Summary Basis of Decision for Januvia ™
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:
JanuviaTM
Sitagliptin phosphate monohydrate, 100 mg, Tablet, Oral
Merck Frosst Canada Ltd.
Submission control no: 103039
Date issued: 2008-08-19
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrJANUVIAMD, sitagliptine, 100 mg, Merck Frosst Canada Ltée, No de contrôle de la présentation 103039
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):
- 02303922
Therapeutic Classification:
Non-medicinal ingredients:
Film coating: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
Submission type and control no:
Date of Submission:
Date of authorization:
JANUVIA™ used under license by Merck Frosst Canada Ltd.
2 Notice of decision
On December 14, 2007, Health Canada issued a Notice of Compliance to Merck Frosst Canada Ltd. for the drug product Januvia™.
Januvia™ contains the medicinal ingredient sitagliptin (as sitagliptin phosphate monohydrate) which is a novel oral antihyperglycemic agent.
Januvia™ is indicated, in combination with metformin, for adult patients with Type 2 diabetes mellitus to improve glycemic control when diet and exercise plus metformin do not provide adequate glycemic control. Januvia™ is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme that breaks down incretin hormones. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In Type 2 diabetics, these changes lead to a lower hemoglobin A1c (HbA1c) and lower fasting and post-prandial glucose concentrations.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. The efficacy of Januvia™ in combination therapy with metformin to reduce the primary and secondary endpoints was demonstrated in a 52-week study. Januvia™ demonstrated a statistically and clinically significant reduction in baseline HbA1c and fasting plasma glucose levels at Week 24 and the effect was persistent through the 52 weeks of treatment. Januvia™ treatment was associated with low incidence of hypoglycemia and slight weight loss and had an acceptable safety profile.
Januvia™ (100 mg, sitagliptin) is available as oral tablets. The recommended dose of Januvia™ is 100 mg once daily. Januvia™ can be taken with or without food. Dosing guidelines are available in the Product Monograph.
Januvia™ is contraindicated for patients who are hypersensitive to this drug or to any ingredients in the formulation. Januvia™ 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 Januvia™ 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 Januvia™ is favourable, when used in combination with metformin, for adult patients with Type 2 diabetes mellitus to improve glycemic control when diet and exercise plus metformin do not provide adequate glycemic control.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for Januvia™ (sitagliptin phosphate monohydrate) was filed with Health Canada on January 20, 2006. On March 9, 2007, the NDS was issued a Notice of Non-compliance (NON) based on the lack of clinical data submitted. The sponsor submitted a complete response on June 7, 2007 addressing all of the concerns raised in the NON, including the questions raised by the Quality evaluators. The sponsor provided additional one-year results from four previously submitted studies; results from a new one-year metformin therapy controlled, non-inferiority, active comparator (glipizide) study; as well as several analyses including population pharmacokinetic data, pooled Phase II and Phase III data; and meta-analyses. Based on the review of the provided studies in response to the NON, Health Canada issued a Notice of Compliance to Merck Frosst Canada Ltd for Januvia™ on December 14, 2007.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Sitagliptin (as sitagliptin phosphate monohydrate), the medicinal ingredient of Januvia™, is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme that breaks down incretin hormones. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In type 2 diabetics, these changes lead to lower hemoglobin A1c (HbA1c) levels and lower fasting and post-prandial glucose concentrations.
Manufacturing Process and Process Controls
Sitagliptin phosphate monohydrate is synthetically derived. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of sitagliptin phosphate monohydrate 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 are considered acceptable.
Control of Drug Substance
Copies of the drug substance specifications and analytical methods/validation reports (where applicable) were provided and are considered satisfactory.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period for sitagliptin phosphate monohydrate is supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Januvia™ tablets are beige, round, film-coated tablets with "277" on one side. They are supplied in HDPE bottles of 30 and 100 tablets.
Each film-coated tablet contains 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 100 mg of free base.
Each film-coated tablet contains the following non-medicinal ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following non-medicinal ingredients: polyvinyl alcohol, polyethylene glycol (macrogol), talc, titanium dioxide, red iron oxide, and yellow iron oxide.
