Summary Basis of Decision for Dexilant ™
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:
DexilantTM
Dexlansoprazole, 30 mg and 60 mg, Capsules (delayed release), Oral
Takeda Canada Inc.
Submission control no: 129674
Date issued: 2010-11-29
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):
- 02354950 -30 mg
- 02354969 -60 mg
Therapeutic Classification:
Non-medicinal ingredients:
Capsule shell: carrageenan, hypromellose, and potassium chloride.
Capsule shell color: blue contains FD&C Blue Number 2 aluminum lake; gray contains black ferric oxide; and both contain titanium dioxide.
Submission type and control no:
Control Number: 129674
Date of Submission:
Date of authorization:
2 Notice of decision
On July 22, 2010, Health Canada issued a Notice of Compliance to Takeda Canada, Inc. for the drug product Dexilant.
Dexilant contains the medicinal ingredient dexlansoprazole which is a proton pump inhibitor that decreases gastric acid by inhibiting the action of the hydrogen/potassium adenosine triphosphatase enzyme (H+/K+ - ATPase), commonly known as the gastric proton pump of the gastric parietal cell. By acting specifically on the proton pump within the parietal cell, Dexilant inhibits the final step of gastric acid production.
Dexilant is indicated for the following in adults 18 years of age and older:
Healing of Erosive Esophagitis - Dexilant is indicated for:
- Healing of all grades of erosive esophagitis for up to 8 weeks.
Maintenance of Healed Erosive Esophagitis - Dexilant is indicated for:
- Maintaining healing of erosive esophagitis for up to 6 months.
Symptomatic Non-Erosive Gastroesophageal Reflux Disease (GERD) - Dexilant is indicated for:
- Treatment of heartburn associated with symptomatic non-erosive GERD for 4 weeks.
The market authorization was based on quality, non-clinical, and clinical information submitted. Two Phase III clinical trials were submitted for each of the three indications, for a total of six Phase III trials, in addition to a long-term safety clinical trial.
Healing of Erosive Esophagitis
Two eight-week studies were conducted in patients with endoscopically confirmed erosive esophagitis. The Severity of disease was classified for each patient based on the Los Angeles Classification Grading System (Grades A-D). A total of 4092 patients were randomized to one of the following three treatment arms: Dexilant 60 mg daily, Dexilant 90 mg daily, or lansoprazole 30 mg daily. Within both studies, treatment results at 8 weeks showed Dexilant 60 mg was non-inferior to lansoprazole 30 mg. Dexilant 90 mg showed no additional clinical benefit over Dexilant 60 mg.
Maintenance for Healed Erosive Esophagitis
A six-month study was conducted in patients who successfully completed an erosive esophagitis study and showed endoscopically confirmed healed erosive esophagitis. A total of 445 patients were enrolled and randomized to one of the following three treatment arms: Dexilant 30 mg daily, Dexilant 60 mg daily, or placebo. The maintenance of healing and symptom relief over a six-month period was evaluated. Results showed that Dexilant 30 mg and 60 mg achieved statistically significantly greater percentages in the maintenance of healed erosive esophagitis compared to placebo.
In a second study of 451 patients, Dexilant 60 mg and 90 mg versus placebo were evaluated. Results from this second study indicated Dexilant 60 mg showed similar results to the first study in the maintenance of healed erosive esophagitis. However, Dexilant 90 mg showed no additional clinical benefit over Dexilant 60 mg.
Symptomatic GERD
A four-week study was conducted in patients diagnosed with symptomatic GERD based primarily on presentation of symptoms. These patients had a history of heartburn over six months or longer and had heartburn on at least 4 of 7 days prior to randomization with no esophageal erosions as confirmed by endoscopy. A total of 947 patients were enrolled and randomized to one of the following three treatment arms: Dexilant 30 mg daily, Dexilant 60 mg daily, or placebo. Results showed Dexilant 30 mg provided a statistically significantly greater percentage of days with heartburn relief compared to the placebo, as assessed by a daily diary over four weeks. Dexilant 60 mg showed no additional clinical benefit over Dexilant 30 mg.
