Glusita 100 Mg/25 mg/50 mg Tablets

Monotherapy: GLUSITA is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus. Combination therapy: GLUSITA is also indicated in patients with type 2 diabetes mellitus to improve glycaemic control in combination with metformin or a PPARu03b3 agonist (e.g. thiazolidinedione) when diet and exercise plus the single medicine does not provide adequate glycaemic control. The combination of sitagliptin and sulphonylureas has not been adequately studied.

Posology: The dose of GLUSITA in combination with metformin or a PPARu03b3 agonist is 100 mg once daily. The dosage of metformin or PPARu03b3 agonist should be maintained, and GLUSITA administered concomitantly. Special populations: Renal impairment: For patients with mild renal insufficiency (creatinine clearance [CrCl] u2265 50 ml/min, approximately corresponding to serum creatinine levels of u2264 150 u03bcmol/litre in men and u2264 133 u03bcmol/litre in women), no dosage adjustment for GLUSITA is required. For patients with moderate renal insufficiency (CrCl u2265 30 to 150 u03bcmol/litre to u2264 265 u03bcmol/litre in men and > 133 u03bcmol/litre to u2264 221 u03bcmol/litre in women), the dose of GLUSITA is 50 mg once daily. The dose should be decreased if CrCl decreases to < 30 ml/min. For patients with severe renal insufficiency (CrCl 265 u03bcmol/litre in men and > 221 u03bcmol/litre in women), or with end-stage renal disease requiring haemodialysis, the dose of GLUSITA is 25 mg once daily. GLUSITA may be administered without regard to the timing of haemodialysis. Hepatic impairment: No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. GLUSITA has not been studied in patients with severe hepatic insufficiency. Elderly: No dosage adjustment is necessary for elderly patients. Paediatric Population: There are no data available on the use of GLUSITA in patients younger than 18 years of age. Therefore, the use of GLUSITA in paediatric patients is not recommended. Method of administration: For oral use. GLUSITA can be taken with or without food. If a dose of GLUSITA is missed, it should be taken as soon as the patient remembers. A double dose of GLUSITA should not be taken on the same day.

GLUSITA is contraindicated in patients who are hypersensitive to sitagliptin or to any of the excipients listed in section 6.1. A history of serious hypersensitivity reactions such as anaphylaxis and angioedema to GLUSITA or other gliptins (DPP-4). GLUSITA has not been studied in patients with severe hepatic insufficiency (see section 5.2 u201cHepatic Impairmentu201d).

General: GLUSITA should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis. Acute pancreatitis: Use of DPP-4 inhibitors has been associated with a risk of developing 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 necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, GLUSITA and other potentially suspect medicines should be discontinued; if acute pancreatitis is confirmed, GLUSITA should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hypoglycaemia when used in combination with other anti-hyperglycaemic medicines: In clinical trials of sitagliptin as contained in GLUSITA as monotherapy and as part of combination therapy with medicines not known to cause hypoglycaemia (i.e. metformin and/or a PPARu03b3 agonist), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. Hypoglycaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea. Therefore, to reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see section 4.2). Renal impairment: Sitagliptin is renally excreted. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in End Stage Renal Disease (ESRD) patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2). Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, GLUSITA should be discontinued. Sodium: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Effects of other medicines on sitagliptin: Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicines is low. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP 3A4, 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 pharmacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effect 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 evaluated in vivo. 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 Cmax 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. Effects of sitagliptin on other medicines: Digoxin: Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of 0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of digoxin was increased on average by 11%, and the plasma Cmax on average by 18%. No dose 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 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 may be a mild inhibitor of p-glycoprotein in vivo.

Pregnancy: There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, GLUSITA should not be used during pregnancy. Breast feeding: It is unknown whether sitagliptin is excreted in human breast milk. Animal studies have shown excretion of sitagliptin in breast milk. GLUSITA should not be used during breastfeeding. Fertility: Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

GLUSITA has no or negligible influence on the ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness and somnolence have been reported. In addition, patients should be alerted to the risk of hypoglycaemia when GLUSITA is used in combination with a sulphonylurea or with insulin.

Summary of the safety profile: Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea and insulin (see section 4.4). Table 1: The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy, and post-marketing experience. System Organ Class Frequent Less frequent Frequency Unknown Blood and Lymphatic System Disorders: Thrombocytopenia. Immune System Disorders: Hypersensitivity reactions including anaphylactic responses*,u2020. Metabolism and Nutrition Disorders: Hypoglycaemiau2020. Nervous System Disorders: Headache, Dizziness, somnolence. Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease*. Gastrointestinal Disorders: Nausea, flatulence, Constipation, diarrhoea, upper abdominal pain, Vomiting*, acute pancreatitis*, fatal and non-fatal haemorrhagic and necrotising pancreatitis*,u2020. Skin and Subcutaneous Tissue Disorders: Pruritus, Angioedema*,u2020, rash*,u2020, urticaria*,u2020, cutaneous vasculitis*,u2020, exfoliative skin conditions including Stevens-Johnson syndrome*,u2020, bullous pemphigoid*. Musculoskeletal and connective tissue disorders: Arthralgia*, myalgia*, back pain*, arthropathy*. Renal and Urinary Disorders: Impaired renal function*, acute renal failure*. Investigations: Decreased blood glucose levels. General disorders: Peripheral oedema. *Adverse reactions were identified through post-marketing surveillance. u2020 See section 4.4.

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. Sitagliptin is modestly dialysable. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis.