Onglyza2.5 mg film-coated tablets

Onglyza5 mg film-coated tablets

Each tablet contains 2.5 mg saxagliptin (as hydrochloride).

Each tablet contains 5 mg saxagliptin (as hydrochloride).

Excipients:

Each tablet contains 99 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Film-coated tablet (tablet).

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

Onglyza 5 mg tablets are pink , biconvex, round, film-coated tablet, with “5” printed on one side and “4215” printed on the other side, in blue ink.

Add-on combination therapy

Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control:

• in combination with metformin, when metformin alone, with diet and exercise, does not provide adequate glycaemic control;

• in combination with a sulphonylurea, when the sulphonylurea alone, with diet and exercise, does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate.

• in combination with a thiazolidinedione, when the thiazolidinedione alone with diet and exercise, does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate.

• in combination with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control.

Posology

Add-on combination therapy

The recommended dose of Onglyza is 5 mg once daily as add-on combination therapy with metformin, insulin, a thiazolidinedione or a sulphonylurea.

The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a thiazolidinedione, or with metformin and a sulphonylurea, has not been established.

Special populations

Elderly (65 years)

No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population (see also sections 4.4, 5.1 and 5.2).

Renal impairment

No dose adjustment is recommended for patients with mild renal impairment.

The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment.

The experience in patients with severe renal impairment is very limited. Therefore, saxagliptin should be used with caution in this population. Onglyza is not recommended for patients with end-stage renal disease (ESRD) requiring haemodialysis (see section 4.4).

Because the dose of Onglyza should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (see section 5.2). 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 4.4).

Paediatric population

The safety and efficacy of Onglyza in children aged birth to < 18 years have not yet been established.No data are available.

Method of administration

Onglyza can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Hypersensitivity to the active substance or to any of the excipients or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase 4 (DPP4) inhibitor (see sections 4.4 and 4.8).

General

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

Onglyza is not a substitute for insulin in insulin-requiring patients.

Pancreatitis

In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of saxagliptin. If pancreatitis is suspected, Onglyza and other potentially suspect medicinal products should be discontinued.

Renal impairment

A single dosage adjustment is recommended in patients with moderate or severe renal impairment. Saxagliptin should be used with caution in patients with severe renal impairment, and is not recommended for use in patients with end-stage renal disease (ESRD) requiring haemodialysis. Assessment of renal function is recommended prior to initiation of Onglyza, and, in keeping with routine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2).

Hepatic impairment

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).

Use with medicinal products known to cause hypoglycaemia

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, a lower dose of sulphonylurea or insulin may be required to reduce the risk of hypoglycaemia when used in combination with Onglyza.

Hypersensitivity reactions

Onglyza should not be used in patients who have had any serious hypersensitivity reaction to a dipeptidyl peptidase 4 (DPP4) inhibitor.

During postmarketing experience, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivity reaction to saxagliptin is suspected, discontinue Onglyza, assess for other potential causes for the event, and institute alternative treatment for diabetes (see sections 4.3 and 4.8).

Elderly patients

Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population (see sections 5.1 and 5.2).

Skin disorders

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there is limited experience in patients with diabetic skin complications. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse event (AE) for Onglyza (see section 4.8). Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.

Cardiac failure

Experience in NYHA class I-II is limited, and there is no experience in clinical studies with saxagliptin in NYHA class III-IV.

Immunocompromised patients

Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome, have not been studied in the Onglyza clinical program. Therefore, the efficacy and safety profile of saxagliptin in these patients has not been established.

Use with potent CYP 3A4 inducers

Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of Onglyza (see section 4.5).

Lactose

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Clinical data described below suggest that the risk for clinically meaningful interactions with co-administered medicinal products is low.

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin and its major metabolite, were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem or ketoconazole.

Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the C_max and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively.

Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the C_max and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin, reduced C_max and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4).

The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite. Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4 inducer.

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

Pregnancy

The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Onglyza should not be used during pregnancy unless clearly necessary.

Breastfeeding

It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy to the woman.

Fertility

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

Onglyza may have a negligible influence on the ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed. However, when driving or using machines, it should be taken into account that dizziness has been reported in studies with saxagliptin.

Summary of the safety profile

There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control.

