DPP-4 Inhibitor

Sitagliptin

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

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

JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycaemic control in combination with metformin when diet and exercise, plus metformin do not provide adequate glycaemic control. For patients with type 2 diabetes mellitus in whom use of a PPAR? agonist (i.e. a thiazolidinedione) is appropriate, JANUVIA is indicated in combination with the PPAR? agonist when diet and exercise plus the PPAR? agonist alone, do not provide adequate glycaemic control.

The dose of JANUVIA is 100 mg once daily. The dosage of metformin or PPARγ agonist should be maintained, and sitagliptin administered concomitantly.

When JANUVIA is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

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.

JANUVIA can be taken with or without food.

Patients with renal insufficiency

For patients with mild renal insufficiency (creatinine clearance [CrCl] 50 ml/min), no dosage adjustment for JANUVIA is required.

Clinical study experience with JANUVIA in patients with moderate or severe renal insufficiency is limited. Therefore, use of JANUVIA is not recommended in this patient population.

Patients with hepatic insufficiency

No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. JANUVIA has not been studied in patients with severe hepatic insufficiency.

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.

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

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

Hypersensitivity to the active substance or to any of the excipients.

General

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

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 or pioglitazone), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. When sitagliptin was added to a sulphonylurea, the incidence of hypoglycaemia was increased over that of placebo. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea may be considered. The use of sitagliptin in combination with insulin has not been adequately studied.

Renal insufficiency

As the experience is limited, patients with moderate to severe renal insufficiency should not be treated with JANUVIA.

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.

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 pglycoprotein, 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 pglycoprotein 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 insufficiency or 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 insufficiency or ESRD. The effects of potent CYP3A4 inhibitors in the setting of renal insufficiency have not been assessed in a clinical study.

In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and 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 evaluated 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: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased on average by 11 %, and the plasma C_max on average by 18 %. No dosage adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.

In 9 large clinical trials of up to 2 years in duration, over 2,700 patients have received treatment with JANUVIA 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin) or a PPARγ agent. In these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8 % with 100 mg per day and 1.5 % with other treatments. No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference> 1 patient) of that in patients treated with control.

Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in excess (> 0.2 % and difference > 1 patient) of that in patients treated with placebo are listed below (Table 1) by system organ class and frequency. Frequencies are defined as: very common ( 1/10); common ( 1/100, < 1/10); uncommon ( 1/1,000, < 1/100); rare ( 1/10,000, < 1/1,000); and very rare (< 1/10,000).

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies

^* In clinical trials of Januvia as monotherapy and sitagliptin as part of combination therapy with metformin or pioglitazone, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.

¹ In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to treatment with placebo/metformin was 9.3 % and 10.1 %, respectively.

In an additional 1-year study of sitagliptin 100 mg in once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/metformin compared to sulphonylurea/metformin was 14.5 % and 30.3 %, respectively.

In pooled studies of up to 1 year in duration comparing sitagliptin/metformin to a sulphonylurea agent/metformin, adverse reactions considered as drug-related reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2 % and difference> 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations; frequency uncommon).

² In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/glimepiride compared to treatment with placebo/glimepiride was 11.3 % and 6.6 %, respectively.

³ In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with glimepiride/metformin compared to treatment with placebo in combination with glimepiride/metformin was 18.1 % and 7.1 %, respectively.

⁴ In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/pioglitazone compared to patients treated with placebo/pioglitazone was 9.1 % and 9.0 %, respectively.

In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions considered as drug-related reported in patients treated with sitagliptin in excess (> 0.2 % and difference> 1 patient) of that in patients receiving placebo are headache, hypoglycaemia, constipation, and dizziness.

In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5 % and more commonly in patients treated with JANUVIA included upper respiratory tract infection and nasopharyngitis.

Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with JANUVIA (not reaching the 5% level, but occurring with an incidence of > 0.5% higher with JANUVIA than that in the control group) included osteoarthritis and pain in extremity.

In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1000 mg), the overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to gastrointestinal adverse reactions.

Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microl difference in WBC vs placebo; mean baseline WBC approximately 6600 cells/microl) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters is not considered to be clinically relevant.

No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with JANUVIA treatment..

Post-marketing Experience:

During post-marketing experience the following additional side-effects have been reported (frequency not known): hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome.

Merck Sharp & Dohme

(POM)

12 August 2009