Leaflet ONGLYZA 5mg film-coated tablets

Onglyza 2.5 mg film-coated tablets

Onglyza 5 mg film-coated tablets

Onglyza 2.5 mg film-coated tablets

Each tablet contains 2.5 mg saxagliptin (as hydrochloride).

Onglyza 5 mg film-coated tablets

Each tablet contains 5 mg saxagliptin (as hydrochloride).

Each tablet contains 99 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Onglyza 2.5 mg film-coated tablets

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 film-coated tablets

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

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

- as monotherapy when metformin is inappropriate due to intolerance or contraindications.

- in combination with other medicinal products for the treatment of diabetes, including insulin,when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 foravailable data on different combinations).

The recommended dose of Onglyza is 5 mg once daily. When Onglyza is used in combination withinsulin or a sulphonylurea, a lower dose of the insulin or sulphonylurea may be required to reduce therisk of hypoglycaemia (see section 4.4).

The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and athiazolidinedione have not been established.

No dose adjustment is recommended based solely on age (see also sections 5.1 and 5.2).

No dose adjustment is recommended for patients with mild renal impairment or in patients withmoderate renal impairment that have GFR ≥ 45 mL/min.

The dose should be reduced to 2.5 mg once daily in patients with moderate renal impairment that have

GFR < 45 mL/min and in patients with severe renal impairment.

Onglyza is not recommended for patients with end-stage renal disease (ESRD) requiringhaemodialysis (see section 4.4).

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

No dose adjustment is necessary for patients with mild or moderate hepatic impairment (seesection 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).

The efficacy of Onglyza in children aged 10 to < 18 years has not been established. Therefore,treatment of children and adolescents with saxagliptin is not recommended. Currently available dataare described in sections 5.1 and 5.2. Onglyza has not been studied in children under 10 years of age.

The tablets can be taken with or without a meal at any time of the day. Tablets must not be split or cut.

If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not betaken on the same day.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, or history of aserious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, andangioedema, to any dipeptidyl peptidase-4 (DPP4) inhibitor (see sections 4.4 and 4.8).

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

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

Acute Pancreatitis

Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patientsshould be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominalpain. If pancreatitis is suspected, Onglyza should be discontinued; if acute pancreatitis is confirmed,

Onglyza should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

In postmarketing experience of saxagliptin, there have been spontaneously reported adverse reactionsof acute pancreatitis.

In patients with GFR < 45 mL/min, the recommended dose is 2.5 mg once daily. Saxagliptin is notrecommended 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 withroutine care, renal assessment should be done periodically thereafter (see sections 4.2 and 5.2).

Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is notrecommended 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 ofsulphonylurea or insulin may be required to reduce the risk of hypoglycaemia when used incombination with Onglyza.

Onglyza must not be used in patients who have had any serious hypersensitivity reaction to adipeptidyl peptidase-4 (DPP4) inhibitor (see section 4.3).

During postmarketing experience, including spontaneous reports and clinical trials, the followingadverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions,including anaphylactic reaction, anaphylactic shock, and angioedema. If a serious hypersensitivityreaction to saxagliptin is suspected, Onglyza should be discontinued, assess for other potential causesfor the event, and institute alternative treatment for diabetes (see section 4.8).

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinicaltoxicology studies (see section 5.3). Skin lesions were not observed at an increased incidence inclinical trials. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash isalso noted as an adverse reaction for Onglyza (see section 4.8). Therefore, in keeping with routine careof the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, isrecommended.

Bullous pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical orsystemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patientdevelops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, thismedicinal product should be discontinued and referral to a dermatologist should be considered fordiagnosis and appropriate treatment (see section 4.8).

Cardiac failure

Experience in NYHA class III-IV is still limited. In the SAVOR trial a small increase in the rate forhospitalisation for heart failure was observed in the saxagliptin treated patients compared to placebo,although a causal relationship has not been established (see section 5.1). Additional analysis did notindicate a differential effect among NYHA classes. Caution is warranted if Onglyza is used in patientswho have known risk factors for hospitalisation for heart failure, such as a history of heart failure ormoderate to severe renal impairment. Patients should be advised of the characteristic symptoms ofheart failure, and to immediately report such symptoms.

