Summary Basis of Decision for Uloric ™
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:
UloricTM
Febuxostat, 80 mg, Tablet, Oral
Takeda Canada Inc.
Submission control no: 129969
Date issued: 2010-12-21
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):
- 02357380
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number:129969
Date of Submission:
Date of authorization:
ULORIC is a trademark of Teijin Pharma Limited and used under license by Takeda Canada, Inc.
2 Notice of decision
On September 22, 2010, Health Canada issued a Notice of Compliance to Takeda Canada Inc. for the drug product, Uloric.
Uloric contains the medicinal ingredient febuxostat which is a non-purine selective inhibitor of xanthine oxidase. Xanthine oxidase is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid.
Uloric is indicated to lower serum uric acid levels in patients with gout. Uloric achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting xanthine oxidase.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy of Uloric was demonstrated in three randomized, double-blind, controlled studies in patients with hyperuricaemia and gout. Hyperuricaemia was defined as a baseline serum uric acid level of ≥8 mg/dL. Two studies were 6 months in duration, and the other study was 1 year in duration. In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In the first 6 month study and in the 1 year study, the duration of prophylaxis was 8 weeks. In the second 6 month study, prophylaxis was given for the duration of the study. In all three studies, Uloric 80 mg daily was superior to the active control, allopurinol (300 mg daily), in lowering serum uric acid levels to <6 mg/dL at the final visit.
Uloric (80 mg febuxostat) is presented in tablet form. The recommended oral dose of Uloric is 80 mg once daily. Dosing guidelines are available in the Product Monograph.
Uloric is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline; and for patients with a history of hypersensitivity to febuxostat or to any other ingredient in the formulation. Uloric 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 Uloric are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Uloric is favourable to lower serum uric acid levels in patients with gout.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Febuxostat, the medicinal ingredient of Uloric, is a non-purine selective xanthine oxidase inhibitor indicated to lower serum uric acid (sUA) levels in patients with gout. The treatment of hyperuricaemia in patients with gout is aimed at decreasing the sUA levels to <6 mg/dL. Febuxostat decreases sUA levels by selectively inhibiting xanthine oxidase.
Manufacturing Process and Process Controls
Febuxostat 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 International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of febuxostat has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are satisfactory.
Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of febuxostat.
The specifications are considered acceptable for the drug substance. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the stress, long-term, real-time, and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Uloric immediate-release film-coated tablets are light green to green in colour, teardrop-shaped, debossed with "TAP" on one side and "80" on the other side, and supplied in high-density polyethylene (HDPE) bottles of 30 tablets.
Uloric tablets contain 80 mg of the medicinal ingredient, febuxostat, per tablet. Inactive ingredients include lactose monohydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium croscarmellose, silicon dioxide, and magnesium stearate. Uloric tablets are coated with Opadry II green which contains polyvinyl alcohol, talc, PEG 3000, titanium dioxide, D&C Yellow Number (No.) 10 aluminum lake, FD&C Blue No. 1, and FD&C Blue No. 2.
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 febuxostat with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Uloric is tested to verify that its identity, appearance, content uniformity, assay, and dissolution are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and release limits for individual and total degradation products are within acceptable limits.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product. The validation process is considered complete.
Stability
Based on the real-time, long-term, accelerated, and stress stability data submitted, the proposed 60-month shelf-life at 15-30°C for Uloric in the proposed packaging is considered acceptable when the product is protected from light.
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 facilities and equipment that are involved in the production of Uloric are considered suitable for the activities and products manufactured.
All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
The excipient, lactose monohydrate, is sourced from bovine milk from cattle in the United States of America. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy (BSE)/ transmissible spongiform encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use. The magnesium stearate used in the formulation is of vegetable source.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Uloric 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
In vitro studies indicate that febuxostat inhibits both the oxidized and reduced forms of xanthine oxidase with inhibition constant (Ki) values in the range of 0.6-10 nM. Febuxostat exhibited no effect on other enzymes involved in purine or pyrimidine metabolism, namely guanine deaminase (GD), hypoxanthine guanine phosphoribosyltransferase (HGPRT), orotate phosphoribosyltransferase (OPRT), orotidine monophosphate decarboxylase (OMPDC), and purine nucleoside phosphorylase (PNP). The in vivo hypouricaemic activity of febuxostat was demonstrated in normal and hyperuricaemic mice and rats, and normal chimpanzees.
