Saxagliptin 2.5mg film-coated tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Saxagliptin 2.5mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg saxagliptin (as hydrochloride dihydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Yellow, biconvex, round film-coated tablets with ‘2.5’ debossed on one side and plain on the other side, with a diameter of approximately 8mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Saxagliptin 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 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 for available data on different combinations).

4 CLINICAL PARTICULARS

4.2 Posology and method of administration

Paediatric population

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

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, 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).

4.4 Special warnings and precautions for use

Saxagliptin film-coated tablets contain sodium

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

4.5 Interaction with other medicinal products and other forms of interaction

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).

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 CYP3A4/5 inducer. 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).

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 in healthy subjects, neither the pharmacokinetics of saxagliptin nor 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, the active components of a combined oral contraceptive (ethinyl estradiol and norgestimate), diltiazem or ketoconazole.

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

4.6 Fertility, pregnancy and lactation

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. Saxagliptin should not be used during pregnancy unless clearly necessary.

Breast-feeding

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).

4.7 Effects on ability to drive and use machines

Saxagliptin 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 in studies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when saxagliptin is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas).

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials reported in ≥ 5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo are upper 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 saxagliptin, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the 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 diabetes have been treated with saxagliptin.

In a pooled analysis of 1,681 patients with type 2 diabetes including 882 patients treated with saxagliptin 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control, 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 from the pooled analysis of five studies of glycaemic control, 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 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), very rare (< 1/10,000), or not known (cannot be estimated from the available data).

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

System organ

class

Frequency of adverse reactions by treatment regimen

Adverse reaction

² Only in the initial combination therapy

³ There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was uncommon for saxagliptin 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 placebo group.

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 8240 patients treated with saxagliptin 5 mg or 2.5 mg once daily and 8173 patients on placebo. The overall incidence of adverse events in patients treated with saxagliptin in this trial was similar to placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and placebo-treated patients in the intent-to-treat population. The incidence of hypersensitivity reactions was 1.1% in both saxagliptin-treated patients and placebo-treated patients.

The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in subjects treated with saxagliptin and 14.8% among patients treated with placebo. The percent of subjects with reported on-treatment events of major hypoglycaemia (defined as an event that required assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observed in the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not in subjects on insulin or metformin monotherapy at baseline. The increased risk of overall and major hypoglycaemia was primarily observed in subjects with A1C < 7% at baseline.

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

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with 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.

Description of selected adverse reactions Hypoglycaemia

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

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

When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for saxagliptin 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/μ l, a mean decrease of approximately 100 cells/μ l 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Saxagliptin had 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).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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-native 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 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 greater reductions 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 metformin plus placebo (n=147) was -0.5% at Week 76

5.2 Pharmacokinetic properties

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 doseproportionality 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 DPP4 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 DPP4 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 DPP4 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 timedependence 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 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 C_max 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.

Hepatic impairment

In subjects with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (ChildPugh 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 (≥ 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 saxagliptin is recommended on the basis of age alone.

Paediatric population

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 diabetes mellitus.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Cellulose, microcrystalline (E460)

Croscarmellose sodium (E468)

Hypromellose 2910 (E464)

Phosphoric acid (for pH adjustment)

Magnesium stearate (E470b)

Film-coating

Hypromellose 2910 (E464)

Macrogol 4000 (E1521)

Talc (E553b)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide black (E172)

Phosphoric acid (for pH adjustment)

6.2 Incompatibilities

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions

6.5 Nature and contents of container

Saxagliptin film-coated tablets are packed in either Aluminium-OPA/Alu/PVC blisters or Alu/PE-PA/Alu/PE blisters with embedded desiccant or in High density polyethylene (HDPE) bottle with moisture absorbing canisters. HDPE bottles are white, plastic containers closed with a white polypropylene (PP) child-resistant cap.

Pack sizes of 28 and 30 film-coated tablets in non-perforated blisters.

Pack sizes of 28×1 and 30×1 film-coated tablets in perforated unit dose calendar blisters.

Pack size of 98 film-coated tablets in High density polyethylene (HDPE) bottle.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Zydus Pharmaceuticals UK Ltd

Sandretto Building

Cavalry Hill Industrial Park

Weedon

Northampton

England, NN7 4PP

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 58839/0116

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05-09-2025

10 DATE OF REVISION OF THE TEXT

11/12/2025