Dexilant is presented in two dosage strengths, 30 mg and 60 mg, per capsule. The recommended dose of Dexilant for treatment of erosive esophagitis is 60 mg once daily. The recommended dose of Dexilant for maintenance treatment for healed erosive esophagitis is 30 mg once daily (or your doctor may prescribe a 60 mg dose depending on your condition). The recommended dose of Dexilant for treatment of heartburn related non-erosive GERD is 30 mg once daily. Further dosing guidelines are available in the Product Monograph.
Dexilant is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Dexilant should not be concomitantly administered with atazanavir. Dexilant may also interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability [for example (e.g.) ampicillin esters, digoxin, iron salts, and ketoconazole]. Patients taking Dexilant and warfarin concomitantly may potentially see in increase in the international normalized ratio (INR) and prothrombin time; a need to monitor for possible increases is recommended. For patients taking Dexilant along with theophylline, although studies did not show any changes in the pharmacokinetics or pharmacodynamics of theophylline, patients should have their theophylline level monitored while taking the two drugs concomitantly.
Dexilant 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 Dexilant 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 Dexilant 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
Dexlansoprazole, the medicinal ingredient of Dexilant, is a proton pump inhibitor. Dexlansoprazole is the R-enantiomer of the racemic mixture lansoprazole (Prevacid®) which has been marketed in Canada for over 15 years. Following the oral administration of lansoprazole, dexlansoprazole is the major circulating isomer of lansoprazole. Dexlansoprazole acts on the hydrogen potassium (H+/K+) adenosine triphosphatase (ATPase) pump in the gastric parietal cell to decrease the acidity of the stomach.
Manufacturing Process and Process Controls
Dexlansoprazole 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 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
Detailed characterization studies were performed to provide assurance that dexlansoprazole consistently exhibits the desired characteristic structure and biological activity.
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, or toxicological studies, and therefore are considered acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of dexlansoprazole are considered acceptable.
Validation reports are considered satisfactory for all analytical procedures used for release testing of 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
Based on the long-term, real-time, accelerated, and stress stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
Dexilant contains dexlansoprazole as a mixture of two types of enteric-coated granules each with different pH-dependent dissolution profiles. One type of granule is designed to release dexlansoprazole in the proximal small intestine; the second type is designed to release dexlansoprazole in the distal region of the small intestine, generally several hours later.
Dexilant is available in two dosage strengths: 30 mg and 60 mg per capsule. Each 30 mg capsule is opaque, blue and gray, with TAP and "30" imprinted on the capsule. Each 60 mg capsule is opaque, blue, with TAP and "60" imprinted on the capsule.
Each capsule contains enteric-coated granules consisting of dexlansoprazole and the following non-medicinal ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose 2910, low-substituted hydroxypropyl cellulose, magnesium carbonate, methacrylic acid copolymer, polyethylene glycol 8000, polysorbate 80, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate.
The components of the capsule shell include the following non-medicinal ingredients: carrageenan, hypromellose, and potassium chloride. Based on the capsule shell color, blue contains FD&C Blue No. 2 aluminum lake; gray contains black ferric oxide; and both colours contain titanium dioxide.
Dexilant is provided in high-density polyethylene (HDPE) bottles in 90-count configurations.
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 dexlansoprazole 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
Dexilant is tested to verify that its identity, appearance, content uniformity, assay, loss on drying, dissolution, and levels of degradation products and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable. The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life of 36-months is considered acceptable when Dexilant is packaged in an HDPE bottle with a silica gel desiccant and a polypropylene closure, and is stored at 15-30°C.
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 Dexilant are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Dexilant 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
Lansoprazole (Prevacid®), a proton pump inhibitor presently marketed in Canada, has a chiral center at the sulfinyl group, resulting in 2 enantiomers; R-lansoprazole, known as dexlansoprazole, and S-lansoprazole. The New Drug Submission (NDS) for Dexilant is for the modified-release formulation of dexlansoprazole.
During the development of lansoprazole (which received market authorization in Canada in 1995), the non-clinical general pharmacology program included safety studies on the central nervous system (CNS), the gastrointestinal system, the cardiovascular system, respiratory rate, and renal function. As dexlansoprazole is the predominant (up to 85%) enantiomeric form of lansoprazole in plasma during lansoprazole administration, the safety studies conducted with lansoprazole (reviewed by Health Canada in the past) are considered adequate for this drug submission.