In a pooled analysis, the overall incidence of adverse events in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to adverse events was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).

Tabulated list of adverse reactions

Adverse reactions reported in 5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in 2% of patients treated with saxagliptin 5 mg and 1% more frequently compared to placebo are shown in Table 1.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as Very common ( 1/10), Common ( 1/100 to <1/10), Uncommon ( 1/1,000 to 1/100), Rare ( 1/10,000 to 1/1,000), or Very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 Frequency of adverse reactions by system organ class

¹Includes saxagliptin in add-on to metformin and initial combination with metformin.

²Only in the initial combination therapy.

³There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).

⁴All of the reported adverse drug reactions of peripheral oedema were of mild to moderate intensity and none resulted in study drug discontinuation.

Postmarketing experience from clinical trials and spontaneous reports

Table 2 shows additional adverse reactions which have been reported in postmarketing experience. The frequencies are based on the experience from clinical trials.

Table 2 Frequency of additional adverse reactions by system organ class

¹ Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initial combination with metformin, add-on to sulphonylurea and add-on to thiazolidinedione clinical trials.

² These reactions were also identified in the pre-approval clinical trials, but do not meet the criteria for Table 1.

Description of selected adverse reactions

Adverse events, considered by the investigator to be at least possibly drug-related and reported in at least two more patients treated with saxagliptin 5 mg compared to control, are described below by treatment regimen.

As monotherapy: dizziness (common) and fatigue (common).

As add-on to metformin: dyspepsia (common) and myalgia (common).

As add-on to sulphonylurea (glibenclamide): fatigue (uncommon), dyslipidemia (uncommon) and hypertriglyceridemia (uncommon).

As initial combination with metformin: gastritis (common), arthralgia (uncommon), myalgia (uncommon), and erectile dysfunction (uncommon).

When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for Onglyza 5 mg and 19.9% for placebo.

Investigations

Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the placebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.

Onglyza has been shown to be safe and well-tolerated with no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Saxagliptin and its major metabolite can be removed by haemodialysis (23% of dose over 4 hours).

Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP-4) inhibitors, ATC code: A10BH03

Mechanism of action and pharmacodynamic effects

Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP-4 inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of 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, which resulted in higher insulin and C-peptide concentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon from pancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucose excursion following 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 safety and efficacy

A total of 4,148 patients with type 2 diabetes, including 3,021 patients treated with, saxagliptin were randomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In these studies 634 patients were 65 years and older, while 59 patients were 75 years and older. Treatment with saxagliptin 5 mg once daily produced clinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fasting plasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and in combination with a thiazolidinedione (see Table 3). There was also no apparent change in body weight associated with saxagliptin. Reductions in HbA1c were seen across subgroups including gender, age, race, and baseline body mass index (BMI) and higher baseline HbA1c was associated with a greater adjusted mean change from baseline with saxagliptin.

Saxagliptin as monotherapy

Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate the efficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies, once-daily treatment with saxagliptin provided significant improvements in HbA1c.

Saxagliptin add-on to metformin therapy

An add-on to metformin placebo-controlled study of 24-week duration 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 significant improvements in HbA1c, FPG and PPG compared to placebo (n=175).

Improvements in HbA1c, PPG, and FPG following treatment with saxagliptin 5 mg plus metformin were sustained up to Week 102. The HbA1c change for saxagliptin 5 mg plus metformin (n=31) compared to placebo plus metformin (n=15) was -0.8% at Week 102.

Saxagliptin add-on to metformin compared with SU add-on to metformin

A 52-week study was conducted to evaluate the efficacy and safety of saxagliptin 5 mg in combination with metformin (428 patients) compared with sulphonylurea (glipizide, 5 mg titrated as needed to 20 mg, mean dose of 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 was approximately 1900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c in the per-protocol analysis (-0.7% vs. –0.8%, respectively, mean baseline HbA1c of 7.5% for both groups). The intent-to-treat analysis showed consistent results. The reduction in FPG was slightly less 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. Saxagliptin also resulted in a significantly lower proportion of patients with hypoglycaemia, 3% (19 events in 13 subjects) vs. 36.3% (750 events in 156 patients) for glipizide. Patients treated with saxagliptin exhibited a significant decrease from baseline in body weight compared to a weight gain in patients administered glipizide (-1.1 vs. +1.1 kg).

