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Summary Basis of Decision (SBD) JANUVIA

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Table of Contents

1 Product and Submission Information 2 Notice of Decision

3 Scientific and Regulatory Basis for Decision 3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient) 3.1.2 Drug Product 3.1.3 Facilities and Equipment

3.1.4 Adventitious Agents Safety Evaluation 3.1.5 Conclusion

3.2 Non-clinical Basis for Decision 3.2.1 Pharmacodynamics 3.2.2 Pharmacokinetics

3.2.3 Toxicology 3.2.4 Conclusion

3.3 Clinical Basis for Decision 3.3.1 Pharmacodynamics 3.3.2 Pharmacokinetics

3.3.3 Clinical Efficacy 3.3.4 Clinical Safety

3.4 Benefit/Risk Assessment and Recommendation 3.4.1 Benefit/Risk assessment 3.4.2 Recommendation

4 Submission Milestones

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.

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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.

.

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.

.

3.1.2 Drug Product

Description and Composition

Januvia™ tablets are beige, round, film-coated tablets with "277" on one side.

.

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.

.

Single-Dose Toxicity

Sitagliptin had a relatively low acute toxicity with a minimal lethal dose of approximately 2000

mg/kg in rodents.

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%).

3.3.4 Clinical Safety

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.

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