Onglyza film-coated tablets 5 mg blister No. 30

Instructions Onglyza film-coated tablets 5 mg blister No. 30

Composition

active ingredient: saxagliptin;

1 film-coated tablet contains saxagliptin hydrochloride equivalent to saxagliptin 2.5 mg or 5 mg;

excipients: lactose monohydrate; microcrystalline cellulose, croscarmellose sodium, magnesium stearate and dyes for 2.5 mg: Opadry II white, Opadry II yellow, Opacode blue; dyes for 5 mg: Opadry II white, Opadry II pink, Opacode blue.

Dosage form

Film-coated tablets.

Main physicochemical properties:

2.5 mg tablets: biconvex, round, film-coated tablets, pale yellow to light yellow in color, with 2.5 on one side and 4214 on the other, printed in blue ink.

Pharmacotherapeutic group

Oral hypoglycemic drugs. Dipeptidyl peptidase inhibitor (DPP-4 inhibitor). Saxagliptin. ATC code A10B H03.

Pharmacological properties

Pharmacodynamics

Mechanism of action and pharmacodynamic effects

Saxagliptin is a highly potent (Ki: 1.3 nM) selective, reversible competitive inhibitor of DPP-4. In patients with type 2 diabetes, saxagliptin inhibits DPP-4 enzymatic activity over a 24-hour period. Following an oral glucose load, this DPP-4 inhibition resulted in a 2- to 3-fold increase in circulating active incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations, and increased glucose-dependent beta-cell responsiveness, leading to increased insulin and C-peptide concentrations. Increased insulin release from beta cells and decreased glucagon synthesis from pancreatic alpha cells were associated with lower fasting glucose concentrations and reduced fluctuations in glucose levels after an oral glucose load or a meal. Saxagliptin improves glycaemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

Clinical efficacy and safety

In randomized, controlled, double-blind clinical trials (including the development period and post-marketing experience), more than 17,000 patients with type 2 diabetes were treated with saxagliptin.

Glycemic control

A total of 4,148 patients with type 2 diabetes mellitus were randomized in 6 double-blind, controlled clinical trials to evaluate the effects of saxagliptin on glycemic control, including 3,021 patients treated with saxagliptin. Saxagliptin 5 mg once daily provided clinically and statistically significant improvements in hemoglobin A1c (HbA1c), fasting plasma glucose, and postprandial plasma glucose compared with placebo when used alone, in combination with metformin (initial or add-on therapy), in combination with a sulfonylurea, and in combination with a thiazolidinedione (see Table 1). There were also no apparent changes in body weight associated with saxagliptin. Reductions in HbA1c were observed across subgroups, including those by gender, age, race, and baseline body mass index (BMI); higher HbA1c was associated with a greater adjusted mean change from baseline with saxagliptin.

Saxagliptin as monotherapy

Two 24-week, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of saxagliptin as monotherapy in patients with type 2 diabetes. In both studies, once-daily saxagliptin provided statistically significant improvements in HbA1c (see Table 1). These findings are supported by two subsequent 24-week, regional (Asia) monotherapy studies comparing saxagliptin 5 mg to placebo.

Saxagliptin as an add-on to metformin therapy

A 24-week, placebo-controlled study of saxagliptin as add-on to metformin was conducted to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided statistically significant improvements in HbA1c, fasting and postprandial glucose compared with placebo (n=175). Improvements in HbA1c, postprandial and fasting glucose with saxagliptin 5 mg and metformin were maintained through 102 weeks of the study. The change in HbA1c in patients receiving saxagliptin 5 mg in combination with metformin (n=31) compared with those receiving placebo and metformin (n=15) was -0.8% at week 102.

A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with a sulfonylurea (glipizide 5 mg titrated to 20 mg as needed, mean dose 15 mg) in combination with metformin (430 patients) in 858 patients with inadequate glycaemic control (HbA1c 6.5%-10%) on metformin alone. The mean metformin dose in each treatment group was approximately 1900 mg. At 52 weeks, the saxagliptin and glipizide groups had similar reductions from baseline in HbA1c as per protocol (-0.7% vs. -0.8%, respectively, mean baseline HbA1c 7.5% in both groups). Analysis in the study treatment population yielded similar results. Reductions in fasting plasma glucose (FPG) were slightly lower in the saxagliptin group, and there were more discontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first 24 weeks of the study. There was also a statistically significantly lower proportion of patients with hypoglycemia with saxagliptin: 3% (19 events in 13 patients) vs. 36.3% (750 events in 156 patients) in the glipizide group.