Arthralgia

Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors (seesection 4.8). Patients experienced relief of symptoms after discontinuation of the medication and someexperienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onsetof symptoms following initiation of drug therapy may be rapid or may occur after longer periods oftreatment. If a patient presents with severe joint pain, continuation of drug therapy should beindividually assessed.

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

Use with potent CYP3A4 inducers

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

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially‘sodium-free’.

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

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).

The co-administration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such ascarbamazepine, dexamethasone, phenobarbital and phenytoin) have not been studied and may result indecreased 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

CYP3A4/5 inducer.

Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem,increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the correspondingvalues 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 Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the correspondingvalues for the active metabolite were decreased by 95% and 88%, respectively.

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

In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8,2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4. In studies conducted inhealthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite, weremeaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole,antacids or famotidine. In addition, saxagliptin did not meaningfully alter the pharmacokinetics ofmetformin, glibenclamide, pioglitazone, digoxin, simvastatin, the active components of a combinedoral contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole.

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

The use of saxagliptin has not been studied in pregnant women. Studies in animals have shownreproductive 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.

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

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observedin 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.

When driving or using machines, it should be taken into account that dizziness has been reported instudies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when

Onglyza is used in combination with other antidiabetic medicinal products known to causehypoglycaemia (e.g. insulin, sulphonylureas).

The most commonly reported adverse reactions in placebo-controlled trials reported in ≥ 5% ofpatients treated with Onglyza 5 mg and more commonly than in patients treated with placebo areupper respiratory tract infection (7.7%), urinary tract infection (6.8%) and headache (6.5%).

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 evaluatethe effects of saxagliptin on glycaemic control. In randomised, controlled, double-blind clinical trials(including developmental and postmarketing experience), over 17 000 patients with type 2 diabeteshave been treated with Onglyza.

In a pooled analysis of 1 681 patients with type 2 diabetes including 882 patients treated with Onglyza5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studiesconducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of adverseevents in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy dueto adverse events was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3%as compared to 1.8%).

Adverse reactions reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly thanin patients treated with placebo or that were reported in ≥ 2% of patients treated with saxagliptin 5 mgand ≥ 1% more frequently compared to placebo from the pooled analysis of five studies of glycaemiccontrol, plus an additional active-controlled study of initial combination with metformin are shown in

Table 1.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are definedas 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), very rare (< 1/10 000), or not known (cannot be estimated from the availabledata).

Table 1 Frequency of adverse reactions by system organ class from clinical trials andpostmarketing experience

System organ class Frequency of adverse reactions by treatment regimen

Adverse reaction

Saxagliptin as

Saxagliptin add-on to

Saxagliptin with a Saxagliptin metformin

Saxagliptin with sulphonylurea with a thia- plus amonotherapy metformin1 (glibenclamide) zolidinedione sulphonylurea

