Ristaben 25, 50 & 100 mg Tablets

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

Combination therapy
RISTABEN is indicated in patients with type 2 diabetes mellitus to improve glycaemic control in combination with metformin, pioglitazone, a sulphonyl urea or combinations thereof or insulin when diet and exercise, plus the other therapies do not provide adequate glycaemic control.

RISTABEN can be taken with or without food. The recommended dose of RISTABEN is 100 mg once daily as monotherapy or as combination therapy with metformin, a sulfonylurea, insulin (with or without metformin), a PPAR u03b3 agonist, metformin plus a sulphonylurea or metformin plus a PPAR u03b3 agonist.

When RISTABEN is used in combination with a sulphonylurea or with insulin, a lower dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see WARNINGS AND SPECIAL PRECAUTIONS, Hypoglycaemia in combination with a sulphonylurea or with insulin).

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

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 u03bcmol/litre in men and u2264 133 u03bcmol/litre in women), no dosage adjustment for RISTABEN 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 RISTABEN is 50 mg once daily. This dose should be decreased if CrCl decreases to < 30ml/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 or peritoneal dialysis, the dose of RISTABEN is 25 mg once daily. RISTABEN may be administered without regard to the timing of dialysis.

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

RISTABEN is contraindicated in:

• patients who are hypersensitive to any components of RISTABEN
• a history of hypersensitivity reactions, such as anaphylaxis and angioedema to RISTABEN or other gliptins (DPP-4)
• Type 1 diabetes mellitus
• Diabetes mellitus associated with ketoacidosis.

RISTABEN has not been studied in patients with severe hepatic insufficiency (see PHARMACOLOGICAL ACTION, Pharmacokinetic properties, Hepatic insufficiency).

Hypoglycaemia in combination with a sulphonylurea or with insulin
In clinical trials of RISTABEN as monotherapy and as part of combination therapy with agents not known to cause hypoglycaemia [i.e. metformin or a PPAR u03b3 agonist (thiazolidinedione)], rates of hypoglycaemia reported with RISTABEN were similar to rates in patients taking placebo. When RISTABEN was used in combination with a sulphonylurea or with insulin, the incidence of hypoglycaemia was increased over that of placebo (see SIDE EFFECTS). Therefore, to reduce the risk of sulphonylurea- or insulin-induced hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered (see DOSAGE AND DIRECTIONS FOR USE).

Renal insufficiency:
A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with end-stage renal disease requiring haemodialysis or peritoneal dialysis (see DOSAGE AND DIRECTIONS FOR USE, Patients with renal insufficiency).

Pancreatitis:
In post-marketing experience there have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotising pancreatitis (see SIDE EFFECTS, Post-marketing experience), in patients taking RISTABEN. Patients should be informed of the characteristic symptom of acute pancreatitis such as persistent, abdominal pain. Resolution of pancreatitis has been observed after discontinuation of RISTABEN. If pancreatitis is suspected, RISTABEN should be discontinued immediately.

Hypersensitivity Reactions:
There have been post-marketing reports of serious hypersensitivity reactions in patients treated with RISTABEN. These reactions include anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions usually occurred within the first 3 months after initiation of treatment with RISTABEN, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue RISTABEN immediately and institute an alternative class of medicines for treatment for diabetes (see CONTRAINDICATIONS and SIDE EFFECTS, Post-marketing experience).

There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors such as RISTABEN. The time to onset of symptoms following initiation of RISTABEN therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of RISTABEN. A subset of patients experienced a recurrence of symptoms when restarting RISTABEN or a different DPP-4 inhibitor. Consider RISTABEN as a possible cause for severe joint pain and discontinue RISTABEN if appropriate.

Effects on ability to drive and use machinery
No studies of the effects of RISTABEN on the ability to drive and use machines have been performed.