Safety pharmacology studies demonstrated that there were no relevant febuxostat-mediated effects on the central nervous and respiratory systems in mice that were exposed to 18- and 101-times the maximum therapeutic exposure in humans.
In vitro studies indicate that febuxostat exhibits an agonist effect on human Ether-à-go-go Related Gene (hERG) tail currents, which was most pronounced during depolarization (+10 to +20 mV. The half maximal effective concentration (EC50) values were calculated to be 0.003 μM (initial effect) and 0.07 μM (steady state). A concentration-dependent inhibition of inward sodium and calcium currents was observed and the half maximal inhibitory concentration (IC50) for inward sodium current was 75 μM, and at 500 μM the calcium current inhibition was 37%. Although there are caveats in comparing in vitro with in vivo drug concentrations, inhibition of calcium currents is unlikely in the clinical setting as human maximum plasma concentration (Cmax) values are substantially less than the calculated IC50 of 500 μM (approximately 150 times). With respect to the inhibition of sodium currents, the calculated IC50 is approximately 22-times greater than the human Cmax. The EC50 for hERG channel potentiation is within the range of human Cmax values.
Safety pharmacology studies indicated that treatment of ventricular Purkinje fibres with febuxostat was associated with a decrease in the maximum rate of depolarization, as well as a rate-independent reduction in action potential duration at 60% repolarization and 90% repolarization at 50 and 500 μM. In vivo, febuxostat was administered to dogs at 5 and 50 mg/kg and there were no remarkable alterations in the electrocardiogram for the RR, PR, QRS, QT or QTc intervals.
A murine model of contact hypersensitivity induced by dinitroflurobenzene was employed to investigate the effects of febuxostat on immunological reactions. Although hypersensitivity reactions were not observed in mice treated with febuxostat, it is noted that the predictive value of animal models for drug-induced hypersensitivity remains low.
3.2.2 Pharmacokinetics
Absorption
Following oral administration of radiolabelled febuxostat to mice, rats, or dogs, maximum plasma concentrations of total radioactivity and febuxostat were rapidly achieved, with time to maximum plasma concentration (tmax) occurring 0.25-2 hours and 0.25-0.5 hours post-dose, respectively, in all species. The absolute bioavailability of febuxostat was approximately 78% in rats and 48% in dogs. A comparison between the amount of total radioactivity absorbed and the bioavailability of parent drug indicates that febuxostat has low gut and hepatic extraction ratios in rats and dogs.
Absorption was decreased 36-48% in rats and 55% in dogs when febuxostat was administered with food. This finding was not related to high dietary protein or dietary fat.
Distribution
Febuxostat was distributed to most of the tissues and organs in rats. Tissues with the greatest concentration included the stomach and small intestine, with lesser amounts in the kidneys, liver, adrenal gland, and lung tissue. The lowest concentrations were found in the brain, eyes, muscle, and testes.
Febuxostat was highly bound to plasma proteins in rats. The percentage of protein-bound drug was ≥98.8%.
Febuxostat does not bind to melanin.
Placental and lacteal transfer was investigated in rats. Febuxostat does not readily cross the placenta (<0.0085% of the administered dose) but is expressed in maternal milk at concentrations similar to or greater than those observed in maternal plasma.
Metabolism
Febuxostat is metabolized by both oxidative and glucuronidation pathways. The metabolic profiles in plasma and urine appeared to be qualitatively similar between mice, rats, and dogs. Febuxostat was the major component found in the plasma of all species studied, and small amounts of several metabolites were also detected in all species studied.
Daily oral administration of febuxostat at doses up to 20 mg/kg/day had little effect on the cytochrome P450 (CYP) drug-metabolizing enzyme system in rats.
