Sitagliptin 100 Mg/25 mg/50 mg Tablets

Monotherapy

SITAGLIPTIN MEDFOUR is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus.

Combination Therapy

SITAGLIPTIN MEDFOUR 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 do not provide adequate glycaemic control. The combination of SITAGLIPTIN MEDFOUR and sulphonylureas has not been adequately studied.

Posology

The dose of SITAGLIPTIN MEDFOUR in combination with metformin or a PPARu03b3 agonist is 100 mg once daily. The dosage of metformin or PPARu03b3 agonist should be maintained, and SITAGLIPTIN MEDFOUR administered concomitantly.

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

Special populations

Patients with Renal Insufficiency

For patients with mild renal insufficiency (creatinine clearance [CrCl] u2265 50 mL/min, approximately corresponding to serum creatinine levels of u2264 150 micromol/litre in men and u2264 133 micromol/litre in women), no dosage adjustment for SITAGLIPTIN MEDFOUR is required.

For patients with moderate renal insufficiency (CrCl u2265 30 to 150 micromol/litre to u2264 265 micromol/litre in men and > 133 micromol/litre to not u2264 221 micromol/litre in women), the dose of SITAGLIPTIN MEDFOUR is 50 mg once daily. This dose should be decreased if CrCl decreases to < 30 mL/min.

For patients with severe renal insufficiency (CrCl 265 micromol/litre in men and > 221 micromol/litre in women) or with end-stage renal disease requiring haemodialysis, the dose of SITAGLIPTIN MEDFOUR is 25 mg once daily. SITAGLIPTIN MEDFOUR may be administered without regard to the timing of haemodialysis.

Patients with Hepatic Insufficiency

No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency. SITAGLIPTIN MEDFOUR 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 SITAGLIPTIN MEDFOUR in patients younger than 18 years of age. Therefore, use of SITAGLIPTIN MEDFOUR in paediatric patients is not recommended.

Method of administration

Oral. SITAGLIPTIN MEDFOUR can be taken with or without food.

• u2212 Hypersensitivity to sitagliptin hydrochloride or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8).
• u2212 A history of serious hypersensitivity reactions, such, as anaphylaxis and angioedema to SITAGLIPTIN MEDFOUR or other gliptins (DPP-4).
• u2212 SITAGLIPTIN MEDFOUR has not been studied in patients with severe hepatic insufficiency (see section 5.2).

General

SITAGLIPTIN MEDFOUR should not be used in patients with type 1 diabetes or 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 MEDFOUR (with or without supportive treatment) but cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, SITAGLIPTIN MEDFOUR and other potentially suspect medicines should be discontinued immediately. If acute pancreatitis is confirmed, SITAGLIPTIN MEDFOUR 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 SITAGLIPTIN MEDFOUR) 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 (as contained in SITAGLIPTIN MEDFOUR) were similar to rates in patients taking placebo. Hypoglycaemia has been observed when SITAGLIPTIN MEDFOUR 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 MEDFOUR is renally excreted. To achieve plasma concentrations of SITAGLIPTIN MEDFOUR similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal impairment, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see section 4.2 and 5.2). When considering the use of SITAGLIPTIN MEDFOUR in combination with another anti-diabetic medicines, its conditions for use in patients with renal impairment should be checked.

Hypersensitivity Reactions:

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin (as contained in SITAGLIPTIN MEDFOUR). These reactions included 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 sitagliptin (as contained in SITAGLIPTIN MEDFOUR), with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue SITAGLIPTIN MEDFOUR immediately. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated (see sections 4.3 and 4.8).

Bullous pemphigoid

There have been post-marketing reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. If bullous pemphigoid is suspected, SITAGLIPTIN MEDFOUR should be discontinued.

SITAGLIPTIN MEDFOUR contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Effects of other medicines on SITAGLIPTIN MEDFOUR

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 MEDFOUR 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 MEDFOUR 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 MEDFOUR 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 MEDFOUR is a substrate for p-glycoprotein and organic anion transporter-3 (OAT3). OAT3 mediated transport of SITAGLIPTIN MEDFOUR 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 MEDFOUR did not meaningfully alter the pharmacokinetics of SITAGLIPTIN MEDFOUR 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 (as contained in SITAGLIPTIN MEDFOUR). Co-administration of a single 100 mg oral dose of sitagliptin (as contained in SITAGLIPTIN MEDFOUR) and a single 600 mg oral dose of ciclosporin increased the AUC and C max of sitagliptin (as contained in SITAGLIPTIN MEDFOUR) by approximately 29 % and 68 %, respectively. These changes in sitagliptin (as contained in SITAGLIPTIN MEDFOUR) pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin (as contained in SITAGLIPTIN MEDFOUR) was not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

Effects of SITAGLIPTIN MEDFOUR on other medicines

Digoxin: Sitagliptin (as contained in SITAGLIPTIN MEDFOUR) 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 C max 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 MEDFOUR 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 MEDFOUR in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Due to lack of human data, SITAGLIPTIN MEDFOUR should not be used during pregnancy.

Breastfeeding

It is unknown whether SITAGLIPTIN MEDFOUR is excreted in human breast milk. Animal studies have shown excretion of SITAGLIPTIN MEDFOUR in breast milk. SITAGLIPTIN MEDFOUR should not be used during breastfeeding.

Fertility

Animal data do not suggest an effect of treatment with SITAGLIPTIN MEDFOUR on male and female fertility. Human data are lacking.

Dizziness and somnolence have been reported with sitagliptin, which may influence the ability to drive and use machines. In addition, patients should be alerted to the risk of hypoglycaemia when SITAGLIPTIN MEDFOUR is used in combination with a sulphonylurea or with insulin.

a. 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).

b. Tabulated list of adverse reactions

Table 1 The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin monotherapy and post-marketing experience

Blood and lymphatic system disorders

Less frequent Thrombocytopenia

Immune system disorders

Frequency unknown Hypersensitivity reactions including anaphylactic responses*,u2020, angioedema*,u2020

Metabolism and nutrition disorders

Frequent Hypoglycaemiau2020

Nervous system disorders

Frequent Headache

Less frequent Dizziness

Respiratory, thoracic and mediastinal disorders

Frequency unknown Interstitial lung disease*

Gastrointestinal disorders

Less frequent Constipation

Frequency unknown Vomiting*, acute pancreatitis*,u2020,u2021, fatal and non-fatal haemorrhagic and necrotising pancreatitis*,u2020

Skin and subcutaneous tissue disorders

Less frequent Pruritus*

Frequency unknown rash*,u2020, urticaria*,u2020, cutaneous vasculitis*,u2020, exfoliative skin conditions including Stevens-Johnson syndrome*,u2020, bullous pemphigoid*

Musculoskeletal and connective tissue disorders

Frequency unknown Arthralgia*, myalgia*, back pain*, arthropathy*

Renal and urinary disorders

Frequency unknown Impaired renal function*, acute renal failure*

*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 (as contained in SITAGLIPTIN MEDFOUR). There is no experience with doses above 800 mg in clinical studies.

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 MEDFOUR is modestly dialysable. In clinical studies, approximately 13,5 % of the dose was removed over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if SITAGLIPTIN MEDFOUR is dialysable by peritoneal dialysis.