Infections andinfestations

Upper respiratory Common Common Common Commoninfection

Urinary tract Common Common Common Commoninfection

Gastroenteritis Common Common Common Common

Sinusitis Common Common Common Common

Naso-pharyngitis Common2

Immune systemdisorders

Hyper- Uncommon Uncommon Uncommon Uncommonsensitivityreactions†‡

Anaphylactic Rare Rare Rare Rarereactions includinganaphylactic shock†‡

Metabolism andnutrition disorders

Hypo- Very common3glycaemia

Dyslipidaemia Uncommon

Hypertri- Uncommonglyceridaemia

Nervous systemdisorders

Dizziness Common Common

Headache Common Common Common Common

Gastro-intestinal disorders

Abdominal pain† Common Common Common Common

Diarrhoea4 Common Common Common Common

Dyspepsia Common

Flatulence Common

Gastritis Common

Nausea† Common Common Common Common

Vomiting Common Common Common Common

Pancreatitis† Uncommon Uncommon Uncommon Uncommon

Constipation† Not known Not known Not known Not known Not known

Skin andsubcutaneous tissuedisorders

Rash† Common Common Common

Dermatitis† Uncommon Uncommon Uncommon Uncommon

Pruritus† Uncommon Uncommon Uncommon Uncommon

Urticaria† Uncommon Uncommon Uncommon Uncommon

Angioedema†‡ Rare Rare Rare Rare

Bullous pemhigoid† Not known Not known Not known Not known Not known

Musculo-skeletal andconnective tissuedisorders

Arthralgia* Uncommon

Myalgia5 Common

Reproductivesystem and breastdisorders

Erectile dysfunction Uncommon

General disordersand administrationsite conditions

Fatigue Common Uncommon Common

Oedema peripheral Common1 Includes saxagliptin in add-on to metformin and initial combination with metformin.2 Only in the initial combination therapy.3 There was no statistically significant difference compared to placebo. The incidence of confirmedhypoglycaemia was uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).

4 The incidence of diarrhoea was 4.1% (36/882) in the saxagliptin 5 mg group and 6.1% (49/799) in the placebogroup.5 As initial combination with metformin, myalgia is reported as uncommon.† Adverse reactions were identified through postmarketing surveillance.‡ See sections 4.3 and 4.4.

* Also reported during postmarketing surveillance (see section 4.4).

SAVOR trial results

The SAVOR trial included 8 240 patients treated with Onglyza 5 mg or 2.5 mg once daily and8 173 patients on placebo. The overall incidence of adverse events in patients treated with Onglyza inthis trial was similar to placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both Onglyza-treated patients andplacebo-treated patients in the intent-to-treat population.

The incidence of hypersensitivity reactions was 1.1% in both Onglyza-treated patients and placebo-treated patients.

The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% insubjects treated with Onglyza and 14.8% among patients treated with placebo. The percent of subjectswith reported on-treatment events of major hypoglycaemia (defined as an event that requiredassistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observedin the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not insubjects on insulin or metformin monotherapy at baseline. The increased risk of overall and majorhypoglycaemia was primarily observed in subjects with A1C < 7% at baseline.

Decreased lymphocyte counts were reported in 0.5% of Onglyza-treated patients and 0.4% of placebo-treated patients.

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) comparedwith the placebo group (2.8%), with nominal statistical significance favouring placebo [HR=1.27;95% CI 1.07, 1.51); P=0.007]. See also section 5.1.

Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucosemeasurement was not required.

When used as add-on combination therapy with metformin plus sulphonylurea, the overall incidenceof reported hypoglycaemia was 10.1% for Onglyza 5 mg and 6.3% for placebo.

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

Across clinical studies, the incidence of laboratory adverse events was similar in patients treated withsaxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocytecount was observed. From a baseline mean absolute lymphocyte count of approximately2 200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in theplacebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with dailydosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated withclinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte countrelative to placebo is not known.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Onglyza had no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mgdaily for 2 weeks (80 times the recommended dose). In the event of an overdose, appropriatesupportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and itsmajor metabolite can be removed by haemodialysis (23% of dose over 4 hours).

Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP4) inhibitors, ATCcode: A10BH03

Mechanism of action and pharmacodynamic effects

Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP4 inhibitor. Inpatients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activityfor a 24-hour period. After an oral glucose load, this DPP4 inhibition resulted in a 2-to 3-fold increasein circulating levels of active incretin hormones, including glucagon-like peptide-1 (GLP-1) andglucose-dependent insulinotropic polypeptide (GIP), decreased glucagon concentrations and increasedglucose-dependent beta-cell responsiveness, which resulted in higher insulin and C-peptideconcentrations. The rise in insulin from pancreatic beta-cells and the decrease in glucagon frompancreatic alpha-cells were associated with lower fasting glucose concentrations and reduced glucoseexcursion following an oral glucose load or a meal. Saxagliptin improves glycaemic control byreducing fasting and postprandial glucose concentrations in patients with type 2 diabetes.

In randomised, controlled, double-blind clinical trials (including developmental and postmarketingexperience), over 17 000 patients with type 2 diabetes have been treated with saxagliptin.