Patients treated with saxagliptin had a significant decrease from baseline in body weight compared with a weight gain in patients treated with glipizide (-1.1 kg vs. +1.1 kg).

Saxagliptin as add-on to metformin compared with sitagliptin as add-on to metformin

An 18-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (403 patients) compared with sitagliptin 100 mg in combination with metformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After 18 weeks of study treatment, saxagliptin was non-inferior to sitagliptin in terms of mean reduction from baseline in HbA1c in both the per-protocol population and the full analysis sample. The reduction from baseline in HbA1c for saxagliptin and sitagliptin, respectively, at the primary per-protocol analysis was -0.5% (mean and median) and -0.6% (mean and median). In the full confirmatory analysis, the mean reductions were -0.4% and -0.6% for saxagliptin and sitagliptin, respectively, with a median reduction of -0.5% for both groups.

Saxagliptin in combination with metformin as initial therapy

A 24-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin as initial combination therapy in treatment-naïve patients with inadequate glycemic control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg and metformin (n=306) provided significant improvements in HbA1c, fasting glucose, and postprandial glucose compared with saxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baseline to week 24 were observed in all evaluable subgroups defined by baseline HbA1c; greater reductions were observed in patients with baseline HbA1c ≥10% (see Table 1). Improvements in HbA1c, postprandial and fasting glucose following initial treatment with saxagliptin 5 mg and metformin were maintained through week 76. The change in HbA1c in patients receiving saxagliptin 5 mg in combination with metformin (n=177) compared with those receiving metformin and placebo (n=147) was -0.5% at week 76.

Saxagliptin as an add-on to glibenclamide therapy

A 24-week, placebo-controlled study was conducted to evaluate the efficacy and safety of saxagliptin in combination with glibenclamide in patients with inadequate glycemic control (HbA1c 7.5-10%) at the time of screening on submaximal doses of glibenclamide alone. Saxagliptin in combination with a sulfonylurea at a fixed intermediate dose (glibenclamide 7.5 mg) was compared with up-titration of glibenclamide (approximately 92% of patients in the placebo and glibenclamide groups were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250) provided significant improvements in HbA1c, fasting glucose, and postprandial glucose compared with up-titration of glibenclamide (n=264). Improvements in HbA1c and postprandial glucose following treatment with saxagliptin 5 mg were maintained through week 76. The change in HbA1c in patients receiving saxagliptin 5 mg (n=56) compared with those receiving glibenclamide up-titration and placebo (n=27) was -0.7% at week 76.

A total of 455 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7.5% and ≤11%) on insulin alone (n=141) or insulin in combination with a stable dose of metformin (n=314) participated in a 24-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (mean baseline dose of 54.2 units). Saxagliptin 5 mg as an add-on to insulin with or without metformin provided statistically significant improvements in HbA1c and postprandial glucose after 24 weeks of treatment compared with the addition of placebo to insulin with or without metformin. Similar reductions in HbA1c compared to placebo were achieved in patients receiving saxagliptin 5 mg as add-on to insulin regardless of metformin use (-0.4% for both subgroups). Improvements from baseline in HbA1c were maintained in the saxagliptin-to-insulin group compared to placebo-to-insulin group with or without metformin through week 52. The change in HbA1c for saxagliptin (n=244) compared to placebo (n=124) was -0.4% at week 52.

Saxagliptin as an add-on to thiazolidinedione therapy

A 24-week, placebo-controlled study was conducted to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycemic control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in HbA1c, fasting glucose, and postprandial glucose compared with placebo (n=180). Improvements in HbA1c and fasting glucose and postprandial glucose with saxagliptin 5 mg were maintained through week 76. The change in HbA1c in patients receiving saxagliptin 5 mg (n=82) compared with those receiving TZD and placebo (n=53) was -0.9% at week 76.

