Summary of medicine characteristics - Onglyza
1. NAME OF THE MEDICINAL PRODUCT
Onglyza 2.5 mg film-coated tablets
Onglyza 5 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
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).
Excipient(s) with known effect:
Each tablet contains 99 mg lactose (as monohydrate).
Onglyza contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
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.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Onglyza is indicated in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
- • as monotherapy when metformin is inappropriate due to 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).
4.2 Posology and method of administration
Posology
The recommended dose of Onglyza is 5 mg once daily. When Onglyza is used in combination with insulin or a sulphonylurea, a lower dose of the insulin or sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).
The safety and efficacy of saxagliptin as triple oral therapy in combination with metformin and a thiazolidinedione have not been established.
Special populations
Elderly (> 65 years)
No dose adjustment is recommended based solely on age (see also sections 5.1 and 5.2).
Renal impairment
No dose adjustment is recommended for patients with mild renal impairment or in patients with moderate 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) requiring haemodialysis (see section 4.4).
Because the dose should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of treatment, 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
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 be taken on the same day.
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
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.
Acute Pancreatitis
Use of DPP4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, Onglyza should be discontinued; if acute pancreatitis is confirmed, Onglyza should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
In postmarketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis.
Renal impairment
In patients with GFR < 45 mL/min, the recommended dose is 2.5 mg once daily. Saxagliptin is not recommended for use in patients with end-stage renal disease (ESRD) requiring 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 must not be used in patients who have had any serious hypersensitivity reaction to a dipeptidyl peptidase-4 (DPP4) inhibitor (see section 4.3).
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, Onglyza should be discontinued, assess for other potential causes for the event, and institute alternative treatment for diabetes (see section 4.8).
Skin disorders
Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Skin lesions were not observed at an increased incidence in clinical trials. Postmarketing reports of rash have been described in the DPP4 inhibitor class. Rash is also noted as an adverse reaction 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.
Bullous pemphigoid
Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this medicinal product should be discontinued and referral to a dermatologist should be considered for diagnosis 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 for hospitalisation 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 not indicate a differential effect among NYHA classes. Caution is warranted if Onglyza is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.
Arthralgia
Joint pain, which may be severe, has been reported in postmarketing reports for DPP4 inhibitors (see section 4.8). Patients experienced relief of symptoms after discontinuation of the medication and some experienced recurrence of symptoms with reintroduction of the same or another DPP4 inhibitor. Onset of symptoms following initiation of drug therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of drug therapy should be individually assessed.
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 CYP3A4 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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 Cmax 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 Cmax 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 Cmax 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. Onglyza 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
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 in studies 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 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 Onglyza 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 Onglyza, 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 Onglyza.
In a pooled analysis of 1,681 patients with type 2 diabetes including 882 patients treated with Onglyza 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 Adverse reaction | Frequency of adverse reactions by treatment regimen | ||||
| Saxagliptin monotherapy | Saxagliptin with metformin1 | Saxagliptin with a sulphonylurea (glibenclamide) | Saxagliptin with a thia-zolidinedione | Saxagliptin as add-on to metformin plus a sulphonylurea | |
| Infections and infestations | |||||
| Upper respiratory infection | Common | Common | Common | Common | |
| Urinary tract infection | Common | Common | Common | Common | |
| Gastroenteritis | Common | Common | Common | Common | |
| Sinusitis | Common | Common | Common | Common | |
| Nasopharyngitis | Common2 | ||||
| Immune system disorders | |||||
| Hypersensitivity reactions' | Uncommon | Uncommon | Uncommon | Uncommon | |
| Anaphylactic reactions including anaphylactic shock' | Rare | Rare | Rare | Rare | |
| Metabolism and nutrition disorders | |||||
| Hypoglycaemia | Very common3 | ||||
| Dyslipidaemia | Uncommon | ||||
| Hypertri-glyceridaemia | Uncommon | ||||
| Nervous system disorders | |||||
| Dizziness | Common | Common | |||
| Headache | Common | Common | Common | Common | |
| Gastrointestinal 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 and subcutaneous tissue disorders | |||||
| Rash1 | Common | Common | Common | ||
| Dermatitis1' | Uncommon | Uncommon | Uncommon | Uncommon | |
| Pruritus' | Uncommon | Uncommon | Uncommon | Uncommon | |
| Urticaria1 | Uncommon | Uncommon | Uncommon | Uncommon | |
| Angioedema11 | Rare | Rare | Rare | Rare | |
| Bullous pemhigoid1 | Not known | Not known | Not known | Not known | Not known |
| Musculoskeletal and connective tissue disorders | |||||
| Arthralgia* | Uncommon | ||||
| Myalgia5 | Common | ||||
| Reproductive system and breast disorders | |||||
| Erectile dysfunction | Uncommon | ||||
| General disorders and administration site conditions | |||||
| Fatigue | Common | Uncommon | Common | ||
| Oedema peripheral | Common |
1 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 confirmed hypoglycaemia 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 placebo group.