A total of 4 148 patients with type 2 diabetes, including 3 021 patients treated with saxagliptin, wererandomised in 6 double-blind, controlled clinical safety and efficacy studies conducted to evaluate theeffects of saxagliptin on glycaemic control. Treatment with saxagliptin 5 mg once daily producedclinically relevant and statistically significant improvements in haemoglobin A1c (HbA1c), fastingplasma glucose (FPG) and postprandial glucose (PPG) compared to placebo in monotherapy, incombination with metformin (initial or add-on therapy), in combination with a sulphonylurea, and incombination with a thiazolidinedione (see Table 2). There was also no apparent change in body weightassociated 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 greateradjusted mean change from baseline with saxagliptin.

Saxagliptin as monotherapy

Two double-blind, placebo-controlled studies of 24-week duration were conducted to evaluate theefficacy and safety of saxagliptin monotherapy in patients with type 2 diabetes. In both studies,once-daily treatment with saxagliptin provided significant improvements in HbA1c (see Table 2). Thefindings of these studies were confirmed with two subsequent 24-week regional (Asian) monotherapystudies comparing saxagliptin 5 mg with placebo.

Saxagliptin add-on to metformin therapy

An add-on to metformin placebo-controlled study of 24-week duration was conducted to evaluate theefficacy and safety of saxagliptin in combination with metformin in patients with inadequateglycaemic control (HbA1c 7-10%) on metformin alone. Saxagliptin (n=186) provided significantimprovements 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 plusmetformin (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 combinationwith metformin (428 patients) compared with a sulphonylurea (glipizide, 5 mg titrated as needed to20 mg, mean dose of 15 mg) in combination with metformin (430 patients) in 858 patients withinadequate glycaemic control (HbA1c 6.5-10%) on metformin alone. The mean metformin dose wasapproximately 1 900 mg in each treatment group. After 52 weeks, the saxagliptin and glipizide groupshad 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 showedconsistent results. The reduction in FPG was slightly less in the saxagliptin-group and there were morediscontinuations (3.5% vs. 1.2%) due to lack of efficacy based on FPG criteria during the first24 weeks of the study. Saxagliptin also resulted in a significantly lower proportion of patients withhypoglycaemia, 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 weightcompared 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 incombination with metformin (403 patients), compared with sitagliptin 100 mg in combination withmetformin (398 patients) in 801 patients with inadequate glycaemic control on metformin alone. After18 weeks, saxagliptin was non-inferior to sitagliptin in mean reduction from baseline in HbA1c in boththe per-protocol and the full analysis sets. The reductions from baseline in HbA1c respectively forsaxagliptin 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 combinationwith metformin as initial combination therapy in treatment-naive patients with inadequate glycaemiccontrol (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 either saxagliptin(n=317) or metformin alone (n=313) as initial therapy. Reductions in HbA1c from baseline to

Week 24 were observed in all evaluated subgroups defined by baseline HbA1c, with greaterreductions observed in patients with a baseline HbA1c ≥ 10% (see Table 2). 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 metforminplus 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 andsafety of saxagliptin in combination with glibenclamide in patients with inadequate glycaemic controlat enrollment (HbA1c 7.5-10%) on a sub-maximal dose of glibenclamide alone. Saxagliptin incombination with a fixed, intermediate dose of a sulphonylurea (glibenclamide 7.5 mg) was comparedto titration to a higher dose of glibenclamide (approximately 92% of patients in the placebo plusglibenclamide group were uptitrated to a final total daily dose of 15 mg). Saxagliptin (n=250) providedsignificant improvements in HbA1c, FPG, and PPG compared to titration to a higher dose ofglibenclamide (n=264). Improvements in HbA1c and PPG following treatment with saxagliptin 5 mgwere sustained up to Week 76. The HbA1c change for saxagliptin 5 mg (n=56) compared to uptitratedglibenclamide 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 stabledose 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 doseof metformin (n=314). Saxagliptin 5 mg add-on to insulin with or without metformin providedsignificant improvements after 24 weeks in HbA1c and PPG compared with placebo add-on to insulinwith or without metformin. Similar HbA1c reductions versus placebo were achieved for patientsreceiving 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 groupcompared to the placebo add-on to insulin group with or without metformin at Week 52. The HbA1cchange 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 ofsaxagliptin in combination with a thiazolidinedione (TZD) in patients with inadequate glycaemiccontrol (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 FPGfollowing treatment with saxagliptin 5 mg were sustained up to Week 76. The HbA1c change forsaxagliptin 5 mg (n=82) compared to TZD plus placebo (n=53) was -0.9% at Week 76.