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 sitagliptin phosphate monohydrate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Adequate pharmaceutical developmental data were provided which support the formulation and method of manufacturing.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: dry blending, sieving, and lubrication, followed by direct compression and aqueous film-coating.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Januvia™ is tested as per the Professed standard to verify that the appearance, identity, assay, content uniformity, levels of degradation products and disintegration are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the storage condition of 15-30°C in HDPE bottles is considered acceptable.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities 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.
3.1.4 Adventitious Agents Safety Evaluation
The excipients magnesium stearate and sodium stearyl fumarate are of animal origin. A letter of attestation confirming that the material is not from a BSE/TSE-affected country/area has been provided for this product indicating that it is considered to be safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Januvia™ 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 and in vivo pharmacological studies have demonstrated that sitagliptin selectively inhibits the activity of DPP-4 and not DPP-8 or DPP-9 and other related enzymes (selectivity: >2500-fold). Evidence from diabetic animal models treated with sitagliptin demonstrated that the inhibition of DPP-4 increased the presence of incretin hormone glucagon-like peptide-1 (GLP-1) which stimulates the release of insulin from the pancreas. An approximate 2-fold increase in GLP-1 and approximate 70% inhibition of plasma DPP-4 activity was obtained in normal mice when the peak concentration of sitagliptin in the plasma was 190 nM. Increased insulin secretion resulted in normalisation of blood glucose levels in diabetic animals with the maximum efficacy dose of 3 mg/kg sitagliptin which corresponds to a plasma concentration of 400 nM. This study provided the non-clinical proof-of-concept for the activity of sitagliptin in glycemic control.
DPP-4 is known to be identical to CD26, a cell surface marker for activated immune cells. Although no secondary pharmacodynamic effects of sitagliptin were observed that would suggest potential pharmacological liability in humans, close attention should be paid to evaluate any signs of immunosuppressive activity and their consequences, such as increased susceptibility to infection, in clinical trials.
In the safety pharmacological studies, sitagliptin was well tolerated at higher than therapeutic doses and had no effects in tests of renal, respiratory, gastrointestinal and behavioural functions. Overall, the safety pharmacological studies did not provide any evidence that sitagliptin had potential for adverse pharmacological activity.
3.2.2 Pharmacokinetics
Absorption
In rats and dogs, sitagliptin was rapidly absorbed and bioavailability was high after oral administration.
Distribution
Radioactive experiments have shown that sitagliptin distributes widely throughout the body and levels decline within 2-4 hours after administration, with a plasma half-life of approximately two hours. Plasma protein binding of sitagliptin was low in rats and dogs. Sitagliptin crossed the placenta in rats and rabbit and appeared in the milk of lactating rats.
Metabolism
Metabolism of sitagliptin was minimal in rats, mice, dogs, and rabbits. The parent compound was the major drug component in the plasma. Approximately 5-16% of the dose was recovered as metabolites. The metabolites were shown to be much less active as inhibitors of DPP-4 activity.
In vitro, sitagliptin was metabolized to a limited extent in hepatocytes and liver microsomes from rats, mice, dogs, rabbits, monkeys, and humans. No unique human metabolites were identified. The oxidative metabolism of sitagliptin in human liver microsomes was mainly catalyzed by the CYP3A4 isozyme. Sitagliptin did not induce or inhibit P-glycoprotein, or the activity of any of the P450 enzymes, and therefore metabolic drug interactions are not anticipated.
Excretion
Sitagliptin was excreted mainly unchanged in the urine and feces.
3.2.3 Toxicology
General toxicity studies with sitagliptin were conducted in mice, rats, and dogs. These studies consisted of single dosing, and repeat dosing with treatment periods of 2-53 weeks. Specific toxicity studies included in vitro and in vivo genotoxicity tests, carcinogenicity studies in mice and rats, and reproductive studies in rats and rabbits. Additional studies in monkeys to assess the potential of sitagliptin to cause necrotic skin lesions were also conducted. All pivotal studies were carried out according to GLP requirements and followed standard protocols as per ICH guidelines, if applicable.