Saxagliptin as an add-on to combination therapy with metformin and a sulfonylurea

A total of 257 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) in combination with metformin and a sulfonylurea (SU) in patients with inadequate glycemic control (HbA1c ≥7% and ≤10%). Saxagliptin (n=127) provided significant improvements in HbA1c and postprandial glucose compared with placebo (n=128). The change in HbA1c for saxagliptin compared with placebo was -0.7% at week 24.

Saxagliptin as an add-on to combination therapy with dapagliflozin and metformin

A 24-week, randomized, double-blind, placebo-controlled study in patients with type 2 diabetes compared saxagliptin 5 mg to placebo as add-on therapy in subjects with HbA1c 7–10.5% who were receiving dapagliflozin (an SGLT2 inhibitor) and metformin. Patients who completed the initial 24-week period were eligible to enter a 28-week, controlled, long-term extension study (52 weeks).

Subjects treated with saxagliptin as add-on to dapagliflozin and metformin (n = 153) achieved statistically significantly (p < 0.0001) greater reductions in HbA1c compared with placebo as add-on to dapagliflozin and metformin (n = 162) at week 24 (see Table 1). The effect on HbA1c observed at week 24 was maintained at week 52. The safety profile of saxagliptin as add-on to dapagliflozin and metformin over the long-term treatment period was consistent with that observed in this study over the 24-week treatment period and in the trial in which saxagliptin and dapagliflozin were administered concomitantly as add-on therapy to patients receiving metformin (described below).

Proportion of patients achieving HbA1c < 7%

The proportion of patients achieving HbA1c < 7% at week 24 was higher in the saxagliptin 5 mg + dapagliflozin + metformin group (35.3% (95% CI [28.2, 42.4]) compared with the placebo + dapagliflozin + metformin group (23.1% (95% CI [16.9, 29.3]). The HbA1c effect observed at week 24 was maintained at week 52.

Table 1. Key results of treatment with Onglyza 5 mg daily in placebo-controlled monotherapy studies and add-on combination therapy studies

n is the number of randomized patients (primary efficacy analysis in the population of all patients assigned to the study treatment) for whom data are available.

1 - In the placebo group, the total daily dose of glibenclamide was titrated from 7.5 mg to 15 mg.

2 - Mean change from baseline adjusted for baseline values (ANCOVA).

3 - p<0.0001 compared to placebo.

4 - p=0.0059 compared to placebo.

5 - p=0.0157 compared to placebo.

6 - Titrate metformin from 500 to 2000 mg per day as tolerated.

7 - Mean change in HbA1c is the difference between the saxagliptin + metformin combination and metformin alone groups (p<0.0001).

8 - Mean change in HbA1c is the difference between the saxagliptin + metformin combination and metformin alone groups.

9 - Mean change in HbA1c is the difference between the saxagliptin + dapagliflozin + metformin and dapagliflozin + metformin groups (p<0.0001).

Saxagliptin and dapagliflozin as add-on to metformin therapy

A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycemic control on metformin alone (HbA1c 8-12%) were enrolled in a 24-week, randomized, double-blind, active comparator study to compare the combination of saxagliptin and dapagliflozin added to metformin with saxagliptin or dapagliflozin added to metformin. Patients were randomized to one of three double-blind treatment groups: 5 mg saxagliptin and 10 mg dapagliflozin added to metformin, 5 mg saxagliptin and placebo added to metformin, or 10 mg dapagliflozin and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c compared with the saxagliptin or dapagliflozin group at 24 weeks (see Table 2).

Table 2. HbA1c values at week 24 in an active-controlled study: the combination of saxagliptin and dapagliflozin added to metformin was compared with the combination of saxagliptin or dapagliflozin added to metformin

1 - PPV – longitudinal repeated measurements (using values before backup therapy).

2 - Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.

3 - Average calculated by the two-step method, adjusted for the initial value.

4 - p < 0.0001.

5 - p = 0.0166.