Saxagliptin add-on combination therapy with metformin and sulphonylurea

A total of 257 patients with type 2 diabetes participated in a 24-week randomised, double-blind,placebo-controlled study to evaluate the efficacy and safety of saxagliptin (5 mg once daily) incombination with metformin plus sulphonylurea (SU) in patients with inadequate glycaemic control(HbA1c ≥ 7% and ≤ 10%). Saxagliptin (n=127) provided significant improvements in HbA1c and

PPG compared with the placebo (n=128). The HbA1c change for saxagliptin compared to placebo was

- 0.7% at Week 24.

Saxagliptin add-on to dapagliflozin plus metformin therapy

A 24-week randomised, double-blind, placebo-controlled study conducted in patients with type 2diabetes mellitus compared saxagliptin 5 mg with placebo as add-on therapy in individuals with

HbA1c 7-10.5% treated with dapagliflozin (a SGLT2-inhibtor) and metformin. Patients whocompleted the initial 24-week study period were eligible to enter a controlled 28-week long-term studyextension (52 weeks).

Individuals treated with saxagliptin added to dapagliflozin and metformin (n=153) achievedstatistically significantly (p-value < 0.0001) greater reductions in HbA1c versus the group withplacebo added to dapagliflozin plus metformin (n=162) at 24 weeks (see Table 2). The effect on

HbA1c observed at Week 24 was sustained at Week 52. The safety profile of saxagliptin added todapagliflozin plus metformin in the long-term treatment period was consistent with that observed inthe 24-week treatment period in this study and in the trial in which saxagliptin and dapagliflozin weregiven concomitantly as add-on therapy to patients treated with 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 plusdapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.4]) compared to the placebo plusdapagliflozin plus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at

Week 24 was sustained at Week 52.

Table 2 Key efficacy results of Onglyza 5 mg per day in placebo-controlled monotherapytrials and in add-on combination therapy trials

Mean 2

Mean change Placebo-correctedbaseline from baseline mean change in

HbA1c HbA1c (%) at HbA1c (%) at(%) Week 24 Week 24 (95% CI)

MONOTHERAPY STUDIES

- Study CV181011 (n=103) 8.0 -0.5 -0.6 (-0.9, -0.4)3

- Study CV181038 (n=69) 7.9 -0.7 (morning) -0.4 (-0.7, -0.1)4(n=70) 7.9 -0.6 (evening) -0.4 (-0.6, -0.1)5

ADD-ON/COMBINATION STUDIES

- Study CV181014: add-on to metformin 8.1 -0.7 -0.8 (-1.0, -0.6)3(n=186)

- Study CV181040: add-on to SU1 8.5 -0.6 -0.7 (-0.9, -0.6)(n=250)

- Study D1680L00006: add-on to 8.4 -0.7 -0.7 (-0.9, -0.5)3metformin plus SU (n=257)

- Study CV181013: add-on to TZD 8.4 -0.9

- 0.6 (-0.8, -0.4)3(n=183)

- Study CV181039: initial combinationwith metformin6

Overall population (n=306) 9.4 -2.5 -0.5 (-0.7, -0.4)7

Baseline HbA1c ≥ 10% stratum 10.8 -3.3 -0.6 (-0.9, -0.3)8(n=107)

- Study CV181168: sequential add-on to 7.9 -0.5 -0.4 (-0.5, -0.2)dapagliflozin + metformin (n=315)

- Study CV181057: add-on to insulin 8.7 -0.7 -0.4 (-0.6, -0.2)3(+/-metformin)

Overall population (n=300)n=Randomised patients (primary efficacy-intention-to-treat analysis) with data available.1 Placebo group had uptitration of glibenclamide from 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 2 000 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.9 Mean HbA1c change is the difference between the saxagliptin+dapagliflozin+metformin anddapagliflozin+metformin groups (p < 0.0001).