Single-Dose Toxicity
Sitagliptin had a relatively low acute toxicity with a minimal lethal dose of approximately 2000 mg/kg in rodents.
Repeat-Dose Toxicity
In a 13-week toxicity study with mice, sitagliptin produced mortality and severe toxicity at doses of 750 and 1000 mg/kg/day. The kidney and the liver were identified as the main target organs of toxicity. Kidney damage was characterized as increased kidney weight and pelvic dilatation. In the liver, slight proliferative change in the form of hepatocellular hypertrophy was observed.
In a 14-week toxicity study with rats, doses of 500, 1000, 1500, and 2000 mg/kg/day sitagliptin were administered. The kidney, liver, and heart were the target organs of toxicity. Tubular necrosis, which caused mortality at doses of 1500 and 2000 mg/kg/day was responsible for the renal toxicity. No evidence of treatment-related kidney toxicity was found at the lower doses of 1000 mg/kg/day or 500 mg/kg/day. Signs of myocardial and hepatic degeneration, and hepatic necrosis were only observed at doses >1000 mg/kg/day. At doses of 500 mg/kg/day and 1000 mg/kg/day, the animals were exposed to 12 and 28 times the human exposure, respectively, based on comparison of plasma drug exposure (AUC) values.
No histopathological changes were observed in dogs that received up to 50 mg/kg/day in a 2-week study. However, there was a slight increase in plasma concentration of alanine transaminase (ALT) which is suggestive of liver damage. In the same study, clinical signs suggestive of transient central nervous system (CNS) effects were also observed. Transient CNS clinical effects were also noted in the 50 mg/kg/day dose group of a 14-week study. In the 14- and 27-week toxicity studies at the 50 mg/kg/day dose, slight skeletal muscle degeneration was observed histologically (CPK levels remained normal). However, no skeletal muscle degeneration was observed in dogs treated with the 50 mg/kg dose for 53 weeks indicating that the muscle degenerative process does not manifest itself following long-term treatment. The 50 mg/kg/day dose in dogs resulted in systemic exposure values 26 times the human exposure at the recommended daily adult human dose of 100 mg/day.
In a 14-week oral toxicity study, no evidence of skin lesions or kidney toxicity was observed in monkeys treated with sitagliptin at doses up to 100 mg/kg/day.
Genotoxicity
Sitagliptin was not genotoxic in a battery of in vitro and in vivo tests designed to detect gene mutation, direct DNA damage, and chromosomal aberration.
Carcinogenicity
Sitagliptin is considered to be carcinogenic in rats but not in mice, based on the increased incidence of hepatic tumours, both hepatocellular adenoma and carcinoma. The tumour formation in rats was most likely due to hepatocellular injury at relatively high doses. The margin of safety is 19-fold, based on drug exposure (AUC levels) at the 150 mg/kg/day dose in the rat versus the human AUC at 100 mg/day. Sitagliptin is unlikely to pose any carcinogenic risk in patients treated daily with the 100 mg dose. Nevertheless, the positive carcinogenic findings are reported in the Product Monograph.
Reproductive and Developmental Toxicity
No evidence of reproductive or developmental toxicity was observed in rats and rabbits at relatively high doses. Although sitagliptin had no teratogenic activity in the animals tested, its potential to cause developmental effects in humans cannot be ascertained precisely. Therefore, sitagliptin should not be used in women during pregnancy. Similarly, its use in lactating women should be discouraged as sitagliptin is expected to pass through the mother's milk.
Local Tolerance
No evidence of skin irritation or skin sensitization in mice and rabbits treated with sitagliptin were found.
