Januvia 100 mg film-coated tablets

Each tablet contains sitagliptin phosphate monohydrate, equivalent to 100 mg sitagliptin.

For a full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Round, beige film-coated tablet with “277” on one side.

For patients with type 2 diabetes mellitus, Januvia is indicated to improve glycaemic control:

as monotherapy

• in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with

• metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.

• a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

• a peroxisome proliferator-activated receptor gamma (PPARγ) agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control.

as triple oral therapy in combination with

• a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.

• a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control.

Januvia is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

Posology

The dose of Januvia is 100 mg once daily. When Januvia is used in combination with metformin and/or a PPARγ agonist, the dose of metformin and/or PPARγ agonist should be maintained, and Januvia administered concomitantly.

When Januvia is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).

If a dose of Januvia is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Special populations

Renal impairment

For patients with mild renal impairment (creatinine clearance [CrCl] 50 ml/min), no dose adjustment for Januvia is required.

Clinical study experience with Januvia in patients with moderate or severe renal impairment is limited. Therefore, use of Januvia is not recommended in this patient population (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment.

Elderly

No dose adjustment is necessary based on age. Limited safety data is available in patients 75 years of age and care should be exercised.

Paediatric population

Januvia is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy.

Method of administration

Januvia can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).

General

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

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 sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Januvia and other potentially suspect medicinal products should be discontinued.

Hypoglycaemia when used in combination with other anti-hyperglycaemic agents

In clinical trials of Januvia as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia (i.e. metformin and/or a PPARγ agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo (see section 4.8). Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2).

Renal impairment

As the experience is limited, patients with moderate to severe renal impairment should not be treated with Januvia (see section 5.2).

Hypersensitivity Reactions

Postmarketing reports of serious hypersensitivity reactions in patients treated with Januvia have been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with Januvia, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue Januvia, assess for other potential causes for the event, and institute alternative treatment for diabetes (see section 4.8).

Effects of other medicinal products on sitagliptin

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

Metformin: Co-administration of multiple twice-daily doses of 1,000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C_max of sitagliptin by approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting of renal impairment has not been assessed in a clinical study.

In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low. Concomitant administration of OAT3 inhibitors has not been eva luated in vivo.

Effects of sitagliptin on other medicinal products

In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-glycoprotein in vivo.

Digoxin: S