Excretion
Following intravenous (IV) or oral administration of radiolabelled febuxostat in mice, rats, and dogs, faecal excretion was generally the main route of elimination, accounting for approximately 53-57%, 47-78% and 85-90%, of the radioactive dose, respectively. Urinary recovery was typically less, ranging from 9-48% in the rodent species, and generally <10% in dogs. The pharmacokinetics of febuxostat was not altered substantially when administered to partially nephrectomized rats.
3.2.3 Toxicology
Single-Dose Toxicity
The toxicity associated with an acute dose of febuxostat was low in rats and dogs. The lethal dose was between 300-600 mg/kg in male and female rats. In dogs, doses up to 2000 mg/kg febuxostat were not lethal.
Repeat-Dose Toxicity
The chronic toxicity profile of febuxostat was evaluated in a series of oral toxicology studies up to 26-weeks duration in rats at doses of 3, 12, and 48 mg/kg/day, and up to 52-weeks duration in dogs at doses of 5, 15, and 45 mg/kg/day. The target organs of toxicity were considered to be the kidney, urinary bladder, and thyroid gland.
Rats and dogs dosed at 48 and 45 mg/kg/day, respectively, exhibited numerous histopathologic alterations in the kidney and urinary bladder that were considered secondary to mechanical irritation caused by deposition of xanthine crystals/calculi in the urinary tract. In dogs, less severe histological alterations were also noted in the kidney at 15 mg/kg/day (4-times the human plasma exposure at 80 mg/day). These findings are unexpected in humans due to differences in physiology.
Increased thyroid weight was observed in rats only at 48 mg/kg/day. In a 13-week repeat-dose rat toxicity study, thyroid hyperplasia was also noted at 75 and 150 mg/kg/day, and was considered secondary to the anti-thyroid hormone action of febuxostat, specifically, the result of a decrease in serum tri-iodothyronine (T3) and thyroxine (T4), thereby stimulating the thyroid tissue to produce additional thyroid hormone leading to follicular hyperplasia. This finding may be relevant to humans in cases where thyroid hormone levels are chronically depressed.
The no-observed-adverse-effect-level (NOAEL) for the 26-week rat study was 12 mg/kg/day (8-times the human plasma exposure at 80 mg/day).
The NOAEL for the 52-week dog study was 5 mg/kg/day (0.5-times the human plasma exposure at 80 mg/day).
Genotoxicity
Febuxostat demonstrated a positive mutagenic response in the in vitro chromosomal aberration test in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. However, febuxostat is not considered genotoxic (mutagenic or clastogenic) as a negative response was observed in the in vitro Ames bacterial reverse mutation assay, the in vitro L5178Y mouse lymphoma thymidine kinase forward mutation assay, the in vitro chromosome aberration test using human peripheral blood lymphocytes, the unscheduled rat hepatocyte deoxyribonucleic acid (DNA) synthesis assay, the in vivo mouse micronucleus test, and the in vivo chromosome aberration test using rat bone marrow cells.
Carcinogenicity
The results of the two-year carcingogenicity studies conducted in mice and rats suggest that febuxostat does not pose a carcinogenic risk to humans.
Reproductive and Developmental Toxicity
In female rats, febuxostat was not associated with impaired fertility or alterations in early embryonic development. The NOAEL for mating and fertility was 48 mg/kg/day febuxostat, approximately 31-times the human plasma exposure at 80 mg/day.
In pregnant female rats and rabbits, febuxostat was not associated with developmental effects in first filial generation (F1) foetuses. Febuxostat was not considered teratogenic in rats or rabbits at doses of up to 48 mg/kg/day (31-times and 40-times the human plasma exposure at 80 mg/day, respectively).