3.2.5 Conclusion
Sitagliptin selectively inhibited DPP-4 and improved glycemic control with no evidence of pharmacologically-mediated adverse effects in the species studied. Toxicity studies have identified dose-limited organ toxicity with a wide margin of safety for each toxicity endpoint. The potential risk of immunosuppression in patients following long-term exposure to sitagliptin however, has not been ruled out. Overall, the results of the non-clinical studies are supportive for the use of this drug in humans for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The pharmacodynamic effects of sitagliptin on proximal biomarkers (DPP-4 activity and incretin hormone levels: active GLP-1 and GIP) and distal biomarkers (glucose, insulin, C-peptide and glucagon levels) were assessed. Sitagliptin inhibited plasma DPP-4 activity in a dose dependent manner. The plasma DPP-4 inhibition time profiles after single oral doses of sitagliptin were generally similar in elderly male, female, young female and young obese male subjects. The observed means of weighted average inhibition of plasma DPP-4 activity over 12 hours were >80% for each of the groups relative to placebo. The maximum reduction of the glucose level was associated with sitagliptin plasma concentration of 100 nM or higher. This plasma concentration was associated with approximately 80% inhibition of DPP-4 and a 2-fold increase in GLP-1 levels, and was achieved with doses of 100 mg or higher. In patients with type 2 diabetes, single oral doses of sitagliptin reduced post-meal glucose, enhanced insulin/C-peptide levels and decreased glucagon levels. In normoglycemic healthy subjects, sitagliptin had no effects on fasting or post-meal glucose, C-peptide, insulin, or glucagon levels.
3.3.2 Pharmacokinetics
Absorption
After oral administration, sitagliptin was well absorbed with an absolute bioavailability of 87%. Absorption was rapid with peak plasma concentrations occurring 1-4 hours post-dose. The drug exposure (AUC values) increased in a dose proportional manner. Steady-state was reached by three days and accumulation was slight. Food had no effect on the pharmacokinetics, therefore Januvia™ may be administered with or without food. Distribution
The mean volume of distribution at steady-state was approximately 198 litres following a single 100 mg intravenous dose of sitagliptin to healthy subjects. Binding to plasma proteins was low.
Metabolism
Metabolism of sitagliptin was limited. Sitagliptin was primarily excreted as unchanged drug. The formation of metabolites was mediated primarily by the enzyme CYP3A4.
Excretion
Approximately 87% of the oral sitagliptin dose was excreted unchanged in urine. The renal clearance was approximately 350 mL/min. This value exceeds the typical glomerular filtration rate for young healthy males (approximately 125 mL/min), suggesting that sitagliptin is subject to active renal secretion.
Special Populations
Age, Gender, Race, and Obesity
Age, gender, race, and obesity had no clinically meaningful effects on sitagliptin pharmacokinetics. Studies were not performed in pediatric patients.
Renal Impairment
Due to the kidney being the major route of sitagliptin excretion, renal function was the most significant factor impacting sitagliptin pharmacokinetics. Patients with moderate renal insufficiency had an approximately 2-fold higher plasma drug exposure compared to subjects with normal renal function. Patients with severe renal insufficiency and end stage renal disease requiring hemodialysis had an approximately 4-fold higher plasma drug exposure compared to subjects with normal renal function. Use of sitagliptin in patients with moderate or severe renal impairment is not recommended.
Hepatic Impairment
Clinical experience in patients with moderate hepatic impairment was limited and no data was available on patients with mild or severe hepatic impairment. Use of sitagliptin in patients with severe hepatic impairment is not recommended.
Drug Interactions
The potential for sitagliptin to be involved in drug-drug interactions is low. Sitagliptin did not inhibit or induce CYP450 enzymes in vitro. Drug interaction studies with metformin, simvastatin, warfarin, oral contraceptives, rosiglitazone and glyburide demonstrated that sitagliptin did not affect the pharmacokinetics of these drugs. The effects of these drugs on sitagliptin pharmacokinetics were not studied.
Drug interaction studies with digoxin have demonstrated that multiple doses of sitagliptin increasd the plasma immunoreactive digoxin concentrations. These increases may not be clinically meaningful, however, appropriate monitoring is required when sitagliptin is given in combination with digoxin.