Saxagliptin add-on to metformin compared with sitagliptin 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, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in both the per-protocol and the full analysis sets . The reductions from baseline in HbA1c respectively for saxagliptin and sitagliptin in the primary per-protocol analysis were -0.5% (mean and median) and -0.6% (mean and median). In the confirmatory full analysis set, mean reductions were -0.4% and -0.6% respectively for saxagliptin and sitagliptin, with median reductions 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 glycaemic control (HbA1c 8-12%). Initial therapy with the combination of saxagliptin 5 mg plus metformin (n=306) provided significant improvements in HbA1c, FPG and PPG compared to with either saxagliptin (n=317) or metformin (n=313) alone as initial therapy. Reductions in HbA1c from baseline to Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greater reductions observed in patients with a baseline HbA1c 10% (see Table 3). Improvements in HbA1c, PPG and FPG following initial therapy with saxagliptin 5 mg plus metformin were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg plus metformin (n=177) compared to metformin plus placebo (n=147) was -0.5% at Week 76.

Saxagliptin add-on to glibenclamide therapy

An add-on placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic control at enrolment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin in combination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was compared to titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plus glibenclamide group were up-titrated to a final total daily dose of 15 mg). Saxagliptin (n=250) provided significant improvements in HbA1c, FPG and PPG compared to titration to a higher dose of glibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitrated glibenclamide plus placebo (n=27) was -0.7% at Week 76.

Saxagliptin add-on combination therapy with insulin (with or without metformin)

A total of 455 patients with type 2 diabetes participated in a 24-week randomised, double-blind, placebo-controlled study to evaluate the efficacy and safety of saxagliptin in combination with a stable dose of insulin (baseline mean: 54.2 Units) in patients with inadequate glycaemic control (HbA1c 7.5% and 11%) on insulin alone (n=141) or on insulin in combination with a stable dose of metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin provided significant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulin with or without metformin. Similar HbA1c reductions versus placebo were achieved for patients receiving saxagliptin 5 mg add-on to insulin regardless of metformin use (−0.4% for both subgroups). Improvements from baseline HbA1c were sustained in the saxagliptin add-on to insulin group compared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1c change for the saxagliptin group (n=244) compared to placebo (n=124) was -0.4% at Week 52.

Saxagliptin add-on to thiazolidinedione therapy

A placebo-controlled study of 24-week duration was conducted to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemic control (HbA1c 7-10.5%) on TZD alone. Saxagliptin (n=183) provided significant improvements in HbA1c, FPG and PPG compared to placebo (n=180). Improvements in HbA1c, PPG and FPG following treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76.

Patients with renal impairment

A 12 week, multi-centre, randomised, double-blind, placebo controlled study was conducted to evaluate the treatment effect of saxagliptin 2.5 mg once daily compared with placebo in 170 patients (85 patients on saxagliptin and 85 on placebo) with type 2 diabetes (HbA1c 7.0-11%) and renal impairment (moderate [n=90]; severe [n=41]; or ESRD [n=39]). In this study, 98.2% of the patients received other antihyperglycaemic treatments (75.3% on insulin and 31.2% on oral antihyperglycaemics; some received both). Saxagliptin significantly decreased HbA1c compared with placebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% for placebo). Improvements in HbA1c following treatment with saxagliptin 2.5 mg were sustained up to Week 52, however the number of patients who completed 52 weeks without modification of other antihyperglycaemic treatments was low (26 subjects in the saxagliptin group versus 34 subjects in the placebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in the saxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with any hypoglycaemic event did not differ between the treatment groups. There was no adverse effect on renal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.

Table 3 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapy trials and in add-on combination therapy trials

n=Randomized patients (primary efficacy-intention-to-treat analysis) with data available.

¹Placebo group had uptitration of glibenclamidefrom 7.5 to 15 mg total daily dose.

² Adjusted mean change from baseline adjusted for baseline value (ANCOVA).

³ p<0.0001 compared to placebo.

⁴ p=0.0059 compared to placebo.

⁵ p=0.0157 compared to placebo.