Proportion of patients achieving HbA1c < 7%

The reduction in HbA1c of less than 7% was achieved in the saxagliptin and dapagliflozin combination group by 41.4% (95% CI [34.5, 48.2]) compared with 18.3% (95% CI [13.0, 23.5]) in the saxagliptin group and 22.2% (95% CI [16.1, 28.3]) in the dapagliflozin group.

Patients with renal impairment

A 12-week, multicenter, randomized, double-blind, placebo-controlled study evaluated the effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients in the saxagliptin group and 85 patients in the placebo group) with type 2 diabetes mellitus (HbA1c 7.0–11%) and renal impairment (moderate [n=90], severe [n=41], or ESRD [n=39]). In this study, 98.2% of patients were receiving other antihyperglycemic therapy (75.3% insulin and 31.2% oral antihyperglycemic agents; some patients were receiving both). Saxagliptin provided significant reductions in HbA1c compared with placebo; change in HbA1c for saxagliptin was -0.9% at week 12 (change in HbA1c -0.4% for placebo). The incidence of confirmed hypoglycemia was slightly higher in the saxagliptin group (9.4%) compared with the placebo group (4.7%), although the number of patients with any hypoglycemic event did not differ between the two treatment groups. There were no adverse effects on renal function, as measured by estimated glomerular filtration rate or CrCL, at week 12 and week 52.

The SAVOR trial examined cardiovascular (CV) outcomes in 16,492 patients with HbA1c ≥ 6.5% and < 12% (12,959 with established CVD; 3,533 with only a few risk factors) who were randomized to saxagliptin (n = 8,280) or placebo (n = 8,212) in addition to regional standard of care for HbA1c and CV risk factors. The study populations included subjects aged ≥ 65 years (n = 8,561) and ≥ 75 years (n = 2,330) with normal or mild (n = 13,916) and moderate (n = 2,240) or severe (n = 336) renal impairment.

The primary safety (non-inferiority) and efficacy (superiority) endpoint was a composite endpoint of time to first occurrence of any of the following major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction, or non-fatal ischemic stroke.

After a median follow-up of 2 years, the trial met its primary safety endpoint, demonstrating that saxagliptin does not increase cardiovascular risk in patients with type 2 diabetes compared with placebo when added to current standard therapy.

There was no advantage for MACE or all-cause mortality. The primary composite endpoint of MACE was observed at a rate of 7.4% in the saxagliptin group and 7.4% in the placebo group (HR = 1.00; 95% CI [0.89, 1.12]. The secondary composite endpoint of MACE plus was observed at a rate of 12.8% in the saxagliptin group and 12.6% in the placebo group (HR = 1.02; 95% CI [0.94, 1.11].

One component of the secondary composite endpoint, hospitalization for heart failure, was more common with saxagliptin (3.5%) compared with placebo (2.8%), with a nominal statistical significance in favor of placebo (HR = 1.27; 95% CI [1.07, 1.51]; p = 0.007). Clinically relevant factors predicting an increased relative risk of saxagliptin therapy could not be definitively determined. Subjects at increased risk of hospitalization for heart failure, regardless of treatment assignment, could be identified by known risk factors for heart failure, such as a baseline history of disease or renal impairment. However, subjects in the saxagliptin group with a baseline history of heart failure or renal impairment were not at increased risk compared with placebo for the primary or secondary composite endpoints or all-cause mortality.

Another secondary endpoint, all-cause mortality, was observed at a rate of 5.1% in the saxagliptin group and 4.6% in the placebo group (HR = 1.11; 95% CI [0.96, 1.27]). Mortality from CV causes was comparable between treatment groups. An imbalance in the number of non-cardiovascular deaths was observed, with more events occurring with saxagliptin (1.8%) than with placebo (1.4%) (HR = 1.27; 95% CI [1.00, 1.62]; p = 0.051).

A1C was lower for saxagliptin compared with placebo in an exploratory analysis.

Children

The European Medicines Agency has waived the obligation to submit the results of studies with Onglyza in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.4 for information on paediatric use).

Elderly people

In the SAVOR trial, efficacy and safety in the 65 and 75 year old age groups were consistent with the overall study population.