The pharmacological activities of dexlansoprazole were assessed by in vivo primary pharmacodynamic (PD) studies. In rats and dogs, the effects of dexlansoprazole on basal and stimulated gastric acid secretion were compared with those of lansoprazole and
S-lansoprazole. In both species, a dose-dependent inhibition of basal and stimulated gastric acid secretion was observed with dexlansoprazole, and dexlansoprazole was shown to be more potent than lansoprazole and S-lansoprazole. A study in rats also demonstrated that dexlansoprazole was more potent than lansoprazole and S-lansoprazole in the inhibition of induced lesion formation in the alimentary tract.
A non-clinical study in dogs compared the antisecretory effects of dexlansoprazole modified release (MR) with delayed-release lansoprazole and enteric-coated esomeprazole. The results indicate that the duration of the antisecretory effect of dexlansoprazole MR was similar to that for esomeprazole, but more prolonged than that of delayed-release lansoprazole.
The drug submission included an in vitro study which examined the effects of dexlansoprazole on the action potential parameters in isolated canine cardiac Purkinje fibres. Dexlansoprazole at the highest concentration tested (100 µM), prolonged the QRS duration and shortened the QT interval in the electrocardiogram (ECG); however, at a clinically relevant dose, the observed effect in the in vitro study is not a concern.
3.2.2 Pharmacokinetics
Absorption
Following oral administration of dexlansoprazole MR to rats and dogs, the absorption of dexlansoprazole appeared to be delayed compared to that obtained following oral administration of dexlansoprazole, with maximum dexlansoprazole plasma concentrations occurring between 1.3 and 2.3 hours for dexlansoprazole MR.
The absolute oral bioavailability of dexlansoprazole MR was determined to be approximately 2.7% in rats and 22% in dogs. Dexlansprazole was absorbed extensively throughout most of the small and large intestines.
Distribution
After oral administration of radiolabelled dexlansoprazole in rats, radioactivity was rapidly and widely distributed with the highest amounts detected in the liver, thyroid, bladder, kidney, blood, and uveal tract.
Dexlansoprazole was shown to be highly bound to plasma proteins.
Metabolism
Dexlansoprazole was extensively metabolized in both rats and dogs, as evidenced by plasma metabolic profiles with up to 22 and 32 metabolites, respectively. The metabolism of dexlansoprazole involved hydroxylation, oxidation, reduction, sulfation, glucuronidation, and glutathione conjugation.
Excretion
Faecal excretion was the main route of elimination in rats and dogs. Approximately 69%-81% and 53%-83% of the administered radioactive dose was recovered in the faeces of rats and dogs, respectively.
3.2.3 Toxicology
Single-Dose and Repeat-Dose Toxicity
Single-dose toxicity studies were not conducted with dexlansoprazole. The main findings in the rat 4-week and 13-week repeat-dose toxicity studies were increased stomach weights, decreased pituitary weights, and decreased thymus weights. There were also changes in faecal material, body weight, and food consumption when dogs were tested in a general toxicity study for 13 weeks. The no-observed-adverse-effect-level (NOAEL) for the dog study was 5 mg/kg.
There was no evidence of cardiovascular toxicity in the studies performed. Dexlansoprazole had no effects on ECGs and platelet counts at doses up to 50 mg/kg/day in the 13-week oral toxicity study in dogs.
The main site of toxicity was the gastrointestinal tract.
Genotoxicity
Dexlansoprazole tested positive for two of the three genotoxicty tests performed; a weak positive Ames test, and an inconclusive (considered conservatively positive) chromosome aberration test in Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.
Other proton pump inhibitors tested positive in chromosome aberration assays using lymphocytes. Lansoprazole, which has been on the market for more than 15 years and contains 50% of dexlansoprazole, was also weakly positive in the Ames test. Lansoprazole was negative however in an in vivo/ in vitro unscheduled deoxyribonucleic acid (DNA) synthesis assay in rat hepatocytes and in a mammalian cell mutagenesis assay. Lansoprazole did induce tumours in the animal model but these tumours were explainable by non-genotoxic mechanisms: gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in rats and mice; testicular interstitial cell adenomas in rats; and hepatic adenomas and tumours in mice. However, no treatment-related tumours occurred in a 26-week carcinogenicity study in mice treated with lanzoprazole.