Saxagliptin and dapagliflozin add-on to metformin therapy

A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control onmetformin alone (HbA1c 8-12%), participated in this 24-week randomised, double-blind, activecomparator-controlled trial to compare the combination of saxagliptin and dapagliflozin addedconcurrently to metformin, versus saxagliptin or dapagliflozin added to metformin. Patients wererandomised to one of three double-blind treatment groups to receive saxagliptin 5 mg anddapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, ordapagliflozin 10 mg and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versuseither the saxagliptin group or dapagliflozin group at 24 weeks (see Table 3).

Table 3 HbA1c at Week 24 in active-controlled study comparing the combination ofsaxagliptin and dapagliflozin added concurrently to metformin with eithersaxagliptin or dapagliflozin added to metformin

Saxagliptin 5 mg+ dapagliflozin Dapagliflozin

Efficacy parameter 10 mg Saxagliptin 5 mg 10 mg+ metformin + metformin + metformin

N=1792 N=1762 N=1792

HbA1c (%) at week 241

Baseline (mean) 8.93 9.03 8.87

Change from baseline (adjustedmean3) −1.47 −0.88 −1.20(95% Confidence interval [CI]) (−1.62, −1.31) (−1.03, −0.72) (−1.35, −1.04)

Difference from saxagliptin +metformin (adjusted mean3) −0.594(95% CI) (−0.81, −0.37) - -

Difference from dapagliflozin +metformin (adjusted mean3) −0.275(95% CI) (−0.48, −0.05) - -1 LRM=Longitudinal repeated measures (using values prior to rescue).2 Randomised and treated patients with baseline and at least 1 post baseline efficacy measurement.3 Least squares mean adjusted for baseline value.4 p-value < 0.0001.5 p-value=0.0166.

Proportion of patients achieving HbA1c < 7%

In the saxagliptin and dapagliflozin combination group, 41.4% (95% CI [34.5, 48.2]) of patientsachieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) of patients in thesaxagliptin group and 22.2% (95% CI [16.1, 28.3]) of patients in the dapagliflozin group.

A 12-week, multi-centre, randomised, double-blind, placebo-controlled study was conducted toevaluate 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 renalimpairment (moderate [n=90]; severe [n=41]; or ESRD [n=39]). In this study, 98.2% of the patientsreceived other antihyperglycaemic treatments (75.3% on insulin and 31.2% on oralantihyperglycaemics; some received both). Saxagliptin significantly decreased HbA1c compared withplacebo; the HbA1c change for saxagliptin was -0.9% at Week 12 (HbA1c change of -0.4% forplacebo). 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 otherantihyperglycaemic treatment was low (26 subjects in the saxagliptin group versus 34 subjects in theplacebo group). The incidence of confirmed hypoglycaemic events was somewhat higher in thesaxagliptin group (9.4%) versus placebo group (4.7%) although the number of subjects with anyhypoglycaemic event did not differ between the treatment groups. There was no adverse effect onrenal function as determined by estimated glomerular filtration rate or CrCL at Week 12 and Week 52.

Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus -

Thrombolysis in Myocardial Infarction (SAVOR) Study

SAVOR was a CV outcome trial in 16 492 patients with HbA1c ≥ 6.5% and < 12% (12 959 withestablished CV disease; 3 533 with multiple risk factors only) who were randomised to saxagliptin(n=8 280) or placebo (n=8 212) added to regional standards of care for HbA1c and CV risk factors.

The study population included those ≥ 65 years (n=8 561) and ≥ 75 years (n=2 330), with normal ormild renal impairment (n=13 916) as well as moderate (n=2 240) or severe (n=336) renal impairment.

The primary safety (noninferiority) and efficacy (superiority) endpoint was a composite endpointconsisting of the time-to-first occurrence of any of the following major adverse CV events (MACE):

CV death, nonfatal myocardial infarction, or nonfatal ischaemic stroke.

After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptindoes not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo whenadded to current background therapy.