GENERATION was a 52-week glycemic control study in 720 elderly patients with a mean age of 72.6 years: 433 (60.1%) were < 75 years of age and 287 (39.9%) were ≥ 75 years of age. The primary endpoint was the proportion of patients achieving an HbA1c < 7% without confirmed or severe hypoglycemia. There was no difference in the percentage of patients who responded to therapy: 37.9% (saxagliptin) and 38.2% (glimepiride) achieved the primary endpoint. A smaller proportion of patients in the saxagliptin group (44.7%) compared with the glimepiride group (54.7%) achieved an HbA1c ≥ 7.0%. A smaller proportion of patients in the saxagliptin group (1.1%) compared with the glimepiride group (15.3%) experienced a confirmed or severe hypoglycemic event.

Pharmacokinetics

The pharmacokinetics of saxagliptin and its major metabolite were similar in healthy volunteers and patients with type 2 diabetes.

Absorption

Saxagliptin is rapidly absorbed after oral administration in the fasted state with peak plasma concentrations (Cmax) of saxagliptin and its major metabolite occurring within 2 and 4 hours (Tmax), respectively. The Cmax and AUC of saxagliptin and its major metabolite increased proportionally with increasing saxagliptin dose; this dose proportionality was observed up to 400 mg. Following a single oral dose of 5 mg saxagliptin to healthy volunteers, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng h/mL and 214 ng h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The coefficients of variation for Cmax and AUC of saxagliptin in one subject were less than 12%.

The inhibition of plasma DPP-4 activity by saxagliptin for at least 24 hours after oral administration of saxagliptin is due to high potency, high affinity, and active site binding.

Food has relatively little effect on the pharmacokinetics of saxagliptin in healthy volunteers. Administration with a high-fat meal did not alter Cmax and resulted in a 27% increase in AUC compared to the fasted state. The time to reach Cmax (Tmax) was delayed by approximately 0.5 hours following administration with food compared to the fasted state. These changes are considered to be clinically insignificant.

Distribution

The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Therefore, changes in serum protein levels due to various pathological conditions (e.g., hepatic or renal dysfunction) are unlikely to affect the disposition of saxagliptin.

Biotransformation

The biotransformation of saxagliptin occurs primarily with the participation of cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive inhibitor of DPP-4 with a potency half that of saxagliptin.

Breeding

The mean plasma half-lives (t1/2) of saxagliptin and its major metabolite were 2.5 hours and 3.1 hours, respectively, and the mean plasma t1/2 for DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic metabolic pathways. Following a single 50 mg oral dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactive material, respectively. The mean renal clearance of saxagliptin (230 mL/min) was greater than the mean estimated glomerular filtration rate (120 mL/min), suggesting some active renal elimination. Renal clearance values for the major metabolite were comparable to estimated glomerular filtration rate. A total of 22% of the ingested radioactive material was recovered in feces, corresponding to the fraction of the saxagliptin dose excreted in bile and/or as unabsorbed drug from the gastrointestinal tract.

Linearity

The Cmax and AUC of saxagliptin and its major metabolite increased proportionally with saxagliptin dose. There was no significant accumulation of saxagliptin or its major metabolite with multiple once-daily dosing at any dose level. There was no dose- or time-dependent relationship between the clearance of saxagliptin and its major metabolite during 14 days of once-daily dosing of saxagliptin over the dose range of 2.5 mg to 400 mg.

Special categories of patients

Kidney dysfunction

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin after oral administration of 10 mg in patients with varying degrees of chronic renal failure compared with patients with normal renal function. The study included patients with renal impairment classified as mild (eGFR approximately ≥ 45 - < 90 mL/min), moderate (eGFR approximately ≥ 30 - < 45 mL/min), or severe (eGFR approximately < 30 mL/min) based on creatinine clearance, and patients with ESRD on hemodialysis.

The degree of renal impairment did not affect the Cmax of saxagliptin and its major metabolite. In patients with mild renal impairment, the mean AUC values for saxagliptin and its major metabolite were 1.2- and 1.7-fold higher, respectively, than the mean AUC values in patients with normal renal function. Since this increase is not clinically meaningful, no dose adjustment is recommended for patients with mild renal impairment. In patients with moderate or severe renal impairment or in patients with ESRD on hemodialysis, the AUC values for saxagliptin and its major metabolite were 2.1- and 4.5-fold higher, respectively, than the AUC values in patients with normal renal function.