Pregnant female rats dosed with febuxostat throughout organogenesis and during lactation exhibited a reduced number of live offspring on post-natal Day 4 and Day 21. Dead neonates exhibited a high incidence of kidney and urinary bladder findings consistent with the presence of xanthine crystals. Decreased F1 body weight was also observed in neonates born to mothers dosed at 48 mg/kg/day, from birth until weaning, which was associated with pre-weaning developmental delays. The NOAEL for F1 males and females was 12 mg/kg (9-times the human plasma exposure at 80 mg/day). Transfer of febuxostat from mother to neonates was considered to occur via maternal milk.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered acceptable. The non-clinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology studies have characterized the non-clinical profile of febuxostat in sufficient detail to support the intended use of Uloric for the clinical indication. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In healthy subjects, oral administration of febuxostat (10 mg to 240 mg once daily [QD]) resulted in decreased uric acid concentrations and increased xanthine concentrations in both serum and urine. In addition, there was a decrease in the total daily urinary uric acid excretion and an increase in total daily urinary xanthine excretion. Following multiple dosing with febuxostat, there appeared to be a linear dose-response relationship for the percent change in 24-hour mean sUA concentrations for the 10-120 mg QD dosage range, and for the 24-hour mean serum xanthine concentrations for the 10-90 mg QD dosage range.
3.3.2 Pharmacokinetics
Absorption
In healthy subjects, febuxostat was rapidly absorbed following oral administration of 10 mg to 240 mg QD. The pharmacokinetics of febuxostat was not time-dependent or dose-dependent and remained linear between the 10 mg QD to 120 mg QD dosage range. For doses >120 mg, a greater than dose-proportional increase in drug exposure [area under the curve (AUC)] was observed. Maximum plasma concentrations occurred between 1-1.5 hours after the administered dose.
An indirect response pharmacokinetic and pharmacodynamic model was used to describe population pharmacokinetics and pharmacodynamics in subjects with gout in Phase II and Phase III studies. Data showed that the pharmacokinetics and pharmacodynamics of febuxostat in gout patients appeared to be similar to the pharmacokinetics of febuxostat in healthy subjects.
Distribution
The apparent volume of distribution for febuxostat was low to medium and had an estimated population mean of 57.1 L in the gout population. The plasma protein binding of febuxostat was approximately 99.2%. There was no preferential binding with red blood cells.
Metabolism
Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes and oxidation via cytochrome P450 (CYP) enzymes. A greater portion of the dose was excreted in urine as the conjugate of febuxostat than as its oxidative metabolites and their conjugates, indicating that conjugation was the major metabolic pathway.
Excretion
Febuxostat is excreted in the urine and faeces. Approximately 49% of the dose (unchanged drug and metabolites) was recovered in the urine and approximately 45% of the dose was recovered in the faeces.
Drug Interactions
Uloric is unlikely to inhibit or induce CYP enzymes at clinically relevant concentrations and therefore has low potential to be involved in drug-drug interactions with drugs that are substrates of CYP. However, Uloric is a xanthine oxidase inhibitor and may cause increased plasma concentrations of drugs metabolized by xanthine oxidase when co-administered, potentially leading to toxicity by these other drugs. Use of Uloric is therefore contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline, although drug interaction studies of Uloric with cytotoxic chemotherapy have not been conducted and therefore no data are available regarding the safety of Uloric during cytotoxic chemotherapy.
Colchicine, a liquid antacid containing magnesium hydroxide and aluminum hydroxide, indomethacin, naproxen, and hydrochlorothiazide were all co-administered with Uloric to determine their possible effects on the pharmacokinetics of febuxostat. In addition, the potential effect of Uloric on the pharmacokinetics of indomethacin, desipramine, colchicine, naproxen, and the pharmacokinetics and pharmacodynamics of warfarin were determined. While minor changes in pharmacokinetics were seen in most of these studies, the changes did not reach a level where dosage adjustment would be necessary. In conclusion, Uloric does not have clinically significant interactions with colchicine, indomethacin, naproxen, or hydrochlorothiazide, and clinical studies have indicated that no dose adjustment for colchicine, indomethacin, naproxen, desipramine, or warfarin is expected to be necessary when they are co-administered with Uloric.
Special Populations
Renal Impairment
Exposure to febuxostat and its metabolites appeared to increase with increasing degrees of renal impairment. Long-term safety for this high exposure in patients with severe renal impairment could not be assessed from the provided study. The pharmacokinetics of febuxostat, and the percent decreases in sUA concentration following 7 days of dosing with febuxostat were similar in subjects with normal renal function and those with renal impairment. Febuxostat was well-tolerated in these populations; therefore, dose adjustments for Uloric in patients with mild or moderate renal impairment are not necessary. There were no data from patients with end-stage renal failure (on dialysis).