⁶ Metformin was uptitrated from 500 to 2000 mg per day as tolerated.

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

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

Paediatric population

The European Medicines Agency has deferred 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 4.2 for information on paediatric use).

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

Absorption

Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (C_max) of saxagliptin and its major metabolite attained within 2 and 4 hours (T_max), respectively. The C_max and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, 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 C_max values were 24 ng/ml and 47 ng/ml, respectively. The intra-subject coefficients of variation for saxagliptin C_max and AUC 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 extended binding to the active site.

Interaction with food

Food had relatively modest effects on the pharmacokinetics of saxagliptin in healthy subjects. Administration with food (a high-fat meal) resulted in no change in saxagliptin C_max and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach C_max (T_max) was increased by approximately 0.5 hours with food compared with the fasted state. These changes were not considered to be clinically meaningful.

Distribution

The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Biotransformation

The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.

Elimination

The mean plasma terminal half-life (t_1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t_1/2 value for plasma DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of ¹⁴C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its major metabolite, and total radioactivity respectively. The average renal clearance of saxagliptin (230 ml/min) was greater than the average estimated glomerular filtration rate (120 ml/min), suggesting some active renal excretion. For the major metabolite, renal clearance values were comparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivity was recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed medicinal product from the gastrointestinal tract.

Linearity

The C_max and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.

Special populations

Renal impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral dose of saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The study included patients with renal impairment classified on the basis of creatinine clearance (based on the Cockcroft-Gault formula) as mild (>50 to 80 ml/min), moderate (30 to 50 ml/min), or severe (<30 ml/min), as well as patients with ESRD on haemodialysis.

The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite. In subjects with mild renal impairment, the mean AUC values of saxagliptin and its major metabolite were 1.2- and 1.7 -fold higher, respectively, than mean AUC values in subjects with normal renal function. Because increases of this magnitude are not clinically relevant, dose adjustment in patients with mild renal impairment is not recommended. In subjects with moderate or severe renal impairment or in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolite were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal function. The dose of Onglyza should be reduced to 2.5 mg once daily in patients with moderate or severe renal impairment (see sections 4.2 and 4.4).

Hepatic impairment

In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4- and 1.8-fold higher, respectively, and the exposures to BMS-510849 were 22%, 7%, and 33% lower, respectively, than those observed in healthy subjects.

Elderly patients (65 years)

Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients (18-40 years). This is not considered clinically meaningful, therefore, no dose adjustment for Onglyza is recommended on the basis of age alone.

In cynomolgus monkeys saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) at doses 3 mg/kg/day. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose of 5 mg/day (RHD).

The clinical relevance of the skin lesions is not known, however clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD.

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD.

Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. No carcinogenic potential was observed in two-year carcinogenicity assays with mice and rats.

Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.

Tablet core:

Cellulose microcrystalline (E460i)

Croscarmellose sodium (E468)

Magnesium stearate

Film coating:

Polyvinyl alcohol

Macrogol/3350

Titanium dioxide (E171)

Talc (E553b)

Iron oxide red (E172) 5 mg Tablets only

Iron oxide yellow (E172) 2.5 mg Tablets only

Printing ink:

Shellac

Indigo carmine aluminium lake (E132)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

2.5 mg Tablets

Alu/Alu blister.

Pack sizes of 14, 28, and 98 film-coated tablets in non-perforated calendar blisters.

Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

5mg Tablets

Alu/Alu blister.

Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated blisters.

Pack sizes of 14, 28, 56 and 98 film-coated tablets in non-perforated calendar blisters.

Pack sizes of 30x1 and 90x1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb/AstraZeneca EEIG

Bristol-Myers Squibb House

Uxbridge Business Park

Sanderson Road

Uxbridge

Middlesex

UB8 1DH

United Kingdom

EU/1/09/545/012 - Onglyza 2.5 mg film-coated tablet oral use non-perforated calendar blister (Alu/Alu)-28 tablets

EU/1/09/545/006 - Onglyza 5 mg film-coated tablet oral use non-perforated calendar blister (Alu/Alu)-28 tablets

5 mg Tablets- 1^st October 2009

2.5 mg Tablets – 28^th February 2011

22^nd December 2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency www.ema.europa.eu