There is no documented evidence that lansoprazole poses a cancer risk in humans. Gastric biopsy specimens from more than 300 patients that were treated continuously with lansoprazole for 8 weeks to 120 weeks have not shown evidence of ECL effects similar to those seen in rats. Thus, based on the fact that tumours observed in animals are unlikely to have resulted from a genotoxic mode of action, in vivo genotoxicity assays were negative, and there is no evidence of a cancer risk associated with the clinical use of lansoprazole and other proton pump inhibitors, the weakly positive Ames test was not considered predictive of a human health risk.
Carcinogenicity
Carcinogenicitiy studies for dexlansoprazole were based on the carcinogenicity studies performed with lansoprazole. These studies indicate that there was an increase in testicular adenomas and liver tumours above historical controls. Additionally, gastric carcinoid tumours and enterochromaffin hyperplasia developed in the stomach based on the 2-year rodent carcinogenicity studies. There was no evidence of genotoxic carcinogenic effects.
Reproductive and Developmental Toxicity
Pregnant rabbits received oral doses of up to 30 mg/kg/day dexlansoprazole (approximately 9-fold the maximum recommended human dose). The dexlansoprazole NOAEL for general toxicity in the dams was 3 mg/kg/day. For reproductive toxicity, the NOAEL was ≥30 mg/kg/day. For embryo-foetal development, the NOAEL was 10 mg/kg.
The effects of dexlansoprazole at 30 mg/kg/day on dams and embryo-foetal development were similar to that of lansoprazole at 30 mg/kg/day.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered acceptable. The safety pharmacology studies were bridged with those reviewed for lansoprazole. Dexlansoprazole is the major circulating isomer of lansoprazole.
There are no pharmacological/toxicological issues within the submission which preclude the approval of Dexilant for the proposed 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
A PD study showed that a greater increase in intragastic pH was produced by both 30 mg and 60 mg of dexlansoprazole MR, compared to the 15 mg of lansoprazole, after a single dose or after 5 consecutive daily doses.
In a separate PD study, administration of 90 mg or 120 mg of dexlansoprazole MR or 30 mg of lansoprazole increased plasma gastrin concentrations, regardless of compound or dose, compared to baseline values. The increase in plasma gastrin appeared to be greater on Day 5 than on Day 1 during each regimen. After a single dose, the plasma gastrin levels appeared to be comparable for all three regimens. After 5 days of dosing, the plasma gastrin levels for the two dexlansoprazole MR regimens seemed similar, and both of these gastrin levels seemed slightly higher than the level for the lansoprazole regimen. This difference among the gastrin values on Day 5 was minimal compared to the variability observed for the Day 5 results. The fasting plasma gastrin concentrations were also increased by multiple doses of dexlansoprazole MR or lansoprazole; these elevated levels slowly decreased after the last dose of study drug during each regimen and returned to near baseline levels by 7 days after the last dose of study drug.
The effects of dexlansoprazole MR (90 mg and 120 mg) on QT interval were evaluated with a placebo control and an active control in a Phase I study. No significant QT prolongation effects associated with dexlansoprazole MR doses of 90 mg and 300 mg were reported.
3.3.2 Pharmacokinetics
Absorption
Dexilant uses Dual Delayed Release technology. The formulation contains two types of enteric-coated granules having different dissolution profiles (released at two different intervals in the gastrointestinal tract). Therefore, the plasma concentration-time profile has two distinct peaks; the first peak occurs 1-2 hours after administration, followed by a second peak within 4-5 hours.
The systemic exposure on Day 8 was generally similar to that observed on Day 5 indicating that steady-state had been achieved by Day 5. Dose proportionality was observed following the oral administration of 30 mg and 60 mg dexplansoprazole MR.
Following daily oral doses of dexlansoprazole MR 60 mg for 5 days, administered 30 minutes before lunch, dinner or an evening snack, the systemic exposure of dexlansoprazole was bioequivalent to that obtained after the administration of dexlansoprazole MR 30 minutes. The intragastric pH results suggest that there were no clinically relevant differences in the PD of dexlansoprazole MR between lunch, dinner or evening snack and breakfast regimen. Administration of dexlansoprazole MR 60 mg prior to consumption of a meal or snack at various times of day did not have a clinically meaningful effect on 24-hour intragastric pH control. Therefore, Dexilant can be taken without regard to food intake or the timing of food.