Co-administration of sitagliptin (100 mg) with Cyclosporine A (600 mg) was associated with increased plasma drug exposure levels of sitagliptin (approx. 29%). The changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. No dosage adjustment is required.
3.3.3 Clinical Efficacy
The efficacy and safety of Januvia™ in combination with metformin were assessed in two multicentre, randomized, double-blind studies (Study 1 and Study 2) in patients with type 2 diabetes who had inadequate glycemic control (HbA1c ‑7 and #10%) on metformin therapy.
Study 1 was previously submitted as a 24-week study, however, in response to the NON the sponsor provided an additional report for a one-year efficacy and safety assessment. Patients with inadequate glycemic control on at least 1500 mg per day of metformin monotherapy (n=701) were randomized in a 2:1 ratio to the addition of 100 mg of Januvia™ or placebo, administered once daily. The double-blind treatment period included a 24-week placebo-controlled treatment period (Phase A) and an 80-week active-controlled treatment period (Phase B). During Phase A, patients who met protocol-specified glycemic criteria were to receive rescue therapy. Patients on rescue therapy were not eligible to continue into Phase B. Patients on placebo treatment during Phase A were started on therapy with glipizide at entry into Phase B. The report includes results from the 24-week placebo-controlled Phase A and the initial 30 weeks of Phase B. The pre-specified analysis at Week 24 provided confirmatory evidence of the efficacy of Januvia™ in combination with metformin, although not confirmatory at Week 54.
In combination with metformin, Januvia™ provided significant improvements in HbA1c, fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG). After 24 weeks, the placebo-adjusted changes from baseline in HbA1c levels were reduced by 0.65% when the analysis of all patients-treated (APT) population was used. The percentage of patients who achieved the target HbA1c level was higher in patients treated with Januvia™ compared to placebo (47% vs 18.3% for HbA1c #7% and 17.2% vs 4.9% for HbA1c #6.5%). The FPG and PPG levels were also reduced in patients treated with Januvia™ compared to placebo. Progressive improvement of FPG in the Januvia™ group was observed throughout the 24-week treatment period. At Week 54, the mean change from baseline in HbA1c was -0.71% in the APT population of the Januvia™ group, reflecting a maintenance of 87% of the Week 24 effect for patients who entered Phase B. In the APT analysis of change from baseline for FPG, a mean change from baseline of -11.9 mg/dL was observed for the Januvia™ group at Week 54. This shows an approximate 57% maintenance of the Week 24 effect at Week 54 for patients who entered Phase B. The FPG profile over time from Week 24 to Week 54 showed a rise in FPG, which was more prominent than the rise in HbA1c over this period. In patients that switched from placebo to glipizide at Week 24, the reduction of HbA1c levels from baseline at Week 54 was greater in the glipizide group relative to the Januvia™ group (-0.91% vs -0.71%).
Study 2 was a comparator study evaluating the addition of Januvia™ compared to glipizide (5-20 mg/day) in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin monotherapy at ‑1500 mg/day. Patients were randomized to the addition of either Januvia™ 100 mg daily (n=588) or glipizide (n=584) for 52 weeks. The main purpose of this study was to demonstrate that Januvia™ had similar glucose lowering efficacy, as assessed by change from baseline in HbA1c at Week 52, compared to glipizide. Januvia™ was shown to be non-inferior to glipizide in reducing HbA1c and FPG levels. At 52 weeks, the reduction from baseline in HbA1c was 0.67% for both Januvia™ and glipizide. The reduction in FPG was 0.6 mmol/L for Januvia™ and 0.4 mmol/L for glipizide.
Efficacy data from Study 1 and Study 2 support the use of Januvia™ in combination with metformin.
3.3.4 Clinical Safety
The clinical safety of Januvia™ in combination with metformin was evaluated in the two studies described in the 3.3.3 Clinical Efficacy section. Januvia™ in combination with metformin was generally well tolerated and the overall incidence of side effects was similar to that reported with placebo. The incidences of serious adverse experiences and discontinuation of therapy due to clinical adverse experiences were also similar to placebo.