Hepatic Impairment
Following the administration of daily 80 mg oral doses of febuxostat for 7 days, neither the pharmacokinetics of febuxostat and its metabolites nor the percent decrease in sUA concentrations were substantially affected by mild or moderate degrees of hepatic impairment. Febuxostat was well-tolerated in these populations; therefore, dose adjustment for Uloric in patients with mild or moderate hepatic impairment is not necessary. There were no data from patients with severe hepatic impairment.
3.3.3 Clinical Efficacy
The efficacy and safety of Uloric (febuxostat) were assessed in three Phase III, randomized, double-blind, controlled studies in patients with hyperuricaemia and gout. Hyperuricaemia was defined as a baseline sUA level ≥8mg/dL.
Study 1 randomized patients to receive Uloric 40 mg QD [number (n) = 757), Uloric 80 mg QD (n=756), or allopurinol (n=756). The allopurinol dose was 300 mg QD for patients with estimated creatinine clearance (Clcr) ≥60 mL/min or 200 mg QD for patients with estimated Clcr ≥30 mL/min and ≤59 mL/min. The duration of this study was 6 months.
Study 2 randomized patients to receive placebo (n=134), Uloric 80 mg QD (n=267), Uloric 120 mg QD (n=269), Uloric 240 mg QD (n=134), or allopurinol (n=268). The allopurinol dose was 300 mg QD for patients with a baseline serum creatinine ≤1.5 mg/dL or 100 mg QD for patients with a baseline serum creatinine >1.5 mg/dL and ≤2 mg/dL. The duration of this study was 6 months.
Study 3 randomized patients to receive Uloric 80 mg QD (n=256), Uloric 120 mg QD (n=251), or allopurinol 300 mg QD (n=253). The duration of this study was 1 year.
In all three studies, patients received naproxen 250 mg twice daily or colchicine 0.6 mg once or twice daily for gout flare prophylaxis. In Study 1, the duration of prophylaxis was 6 months. In Studies 2 and 3, the duration of prophylaxis was 8 weeks.
The primary endpoint for Study 1 was the proportion of patients that achieved sUA levels of <6 mg/dL at the final visit (a secondary endpoint for Studies 2 and 3); and the primary endpoint for Studies 2 and 3 was the proportion of patients that achieved sUA levels of <6 mg/dL on the last three visits.
In all three pivotal studies, Uloric 80 mg QD demonstrated superiority to placebo (Study 2) and allopurinol 300/200/100 mg QD (Studies 1, 2, and 3), as determined by the proportion of patients that achieved sUA levels of <6.0 mg/dL both at the final visit and at the last three visits.
The proportion of patients that achieved sUA levels of <6.0 mg/dL at the final visit for patients that were administered Uloric 80 mg QD and allopurinol were respectively: 67% and 42% in Study 1, 72% and 39% in Study 2, and 74% and 36% in Study 3.
The proportion of patients that achieved sUA levels of <6.0 mg/dL on the last three visits for Studies 2 and 3 for patients that were administered Uloric 80 mg QD and allopurinol were respectively: 48% and 22% in Study 2, and 53% and 21% in Study 3.
Other secondary endpoints across the studies were the percent reduction in sUA levels from baseline and the proportion of patients requiring treatment for gout flare. Uloric significantly lowered sUA levels from baseline. This decrease appeared to occur within the first two weeks and to be maintained for the duration of the study. However, across the three pivotal trials, Uloric did not reduce the incidence of gout flares. Moreover, in Study 1, a greater proportion of patients treated with Uloric 80 mg QD required treatment for gout flares than those treated with allopurinol.