Distribution
Dexlansoprazole was highly bound to human plasma proteins (95.6% to 97.4%) and the fraction of unbound dexlansoprazole was similar in male and female subjects as well as in young and elderly subjects.
The apparent volume of distribution after multiple doses in symptomatic GERD patients was 40.3 L.
Metabolism
Dexlansoprazole was metabolized by oxidation, reduction and conjugation to at least 19 metabolites in the plasma, urine, and faeces. In addition to the parent compound, up to 10 metabolites were detected in the plasma.
Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system including hydroxylation mainly by CYP2C19, and oxidation to the sulfone by CYP3A4.
Excretion
Following the oral administration of radiolabelled dexlansoprazole, no unchanged dexlansoprazole was excreted in the urine. At least 16 metabolites were excreted in the urine, and at least 7 metabolites were excreted in the faeces. Ninety-eight percent of the dosed radioactivity was excreted in the excreta after 7 days post-dose and with nearly equal distribution between urine and faeces.
Special Populations
Hepatic Impairment
A hepatic impairment study was conducted in which subjects with normal hepatic function and subjects with moderately impaired hepatic function were administered a single dose of dexlansoprazole MR 60 mg. The maximum plasma concentration (Cmax) in subjects with hepatic impairment was approximately 1.5 times higher than the Cmax of subjects with normal hepatic function. The systemic exposure parameter, area under the curve (AUC), was doubled. As a result, patients with moderate hepatic impairment should not use a dose >30 mg of Dexilant.
Renal Impairment
Dose adjustments of Dexilant are not required for patients with renal impairment because there is limited urinary excretion of dexlansoprazole.
Drug Interaction Studies
Drug interaction studies were conducted with warfarin, phenytoin, theophylline and diazepam. Although none of these studies demonstrated the need for dose modification, it is still advisable to monitor warfarin and theophylline concentrations if either of these drugs is co-administered with Dexilant.
Drugs that are dependent on the pH of the stomach should not be co-administered with Dexilant. Some of these drugs include atazanavir, ampicillin esters, digoxin, iron salts, and ketoconazole.
3.3.3 Clinical Efficacy
Two Phase III clinical studies were submitted for each of the three indications.
The three indications for Dexilant in adults 18 years of age and older are:
- Healing of Erosive Esophagitis - Dexilant is indicated for healing of all grades of erosive esophagitis for up to 8 weeks.
- Maintenance of Healed Erosive Esophagitis - Dexilant is indicated for maintaining healing of erosive esophagitis for up to 6 months.
- Symptomatic Non-Erosive Gastroesophageal Reflux Disease (GERD) - Dexilant is indicated for treatment of heartburn associated with symptomatic non-erosive GERD for 4 weeks.
Healing of Erosive Esophagitis
Two multicentre, double-blind, active-controlled, randomized, 8-week studies (Study 084 and Study 085) were conducted in patients with endoscopically confirmed erosive esophagitis (EE). Patients were randomized to one of the following three treatment groups: Dexilant 60 mg once a day (QD), Dexilant 90 mg QD or the active comparator, lansoprazole 30 mg QD. Both studies were non-inferiority studies. A total of 4092 patients were enrolled. Severity of erosive esophagitis was classified based on the Los Angeles (LA) Classification Grading System (Grades A-D). The primary efficacy endpoint for both studies was the percentage of subjects who had complete healing of EE by Week 8 as assessed by endoscopy. Both studies established non-inferiority for both doses of Dexilant (60 mg QD and 90 mg QD) compared to lansoprazole.
In Study 084, the 60 mg dose of Dexilant and the 90 mg dose of Dexilant were tested for superiority to the comparator arm. Crude healing rates were used for the analysis of the primary efficacy variable and the secondary efficacy variables. Analysis based on life-table methods were considered supportive. Both doses of Dexilant were found to be superior to lansoprazole 30 mg based on crude rates analysis at 8 weeks. These healing rates were 85.3%, 85.8% and 79%, respectively, for Dexilant 60 mg, Dexilant 90 mg and lansoprazole 30 mg. Statistical superiority of Dexilant 60 mg over lansoprazole 30 mg was established. There was no statistical difference between the two Dexilant doses, indicating that the higher dose of Dexilant (90 mg) did not provide a clinical advantage.