Safety assessments were provided for Week 24 and Week 54 of Study 1, and the tolerability of Januvia™ was generally consistent. The most common adverse events included diarrhea, bronchitis, influenza, nasopharyngitis, upper respiratory infection, urinary tract infection, arthralgia, back pain, headache, and cough. A higher incidence of nasopharyngitis was observed in the Januvia™ group (6.3%) compared to the
placebo/glipizide group (4.2%). Also, more patients with pneumonia were reported in the Januvia™ group compared to the placebo/glipizide group; 6 (1.3%) and 0 patients, respectively.
In Study 2, the safety profile of Januvia™ was comparable to glipizide. Moreover, Januvia™ treatment was associated with low incidence of hypoglycemia and slight weight loss while glipizide treatment was associated with a higher incidence of hypoglycemia and weight gain. A higher incidence of urinary tract infections were reported in the Januvia™ group (32 patients, 5.4%) compared with the glipizide group (16 patients, 2.7%), however all urinary tract infections reported in both treatment groups were considered mild or moderate. There was a higher incidence of the adverse experience of osteoarthritis reported in patients treated with Januvia™ (15 patients, 2.6%) compared with the glipizide treatment group (4 patients, 0.7%). Only two adverse experiences of osteoarthritis reported in the Januvia™ group were considered severe.
Limited data were available on the use of Januvia™ in patients with congestive heart failure and renal insufficiency, therefore treatment with Januvia™ in these populations is not recommended.
Limited clinical experiences from patients with moderate hepatic insufficiency along with the submitted pharmacokinetic data support the use of Januvia™ in patients with a moderate degree of hepatic insufficiency. There were no clinical experiences from patients with severe hepatic insufficiency, therefore the use of Januvia™ in patients with severe hepatic insufficiency is not recommended.
The Product Monograph and the labelling clearly identify that the use of Januvia™ is not recommended in patients with congestive heart failure, renal failure and severe hepatic insufficiency, based on the limitations of the provided clinical data. Other safety issues raised in the NON were resolved with the information provided in the NON response.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk assessment
Januvia™ in combination with metformin provided glycemic control in adult patients with type 2 diabetes mellitus when metformin plus diet and exercise did not provide adequate glycemic control. The glucose-lowering efficacy was persistent through 54 weeks of treatment.
Januvia™ was generally well tolerated. No significant safety concerns were noted. The comparative study data showed Januvia™ in combination with metformin to be non-inferior to glipizide in combination with metformin. The two treatment arms had similar safety profiles, however, Januvia™ treatment was associated with a low incidence of hypoglycemia and slight weight loss.
The benefits of Januvia™ outweigh the risks. Restrictions to manage risks associated with unknown long-term effects of this drug have been incorporated into the labelling and Product Monograph to manage the use ofJanuvia™.
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 Januvia™ in combination with metformin is favourable in the treatment of adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise plus metformin do not provide adequate glycemic control. 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: JanuviaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2006-01-12 |
| Submission filed | 2006-01-20 |
| Screening 1 | |
| Screening Deficiency Notice issued | 2006-03-09 |
| Response filed | 2006-03-27 |
| Screening Acceptance Letter issued | 2006-05-15 |
| Review 1 | |
| Biopharmaceutics Evaluation complete | 2006-12-14 |
| Quality Evaluation complete | 2007-03-07 |
| Clinical Evaluation complete | 2007-03-08 |
| Biostatistics Evaluation complete | 2007-02-14 |
| NON issued by Director General (safety, effectiveness, quality issues) | 2007-03-09 |
| Response filed | 2007-06-07 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2007-07-19 |
| Review 2 | |
| Quality Evaluation complete | 2007-11-27 |
| Clinical Evaluation complete | 2007-12-13 |
| Biostatistics Evaluation complete | 2007-09-10 |
| Labelling Review complete | 2007-12-14 |
| NOC issued by Director General | 2007-12-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| JANUVIA | 02303922 | MERCK CANADA INC | SITAGLIPTIN (SITAGLIPTIN PHOSPHATE MONOHYDRATE) 100 MG |