5 As initial combination with metformin, myalgia is reported as uncommon.
t 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 Onglyza 5 mg or 2.5 mg once daily and 8173 patients on placebo. The overall incidence of adverse events in patients treated with Onglyza in this 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 and placebo-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% in subjects treated with Onglyza 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 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%) 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 Onglyza 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 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/pl, a mean decrease of approximately 100 cells/pl 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 national reporting system listed in Appendix V.
4.9 Overdose
Onglyza 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 PROPERTIES5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes. Dipeptidyl peptidase 4 (DPP4) inhibitors, ATC code: A10BH03
Mechanism of action and pharmacodynamic effects
Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible, competitive, DPP4 inhibitor. In patients with type 2 diabetes, administration of saxagliptin led to inhibition of DPP4 enzyme activity for a 24-hour period. After an oral glucose load, this DPP4 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 efficacy and safety
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.
Glycaemic control
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. 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 2). 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 (see Table 2). The findings of these studies were confirmed with two subsequent 24-week regional (Asian) monotherapy studies 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 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 a 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 HbAlc 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 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 HbAlc > 10% (see Table 2). Improvements in HbAlc, 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 enrollment (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 uptitrated 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.
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) in combination with metformin plus sulphonylurea (SU) in patients with inadequate glycemic 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 2 diabetes 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 who completed the initial 24-week study period were eligible to enter a controlled 28-week long-term study extension (52 weeks).
Individuals treated with saxagliptin added to dapagliflozin and metformin (n=153) achieved statistically significantly (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo 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 to dapagliflozin plus metformin in the long-term treatment period was consistent with that observed in the 24-week treatment period in this study and in the trial in which saxagliptin and dapagliflozin were given 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 plus dapagliflozin plus metformin group 35.3% (95% CI [28.2, 42.4]) compared to the placebo plus dapagliflozin 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 monotherapy trials and in add-on combination therapy trials
| Mean baseline HbA1c (%) | Mean change2 from baseline HbA1c (%) at Week 24 | Placebo-corrected mean change in HbA1c (%) at Week 24 (95% CI) | |
| MONOTHERAPY STUDIES
| 8.0 | –0.5 | –0.6 (-0.9, –0.4)3 |
| 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
| 8.1 | –0.7 | –0.8 (-1.0, –0.6)3 |
| (n=186)
| 8.5 | –0.6 | –0.7 (-0.9, –0.6)3 |
| (n=250)
| 8.4 | –0.7 | –0.7 (-0.9, –0.5)3 |
| metformin plus SU (n=257)
| 8.4 | –0.9 | –0.6 (-0.8, –0.4)3 |
| (n=183)
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)
| 7.9 | –0.5 | –0.4 (-0.5, –0.2)9 |
| 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 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.
-
9 Mean HbA1c change is the difference between the saxagliptin+dapagliflozin+metformin and dapagliflozin+metformin groups (p< 0.0001).
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 (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 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 ngJVml and 214 ngJVml, respectively. The corresponding plasma Cmax values were 24 ng/ml and 47 ng/ml, respectively. The intra-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 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 Cmax and a 27% increase in AUC compared with the fasted state. The time for saxagliptin to reach Cmax (Tmax) 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 (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 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 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 Cmax 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 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. 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 (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 (> 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.
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 PARTICULARS6.1 List of excipients
Tablet core
Lactose monohydrate
Cellulose, microcrystalline (E460i)
Croscarmellose sodium (E468)
Magnesium stearate
Film-coating
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)
Printing ink Shellac
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
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
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 30×1 and 90×1 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 30×1 and 90×1 film-coated tablets in perforated unit dose blisters.
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
AstraZeneca AB
SE-151 85 Sodertalje
Sweden
8. MARKETING AUTHORISATION NUMBER(S)
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 30×1 (unit dose) film-coated tablets
EU/1/09/545/015 90×1 (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 30×1 (unit dose) film-coated tablets
EU/1/09/545/010 90×1 (unit dose) film-coated tablets
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 01 October 2009
Date of latest renewal: 18 July 2014