Saxagliptin

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

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.

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

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.

The dose should be reduced to 2.5 mg once daily in patients with moderate renal impairment that have GFR <45 mL/min.

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.

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

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.

Saxagliptin should be used with caution in patients with moderate hepatic impairment, and is not recommended for use in patients with severe hepatic impairment.

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 saxagliptin.

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.

Caution is warranted if saxagliptin 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.

The use of saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Saxagliptin should not be used during pregnancy unless clearly necessary.

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.

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).

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 the table below.

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).

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

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 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.
^* Also reported during postmarketing surveillance.

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].

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/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.