No benefit was observed for MACE or all-cause mortality.

Table 4 Primary and secondary clinical endpoints by treatment group in the SAVOR study*

Saxagliptin Placebo(N=8 280) (N=8 212)

Subjects with Event rate Subjects Hazardevents per 100 with events Event rate per Ratio

Endpoint n (%) patient-yrs n (%) 100 patient-yrs (95% CI)†

Primary composite 613 3.76 609 3.77 1.00endpoint: MACE (7.4) (7.4) (0.89, 1.12)‡,§, #

Secondary composite 1 059 6.72 1 034 6.60 1.02endpoint: MACE plus (12.8) (12.6) (0.94, 1.11)¶

All-cause mortality 420 2.50 378 2.26 1.11(5.1) (4.6) (0.96, 1.27)¶

* Intent-to-treat population.† Hazard ratio adjusted for baseline renal function category and baseline CVD risk category.‡ p-value < 0.001 for noninferiority (based on HR < 1.3) compared to placebo.§ p-value=0.99 for superiority (based on HR < 1.0) compared to placebo.# Events accumulated consistently over time, and the event rates for Onglyza and placebo did not divergenotably over time.¶ Significance not tested.

One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at agreater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominalstatistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); p=0.007]. Clinicallyrelevant factors predictive of increased relative risk with saxagliptin treatment could not bedefinitively identified. Subjects at higher risk for hospitalisation for heart failure, irrespective oftreatment assignment, could be identified by known risk factors for heart failure such as baselinehistory of heart failure or impaired renal function. However, subjects on saxagliptin with a history ofheart failure or impaired renal function at baseline were not at an increased risk relative to placebo forthe primary or secondary composite endpoints or all-cause mortality.

Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin groupand 4.6% in the placebo group (see Table 4). CV deaths were balanced across the treatment groups.

There was a numerical imbalance in non-CV death, with more events on saxagliptin (1.8%) thanplacebo (1.4%) [HR=1.27; (95% CI 1.00, 1.62); p=0.051].

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

In a paediatric study, patients aged 10 to < 18 years old with inadequately controlled type 2 diabetesmellitus were randomised to saxagliptin (88 patients) or placebo (76 patients) as add-on to metformin,insulin or a combination of metformin and insulin. In this 26-week, placebo-controlled, double-blindrandomised clinical study with a 26-week safety extension, patients received 2.5 mg saxagliptin (withpotential dose-increase to 5 mg) or placebo once daily following a lead-in period. The primaryefficacy endpoint was the change in HbA1c from baseline to 26 weeks of treatment. The treatmentdifference from placebo was not statistically significant [-0.44% (95% CI: -0.93, 0.05)]. The safetyprofile was similar to that observed in the adult population treated with saxagliptin.

In the SAVOR study subgroups over 65 and over 75 years of age, efficacy and safety were consistentwith the overall study population.

GENERATION was a 52-week glycaemic control study in 720 elderly patients, the mean age was72.6 years; 433 subjects (60.1%) were < 75 years of age, and 287 subjects (39.9%) were ≥ 75 years ofage. Primary endpoint was the proportion of patients reaching HbA1c < 7% without confirmed orsevere hypoglycaemia. There appeared to be no difference in percentage responders: 37.9%(saxagliptin) and 38.2% (glimepiride) achieved the primary endpoint. A lower proportion of patientsin the saxagliptin group (44.7%) compared to the glimepiride group (54.7%) achieved an HbA1ctarget of 7.0%. A lower proportion of patients in the saxagliptin group (1.1%) compared to theglimepiride group (15.3%) experienced a confirmed or severe hypoglycaemic event.

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

Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasmaconcentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax),respectively. The Cmax and AUC values of saxagliptin and its major metabolite increasedproportionally with the increment in the saxagliptin dose, and this dose-proportionality was observedin doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the meanplasma 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. Theintra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.

The inhibition of plasma DPP4 activity by saxagliptin for at least 24 hours after oral administration ofsaxagliptin 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 Cmax and a 27%increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) wasincreased by approximately 0.5 hours with food compared with the fasted state. These changes werenot considered to be clinically meaningful.