Liver dysfunction

In patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, saxagliptin exposure was 1.1-, 1.4-, and 1.8-fold higher, respectively, and BMS-510849 exposure was 22%, 7%, and 33% lower, respectively, compared to healthy volunteers.

Elderly patients (≥ 65 years)

Elderly patients (65–80 years) had approximately 60% higher AUC of saxagliptin compared to younger patients (18–40 years). This difference is not considered clinically relevant, and therefore dose adjustment of Onglyza based on patient age alone is not recommended.

Indication

Onglyza is indicated in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:

as monotherapy when metformin is inappropriate due to contraindications or intolerance;

in combination with other medicinal products for the treatment of diabetes mellitus, including insulin, if they do not provide adequate glycaemic control (available data on various combinations are provided in the sections “Special instructions for use”, “Interaction with other medicinal products and other types of interactions” and “Pharmacodynamics”).

Contraindication

Hypersensitivity to the active substance or to any of the excipients or history of serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock and angioedema to any dipeptidyl peptidase 4 (DPP-4) inhibitor (see sections 4.4 and 4.8).

Interaction with other medicinal products and other types of interactions

The clinical data presented below indicate that the risk of clinically significant interactions with concomitantly administered medicinal products is low.

The metabolism of saxagliptin occurs primarily with the participation of cytochrome P450 3A4/5 (CYP3A4/5).

In in vitro studies, saxagliptin and its major metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induce CYP1A2, 2B6, 2C9, or 3A4. In studies in healthy volunteers, no significant changes in the pharmacokinetics of saxagliptin and its major metabolite were observed when metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids, or famotidine were administered. In addition, saxagliptin did not significantly affect the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, the active ingredients of combined oral contraceptives (ethinyl estradiol and norgestimate), diltiazem, or ketoconazole.

When saxagliptin was co-administered with the moderate CYP3A4/5 inhibitor diltiazem, the Cmax and AUC of saxagliptin increased by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite decreased by 44% and 34%.

When saxagliptin was co-administered with the potent CYP3A4/5 inhibitor ketoconazole, the Cmax and AUC of saxagliptin increased by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite decreased by 95% and 88%.

When saxagliptin was co-administered with the potent CYP3A4/5 inducer rifampicin, the Cmax and AUC of saxagliptin were decreased by 53% and 76%, respectively. The exposure of the active metabolite and the inhibition of plasma DPP-4 activity were not altered by rifampicin over the dosing interval (see section 4.4).

Concomitant use of saxagliptin and CYP3A4/5 inducers other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital, and phenytoin) has not been studied and may result in decreased plasma concentrations of saxagliptin and increased concentrations of its major metabolite. Careful glycemic control is required when saxagliptin is coadministered with potent CYP3A4 inducers.

The effects of smoking, diet, herbal products, and alcohol consumption on the pharmacokinetics of saxagliptin have not been specifically studied.

Application features

General

Onglyza should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Onglyza is not a substitute for insulin in patients who require insulin treatment.

This medicinal product contains less than 1 mmol (23 mg) sodium, i.e. essentially 'sodium-free'.

Acute pancreatitis

The use of DPP-4 inhibitors is associated with the risk of developing acute pancreatitis.

During post-marketing surveillance of saxagliptin, spontaneous reports of adverse reactions of acute pancreatitis have occurred. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, Onglyza should be discontinued; if acute pancreatitis is confirmed, Onglyza should not be restarted. The drug should be used with caution in patients with a history of pancreatitis.

Kidney dysfunction

For patients with GFR < 45 mL/min, the recommended dose is 2.5 mg once daily. Saxagliptin is not recommended for use in patients with end-stage renal disease (ESRD) requiring hemodialysis. It is recommended that renal function be assessed prior to initiating treatment with Onglyza and periodically thereafter, as per standard of care (see Dosage and Administration and Pharmacokinetics).

Liver dysfunction

Saxagliptin should be used with caution in patients with moderate hepatic impairment and is not recommended for use in patients with severe hepatic impairment (see section 4.2).

Application of medicine