exhibited between monkey and human in vitro microsomal preparations.
Single Dose Toxicology
In rats, single oral doses of retapamulin up to 450 mg/kg and single bolus intravenous doses up to 10 mg/kg were well-tolerated, whereas mortality occurred at 30 mg/kg intravenously. In monkeys, single-dose oral administration of retapamulin was well-tolerated up to 150 mg/kg with emesis occurring at 450 mg/kg.
Repeat Dose Toxicology
In rats, repeated oral administration of retapamulin (up to 450 mg/kg/day) for 14 days was associated with increased liver weight, hepatocellular hypertrophy/vacuolation, decreased serum total thyroxine (T4) and/or total triiodothyronine (T3), increased serum thyroid stimulating hormone (TSH), thyroid follicular cell hypertrophy, and localized hair loss. Increased levels of TSH were observed in male rats even at the lowest oral dose of retapamulin (50 mg/kg). Emesis was the principal finding in monkeys (oral; ≥50 mg/kg; 14 days).
The clinical observation of localized hair loss with oral administration of retapamulin was not associated with microscopic evidence of anagen phase arrest, apoptosis or necrosis of follicular epithelial cells as seen with antineoplastic agents, indicating that retapamulin was not affecting dividing cells of the germinal matrix epithelium. Hair loss could be associated with thyroid hormone deprivation (hypothyroidism) secondary to increased metabolism and clearance of T3 and T4.
Genotoxicity
The Ames agar plate assay was unsuitable for genotoxicity studies as it was not possible to test sufficiently high concentrations of retapamulin, due to its antibacterial effect. Retapamulin showed no genotoxic activity in the presence and absence of a mammalian oxidative metabolism system, at concentrations up to 130 and 80 ug/mL in the mouse lymphoma cell assay. One of the manufacturing impurities present with retapamulin was found not mutagenic in bacterial mutation assay but the study was conducted only in the absence of mammalian oxidative metabolism system.
Mutagenicity
The potential of retapamulin to induce structural and numerical chromosome damage in vitro was assessed in cultured human lymphocytes. Retapamulin did not induce structural chromosome damage at any of the concentration studied. Numerical aberration, however, was observed at higher concentrations of retapamulin, thus indicating that there was a tendency to increase the number of polyploidy cells. Scientific review of literature indicates that polyploidy in vitro is induced by many types of insult and does not necessarily reflect a potential for aneuploidy.
In the intravenous micronucleus assay, retapamulin did not cause structural chromosome damage or numerical aberration. In previous studies, it has been concluded that when the results of the test indicate a negative micronucleus assay, there is no further need to test for aneuploidy-inducing potential. Based on the validity of the micronucleus assay, retapamulin did not induce mutagenicity.
Carcinogenicity
Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.
Reproductive and Developmental Toxicity
Reproductive and developmental toxicity studies were performed in rats and rabbits. Retapamulin produced developmental toxicity (decreased fetal body weight and delayed skeletal ossification) in rats (oral; 150 mg/kg/day) and maternal toxicity in rabbits (intravenous; ≥7.2 mg/kg/day), but there was no evidence of teratogenic effects. The increased incidence of incompletely ossified skull bones in rats may reflect a combination of effects including maternal hypothyroidism, reduced maternal food consumption, and decreased fetal body weight. Retapamulin had no effects on male or female fertility in rats. The no observed adverse effect level for reproductive and developmental toxicity was 50 mg/kg/day in rats and 7.2 mg/kg/day in rabbits. There were no adverse effects on reproductive performance in male or female rats or in the offspring of male rats at doses up to 450 mg/kg/day.
Repeated daily topical application of 0.5 and 1% retapamulin ointment to intact skin of neonatal male and female rats, beginning on post-natal day 9 for 43 days under semi-occluded conditions, was associated with minimal erythema and/or scabbing in both treatment groups. Systemic exposure to retapamulin was low, with quantifiable levels of retapamulin at either dosage level achieved on post-natal day 51. There was no evidence of systemic toxicity. The no observed adverse effect level for developmental toxicity was 1%.
Local Tolerance
In rabbits, a single dose of 1% w/v retapamulin given subcutaneously was associated with mild to moderate irritation (dermal edema and/or necrosis of cutaneous muscle) and given intramuscularly was associated with skeletal muscle necrosis. Retapamulin was not allergenic in mice and was only a weak skin sensitizer in guinea pigs.
In rabbits, repeated topical applications of retapamulin were associated with a concentration-dependent irritant potential on intact and abraded skin. The severity was more on abraded skin. Topical application of 0.5% retapamulin ointment to intact and abraded skin for 14 days induced erythema and edema; however, microscopic dermal changes were not present. After application of 2.0 and 5.0% retapamulin ointments for 14 days, acanthosis, hyperkeratosis, inflammation, ulceration and dermal fibrosis was present microscopically at most sites.
3.2.4 Conclusion
The safety pharmacology, pharmacokinetics, and toxicological effects of retapamulin have been well-characterized in animal studies. The non-clinical studies provide an adequate assurance of safety for short-term topical administration of retapamulin in humans.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Altargo™ (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.
Skin Irritations
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%.
QTc Interval
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.
3.3.2 Microbiology
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.
3.3.3 Pharmacokinetics
Absorption
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.
Distribution
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.
Metabolism
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.
Drug Interaction
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.
Elimination
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.
Special Populations
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.
3.3.4 Clinical Efficacy
Four pivotal Phase III studies were submitted to support the use of retapamulin ointment, 1% (Altargo™) 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 Altargo™ 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 Altargo™ 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 Altargo™ointment topically twice daily for five days.
Impetigo
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 Altargo™ (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. Altargo™ 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 Altargo™, 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 Altargo™ 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 Altargo™ (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. Altargo™ 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. Altargo™ 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.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Altargo™ (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. Altargo™ 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 microbial resistance concerns. The efficacy of Altargo™ is neither dependent on nor compromised by dressing-type.
The frequency of adverse events was low with Altargo™. Drug-related site reactions were non-serious and resolved with removal or discontinuation of ointment. Altargo™ should not be ingested or used in eyes or on mucosal surfaces. Altargo™ contains a preservative, butylated hydroxytoluene, which may cause a local skin reaction or irritation to the eyes and mucosal membranes.
Altargo™ is considered to be effective and was well tolerated. The benefit and risk profile for Altargo™is considered positive.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Altargo™ 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). The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: AltargoTM
| Submission Milestone | Date |
|---|---|
| Submission filed | 2007-02-09 |
| Screening | |
| Screening Deficiency Notice issued | 2007-04-05 |
| Response filed | 2007-05-09 |
| Screening Acceptance Letter issued | 2007-05-28 |
| Review | |
| Quality Evaluation complete | 2008-03-17 |
| Clinical Evaluation complete | 2008-03-17 |
| Labelling Review complete | 2008-03-18 |
| NOC issued by Director General | 2008-03-19 |