In addition to the pivotal studies, there were two extension studies. One was a Phase III randomized, open-label, extension study in which 1086 patients who completed Studies 2 and 3 were treated with Uloric (80 and 120 mg QD) or allopurinol (100 or 300 mg QD) for up to 40 months. In this study, patients were allowed dose and treatment adjustments in order to maintain sUA levels of >3.0 and <6.0 mg/dL. The other study was a Phase II study in which 116 patients with gout were treated with Uloric (40 mg, 80 mg, or 120 mg QD) for up to 5.5 years. Patients who completed a 4-week dose-finding study were eligible to enroll in this study. Patients were initially treated with Uloric 80 mg QD, and were subsequently allowed dose-adjustments to 40 or 120 mg QD in order to maintain sUA levels of >3.0 and <6.0 mg/dL. These studies were primarily used to acquire additional safety information since interpretation of efficacy was compromised by dose and treatment alterations aimed at achieving a predefined target sUA level.
3.3.4 Clinical Safety
The key safety data for Uloric were provided from the three randomized controlled pivotal studies (Studies, 1, 2, and 3), and the two open-label, long-term extension studies. See section 3.3.3 Clinical Efficacy. In the submitted clinical studies, patients received Uloric (febuxostat) in doses ranging from 10 mg to 300 mg. The total exposure to Uloric 80 mg in randomized controlled studies and long-term extension studies was greater than 2300 patient-years (PY). For the Uloric 80 mg QD dose, 1377 patients with gout were treated for ≥6 months, 674 patients were treated for ≥1 year, and 515 patients were treated for ≥2 years. Overall, in the three randomized controlled studies (6-12 months in duration) and two open-label extension studies (3 to 5.5 years in duration), the recommended Uloric dose of 80 mg QD was well-tolerated with a safety profile similar to that of allopurinol.
In the combined Phase III randomized controlled studies, the overall incidences of treatment-emergent adverse events (AEs) were similar between the Uloric 80 mg (62.3%) and allopurinol (66.4%) groups. The most frequently reported treatment-emergent AEs in the Uloric 80 mg QD and allopurinol groups were upper respiratory tract infections (13.2%, and 14.3%, respectively), musculoskeletal and connective tissue signs and symptoms (7.7% and 7.8%, respectively), joint-related signs and symptoms (6.3% and 6.0%, respectively), diarrhoea (7.3% and 7.1%, respectively), and liver function analyses abnormalities (6.4% and 6.0%, respectively). The majority of the treatment-emergent AEs were mild or moderate in severity, and were considered to be not related to the study drug.
Uloric was also well-tolerated in the long-term extension studies in patients with gout for up to 5.5 years. In the long-term extension studies, the incidence of treatment-emergent AEs per 100 PY was 252.5 events for the Uloric 80 mg QD group and 245.6 events for the allopurinol group. The most frequently reported treatment-emergent AEs in the Uloric and allopurinol groups were similar to those reported in the combined Phase III randomized controlled studies.
The most frequently reported adverse drug reactions (ADRs) in the Phase III randomized-controlled studies with Uloric 80 mg were: liver function abnormalities (4.6%), diarrhoea (3.0%), rash (1.6%), nausea (1.3%), and dizziness (1.1%). The most frequently reported ADR in the long-term open-label extension studies with Uloric 80 mg was liver function abnormalities (1.8/100 PY). Adverse drug reactions were generally self-limiting and mild to moderate in severity. The overall incidence of ADRs did not increase during the long-term studies.
The percentage of patients with treatment-emergent serious adverse events (SAEs) in the combined Phase III randomized controlled studies was 3.8% and 4.4% in the Uloric 80 mg QD and allopurinol groups, respectively. In general, the percentage of treatment-emergent specific SAEs was low (≤0.5% of patients in any treatment group). The SAEs experienced in >0.2% of patients in the Uloric 80 mg QD group were ischaemic coronary artery disorders (0.5%) and pain and discomfort (0.3%). The SAEs reported in >0.2% of the patients in the allopurinol group were coronary artery disorders (0.5%), disturbances in consciousness (0.3%), abdominal and gastrointestinal infections (0.3%), and acute cholecystitis and cholelithiasis (0.3%). Similar results were seen in the long-term extension studies.
The most common adverse reaction leading to discontinuation from therapy in the randomized controlled studies was liver function analyses abnormalities in 1.2% of the patients treated with Uloric 80 mg and in 0.9% of the allopurinol-treated patients. Liver function analyses abnormalities were also the most common AEs leading to discontinuation from therapy in long-term studies. The hepatic AEs that resulted in premature discontinuation were generally mild to moderate in severity, and the majority of patients who were followed after discontinuation of treatment had liver function tests which resolved or returned to baseline levels; no permanent hepatic damage was observed.