In Study 084, for the life-table method of analysis, statistical superiority was not established for Dexilant (60 or 90 mg) compared to lansoprazole 30 mg according to the pre-defined p values for Hochberg analysis. However, the life-table healing rates at Week 8 for patients with moderate to severe erosive esophagitis were 88.9% and 74.5% for Dexilant 60 mg and lansoprazole 30 mg, respectively.
In Study 085, only the higher dose of Dexilant (90 mg) was found to be superior to the lansoprazole 30 mg dose, based on crude rates analysis at 8 weeks. The healing rates were 86.4%, 89.4% and 84.6%, for Dexilant 60 mg, Dexilant 90 mg and lansoproazole 30 mg, respectively. The 60 mg dose of Dexilant was not superior to lansoprazole 30 mg in this second clinical study. For the supportive life-table analysis, neither dose of Dexilant was found to be superior to lansoprazole. Therefore there was no confirmatory study to establish superiority of Dexilant 60 mg to lansoprazole 30 mg that was noted in Study 084.
Additionally for Study 084, based on the primary analysis using crude healing rates, Dexilant 60 mg QD was statistically superior to lansoprazole 30 mg QD (79.7% versus 65%) for the healing of the more severe grades of EE (LA Grades C and D combined). However, it is important to point out that the 90 mg dose of Dexilant did not demonstrate statistical superiority over lansoprazole 30 mg (74.1% versus 65%). In Study 085, neither Dexilant 60 mg nor Dexilant 90 mg had statistically superior rates of treated EE for the more severe grades (LA Grades C and D combined) as compared to lansoprazole 30 mg. Therefore, Dexilant did not demonstrate superiority over the comparator arm for patients with more severe EE at baseline.
Maintenance of Healed Erosive Esophagitis
Two Phase III randomized, double-blind, multicentre placebo-controlled studies (Study 135 and Study 086) provided evidence for the efficacy of Dexilant for the maintenance of healed EE. For both studies, the primary efficacy endpoint was the percentage of patients who maintained healed EE over a 6-month period of treatment as assessed by endoscopy. The number of patients enrolled in Study 135 and Study 086 were 445 and 451, respectively. The treatment arms in Study 35 included Dexilant 30 mg QD, Dexilant 60 mg QD, and placebo. In Study 086, Dexilant 60 mg QD and Dexilant 90 mg QD were compared to placebo.
In Study 135, the crude-rate analysis demonstrated that the percentage of patients who maintained healed EE at Month 6 was statistically greater in the Dexilant 30 mg QD group or the 60 mg QD treatment group (66.4% of each group) compared to the placebo group (14.3%). When supportive life table methods were used which account for the subjects who prematurely discontinued by censoring, the rates were 74.9% and 82.5% for the Dexilant 30 mg and 60 mg treatment groups compared to 27.2% for the placebo group. The percentages in the Dexilant arms were statistically greater than in the placebo arm.
Using the crude-rate analysis and the life-table analysis, Dexilant 30 mg and Dexilant 60 mg also achieved statistically significantly higher 6-month maintenance rates compared to placebo, for patients with more severe grades of EE (Grades C or D) before healing.
Dexilant 30 mg and Dexilant 60 mg achieved statistically significantly greater percentages of heartburn relief during the 6-month treatment period according to the twice-daily diary entries. The median percentages of 24-hour heartburn-free days were 96.1%, 90.9% and 28.6% for Dexilant 30 mg, Dexilant 60 mg, and placebo, respectively. The median percentages of nights without heartburn were 98.9%, 96.2%, and 71.7% for Dexilant 30 mg, Dexilant 60 mg, and placebo, respectively.
In Study 086, Dexilant 60 mg and Dexilant 90 mg achieved statistically greater percentages of patients who maintained healed EE at 6 months compared to placebo, in both the crude-rate analysis and the life-table analysis. This study showed similar results to Study 135 with regard to the maintenance of healed EE and heartburn relief. Dexilant 90 mg showed no additional clinical benefit over Dexilant 60 mg. There were no statistical differences between Dexilant 60 mg and Dexilant 90 mg QD in any clinical efficacy variable.
