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

saxagliptin hydrochloride

Each tablet contains 2.5 mg saxagliptin (as hydrochloride). Each tablet contains 5 mg saxagliptin (as hydrochloride). Excipients: Each tablet contains 99 mg lactose monohydrate.

Film-coated tablet (tablet). Onglyza 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets, with “2.5” printed on one side and “4214” printed on the other side, in blue ink. Onglyza 5 mg tablets are pink , biconvex, round, film-coated tablet, with “5” printed on one side and “4215” printed on the other side, in blue ink.

Add-on combination therapy

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

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

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

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

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

Posology

Add-on combination therapy

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

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

Special populations

Renal impairment

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

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

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

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

Hepatic impairment

No dose adjustment is necessary for patients with mild or moderate 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.

Method of administration

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

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

No dose adjustment is recommended based solely on age. Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population.

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

General

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

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

Pancreatitis

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

Renal impairment

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

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.

Use with medicinal products known to cause hypoglycaemia

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

Hypersensitivity reactions

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

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

Elderly patients

Experience in patients aged 75 years and older is very limited and caution should be exercised when treating this population.

Skin disorders

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

Cardiac failure

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

Immunocompromised patients

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

Use with potent CYP 3A4 inducers

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

Lactose

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

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

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

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

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

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

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

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

Summary of the safety profile

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

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

Tabulated list of adverse reactions

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

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

Table 1 Frequency of adverse reactions by system organ class

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

²Only in the initial combination therapy.

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

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

Postmarketing experience from clinical trials and spontaneous reports

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

Table 2 Frequency of additional adverse reactions by system organ class

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

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

Description of selected adverse reactions

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

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

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

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

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

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

Investigations

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

Bristol Myers Squibb-AstraZeneca EEIG

(POM)

28 February 2012