During the randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal were observed [aspartate aminotransferase (AST) 1% and 2%, and alanine aminotransaminase (ALT) 3% and 2%, in Uloric 80 mg QD and allopurinol-treated patients, respectively]. No dose-effect relationship for these transaminase elevations was noted. Similar results were seen in the long-term extension studies.
Hepatic transaminase elevations with Uloric treatment were mild, self-limiting, and similar to allopurinol. For the Phase III randomized controlled studies and the long-term extensions studies, many of these hepatic transaminase elevations returned to normal while patients continued on treatment.
Uloric was well-tolerated in patients with renal impairment. In the Phase III randomized controlled studies, the most frequent AEs reported in subjects with mild-to-moderate renal impairment (Clcr <90 mL/min were similar to those reported in patients with normal renal function. Additionally, in Study 1, in which 65% of the patients had renal impairment, the AE rates did not change when evaluated in patients with mild-to-moderate renal impairment.
In the randomized controlled and long-term extension studies, cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists' Collaboration (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke). In the Phase III randomized controlled studies, the incidences of adjudicated APTC events per 100 PY of exposure were: placebo 0, Uloric 80 mg 1.09 and allopurinol 0.60. In the long-term extension studies, the incidences of adjudicated APTC events were: Uloric 80 mg 0.97 and allopurinol 0.58. Overall, a non-statistically significant higher rate of APTC events was observed in Uloric-treated patients than in allopurinol-treated patients. No causal relationship with Uloric has been established.
In the combined Phase III randomized controlled studies, the overall percentages of treatment-emergent rash AEs were 6.6% and 7.6% in the Uloric 80 mg QD and allopurinol groups, respectively. The most frequent rash AE was dermatitis and eczema, which was reported in 2.0% and 3.3% of patients in the Uloric 80 mg QD and allopurinol groups, respectively. Rashes, eruptions and exanthems were experienced by 2.0% and 1.3% of the patients in the Uloric 80 mg QD and allopurinol groups, respectively. Similar results were seen in the long-term extension studies.
In the Phase III randomized controlled studies and long-term extension studies, no event of Stevens-Johnson-Syndrome was observed in the Uloric-treated population and the majority of dermatologic events were mild to moderate in severity and were non-serious. There have been some post-marketing reports of serious skin reactions (erythema, generalized rash) and hypersensitivity to Uloric therapy. Many, but not all of the patients who reported these events had previously reported hypersensitivity to allopurinol.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Uloric (febuxostat) 80 mg was well-tolerated in the clinical studies in patients with hyperuricaemia and gout. The clinical efficacy studies demonstrated that Uloric 80 mg was superior to allopurinol (at the dose most often used in clinical practice) in its ability to lower sUA levels to <6.0 mg/dL. Uloric 80 mg showed superior efficacy compared to allopurinol in lowering sUA levels in patients with baseline tophi or sUA levels ≥10.0 mg/dL, and in patients with mild-to-moderate renal impairment. The analyses of safety data from the randomized-controlled studies and long-term extension studies demonstrated that, overall, the recommended Uloric 80 mg QD dose is well-tolerated and has a safety profile similar to that of allopurinol. The benefit/risk assessment supports the use of Uloric 80 mg QD to lower sUA levels in patients with gout.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Uloric is favourable to lower serum uric acid levels in patients with gout. 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: UloricTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-05-21 |
| Screening | |
| Screening Deficiency Notice issued: | 2009-10-06 |
| Response filed: | 2009-10-14 |
| Screening Acceptance Letter issued: | 2009-11-26 |
| Review | |
| Quality Evaluation complete: | 2010-09-20 |
| Clinical Evaluation complete: | 2010-09-21 |
| Biostatistics Evaluation complete: | 2010-07-30 |
| Labelling Review complete: | 2010-09-15 |
| Notice of Compliance issued by Director General | 2010-09-22 |