4.1. 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 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 data are described in sections 5.1 and 5.2. Onglyza has not been studied in children under 10 years of age.

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.

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 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 thiazolidinedione

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

Hypertriglyceridaemia

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

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

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

† 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 and 8 173 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/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the placebo‑controlled‑pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.

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

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).