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) arenot expected to alter the disposition of saxagliptin.

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 DPP4 inhibitor, half aspotent as saxagliptin.

The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hoursand 3.1 hours respectively, and the mean t1/2 value for plasma DPP4 inhibition was 26.9 hours.

Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its majormetabolite, 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 werecomparable to estimated glomerular filtration rate. A total of 22% of the administered radioactivitywas recovered in faeces representing the fraction of the saxagliptin dose excreted in bile and/orunabsorbed medicinal product from the gastrointestinal tract.

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

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a 10 mg oral doseof saxagliptin in subjects with varying degrees of chronic renal impairment compared to subjects withnormal renal function. The study included patients with renal impairment classified on the basis ofcreatinine clearance as mild (approximately GFR ≥ 45 to < 90 mL/min), moderate (approximately

GFR ≥ 30 to < 45 mL/min), or severe (approximately GFR < 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. Insubjects with mild renal impairment, the mean AUC values of saxagliptin and its major metabolitewere 1.2- and 1.7- fold higher, respectively, than mean AUC values in subjects with normal renalfunction. Because increases of this magnitude are not clinically relevant, dose adjustment in patientswith mild renal impairment is not recommended. In subjects with moderate or severe renal impairmentor in subjects with ESRD on haemodialysis, the AUC values of saxagliptin and its major metabolitewere up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renalfunction.

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, thanthose observed in healthy subjects.

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 Onglyzais recommended on the basis of age alone.

The pharmacokinetics of saxagliptin and its major metabolite in paediatric patients aged 10 to< 18 years with type 2 diabetes mellitus were similar to that observed in adults with type 2 diabetesmellitus.

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 metaboliterespectively, 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 inmonkeys have not been observed in human clinical trials of saxagliptin.

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

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

Saxagliptin was not genotoxic in a conventional battery of genotoxicity studies in vitro and in vivo. Nocarcinogenic 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 oftoxicity. 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 decreasedfoetal body weight (in the presence of maternal toxicity), with a NOEL 303- and 30-times the humanexposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects ofsaxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL158- 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 atmaternally toxic doses, with NOEL 488- and 45-times the human exposure for saxagliptin and themajor metabolite, respectively at RHD. The effect on offspring body weights were noted untilpostnatal day 92 and 120 in females and males, respectively.

Lactose monohydrate

Cellulose, microcrystalline (E460i)

Croscarmellose sodium (E468)

Magnesium stearate

Onglyza 2.5 mg film-coated tablets

Polyvinyl alcohol

Macrogol 3350

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Onglyza 5 mg film-coated tablets

Polyvinyl alcohol

Macrogol 3350

Titanium dioxide (E171)

Talc (E553b)

Iron oxide red (E172)

Shellac

Indigo carmine aluminium lake (E132)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Alu/Alu blister.

Onglyza 2.5 mg film-coated tablets

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.

Onglyza 5 mg film-coated tablets

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.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

Onglyza 2.5 mg film-coated tablets

EU/1/09/545/011 14 film-coated tablets (calendar blister)

EU/1/09/545/012 28 film-coated tablets (calendar blister)

EU/1/09/545/013 98 film-coated tablets (calendar blister)

EU/1/09/545/014 30x1 (unit dose) film-coated tablets

EU/1/09/545/015 90x1 (unit dose) film-coated tablets

Onglyza 5 mg film-coated tablets

EU/1/09/545/001 14 film-coated tablets

EU/1/09/545/002 28 film-coated tablets

EU/1/09/545/003 56 film-coated tablets

EU/1/09/545/004 98 film-coated tablets

EU/1/09/545/005 14 film-coated tablets (calendar blister)

EU/1/09/545/006 28 film-coated tablets (calendar blister)

EU/1/09/545/007 56 film-coated tablets (calendar blister)

EU/1/09/545/008 98 film-coated tablets (calendar blister)

EU/1/09/545/009 30x1 (unit dose) film-coated tablets

EU/1/09/545/010 90x1 (unit dose) film-coated tablets

Date of first authorisation: 01 October 2009

Date of latest renewal: 18 July 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.