Symptomatic Non-Erosive GERD
Two Phase III multicentre, double-blind, placebo-controlled, 4-week studies (Study 137 and Study 082) assessed the efficacy of Dexilant on symptom relief in patients with non-erosive GERD. Study 137 and Study 082 enrolled 947 patients and 900 patients, respectively. For both studies, the primary efficacy endpoint for the treatment of symptomatic non-erosive GERD was the percentage of patients after 4 weeks of treatment with no daytime or nighttime heartburn (24-hour heartburn control). In the comparison to placebo, Study 137 used daily doses of 30 mg and 60 mg Dexilant and Study 082 used 60 mg and 90 mg Dexilant.
In Study 137, the percentage of days that patients had neither daytime nor nighttime heartburn during treatment according to the daily electronic diaries was statistically significantly greater in both the Dexilant 30 mg QD and Dexilant 60 mg QD treatment groups than in the placebo treatment group. There was no statistically significant difference between the two Dexilant treatment groups, in the percentage of days that patients had neither daytime nor nighttime heartburn.
In Study 082, after 4 weeks of treatment with either Dexilant (60 mg or 90 mg) or placebo, the percentage of patients with neither daytime nor nighttime heartburn was statistically greater in both the Dexilant 60 mg QD and Dexilant 90 mg QD treatment groups than in the placebo treatment group. There was no statistically significant difference between the two Dexilant groups for this efficacy variable.
In conclusion, the efficacy results provide evidence for the efficacy of Dexilant for the three indications stated above, although any superiority demonstrated over lansoprazole for either dose of Dexilant for the treatment of EE is not supportive or consistent. Non-inferiority with lansoprazole for the first indication (healing of EE) and superiority over placebo for the second and third indications have clearly been established.
3.3.4 Clinical Safety
The safety of Dexilant (30 mg, 60 mg, and 90 mg) was evaluated in 4548 patients in controlled and uncontrolled clinical studies including 863 patients treated for at least 6 months and 282 patients treated for one year.
In the placebo-controlled studies, patients treated with Dexilant (30 mg and 60 mg, number [n] =1399) had a higher incidence of gastrointestinal disorders than those that were treated with placebo, e.g., diarrhoea (3.7% vs. 1.9%), abdominal pain (2.6% vs. 1.6%), nausea (2.2% vs. 1.8%), and flatulence (1.8% vs. 2.2%). In the active-controlled studies, patients treated with Dexilant 60 mg had a higher incidence of diarrhoea (3.2% vs. 2.1%) than those that were treated lansoprazole 30 mg. The incidences of other common adverse reactions for Dexilant were similar to or lower than placebo or lansoprazole. The Product Monograph has a list of the less common adverse drug reactions that were reported with Dexilant.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Dexilant has been shown to inhibit gastric acid production. In the clinical studies submitted, Dexilant was non-inferior to lansoprazole for the treatment of EE; superiority over lansoprazole was not consistent. Dexilant demonstrated superiority over placebo for the maintenance of healed EE and for the treatment of heartburn associated with symptomatic non-erosive GERD. The efficacy of Dexilant was demonstrated for the three indications, with the first indication (treatment of EE) using the higher dose of Dexilant (60 mg) and the two other indications using the lower dose of Dexilant (30 mg).
Dexlansoprazole, the active ingredient of Dexilant, is an isomer of lansoprazole (Prevacid®) which has been on the market for approximately 15 years in Canada. Based on the important post-market experience with lansoprazole and the data provided in this submission, the benefit-risk profile of Dexilant is considered favourable for the three indications stated in the Product Monograph.
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 Dexilant is favourable in adults 18 years of age and older for the healing of all grades of erosive esophagitis for up to 8 weeks, maintaining healing of erosive esophagitis for up to 6 months, and for the treatment of heartburn associated with symptomatic non-erosive GERD for 4 weeks. The NDS 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: DexilantTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2009-06-04 |
| Submission filed: | 2009-08-11 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2009-09-25 |
| Review 1 | |
| Biopharmaceutics Evaluation complete: | 2010-07-19 |
| Quality Evaluation complete: | 2010-07-21 |
| Clinical Evaluation complete: | 2010-07-15 |
| Labelling Review complete: | 2010-07-16 |
| Notice of Compliance issued by Director General: | 2010-07-22 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| DEXILANT | 02354950 | TAKEDA CANADA INC | DEXLANSOPRAZOLE 30 MG |
| DEXILANT | 02354969 | TAKEDA CANADA INC | DEXLANSOPRAZOLE 60 MG |