In interaction studies, RISTABEN did not have clinically meaningful effects on the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin and oral contraceptives. Based on these data, RISTABEN does not inhibit CYP isoenzymes CYP3A4, 2C8 or 2C9. Based on in vitro data, sitagliptin is also not expected to inhibit CYP2D6, 1A2, 2C19 or 2B6 or to induce CYP3A4. There is limited information on multiple dose co-administration of these agents.

There was an increase in the area under the curve (AUC, 11 %) and mean peak medicine concentration (C max 18 %) of digoxin with the co-administration of sitagliptin. Patients receiving digoxin should be monitored appropriately.

The AUC and C max of RISTABEN were increased approximately 29 % and 68 % respectively, in subjects with co-administration of a single 100 mg oral dose of RISTABEN and a single 600 mg oral dose of ciclosporin, a potent probe inhibitor of p-glycoprotein. The observed changes in RISTABEN pharmacokinetics are not considered likely to be clinically meaningful. No dosage adjustment for RISTABEN is recommended when co-administered with ciclosporin or other p-glycoprotein inhibitors (e.g. ketoconazole).

Pregnancy
There are no studies in pregnant women; therefore, RISTABEN is not recommended for use in pregnancy.

Lactation
RISTABEN is secreted in the milk of lactating rats. It is not known whether RISTABEN is secreted in human milk. Therefore, RISTABEN should not be used by women who are breastfeeding their infants.

Adverse reactions considered as medicine 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 by system organ class and frequency. Frequencies are defined as: Very common (u2265 1/10); Common (u2265 1/100, < 1/10); Uncommon (u2265 1/1 000, < 1/100); Rare (u2265 1/10 000, < 1/1 000); and Very rare (< 1/10 000).

Sitagliptin monotherapy
Infections and infestations
Common: upper respiratory tract infection, nasopharyngitis
Metabolism and nutrition disorders
Common: hypoglycaemia
Nervous system disorders
Common: headache
Uncommon: dizziness
Gastrointestinal disorders
Uncommon: constipation
Musculoskeletal and connective tissue disorders
Common: osteoarthritis, pain in extremity.

Sitagliptin with metformin
Metabolism and nutrition disorders
Common: hypoglycaemia
Nervous system disorders
Uncommon: somnolence
Gastrointestinal disorders
Common: nausea, flatulence, vomiting
Uncommon: diarrhoea, constipation, upper abdominal pain
Investigations
Uncommon: blood glucose.

Sitagliptin with sulphonylurea
Metabolism and nutrition disorders
Common: hypoglycaemia.

Sitagliptin with a sulphonylurea and metformin
Metabolism and nutrition disorders
Common: hypoglycaemia
Respiratory, thoracic and mediastinal disorders
Uncommon: rhinorrhoea
Gastrointestinal disorders
Uncommon: nausea.

Sitagliptin with a PPAR u03b3 agonist (pioglitazone)
Metabolism and nutrition disorders
Common: hypoglycaemia
Gastrointestinal disorders
Common: flatulence
General disorders and administration site conditions
Common: peripheral oedema
Investigations
Common: blood glucose.

Sitagliptin with a PPAR u03b3 agonist (pioglitazone) and metformin
Metabolism and nutrition disorders
Common: hypoglycaemia
General disorders and administration site conditions
Common: peripheral oedema.

Sitagliptin with insulin (+/-) metformin
Infections and infestations
Common: influenza
Metabolism and nutrition disorders
Common: hypoglycaemia
Nervous system disorders
Common: headache
Gastrointestinal disorders
Uncommon: dry mouth, constipation.

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 medicine 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 medicine-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 RISTABEN 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 RISTABEN (not reaching the 5 % level but occurring with an incidence of > 0,5 % higher with RISTABEN than that in the control group) included osteoarthritis and pain in extremity.

Post-marketing experience
During post-marketing experience the following additional side effects have been reported: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis and exfoliative skin conditions including Stevens-Johnson syndrome (see WARNINGS AND SPECIAL PRECAUTIONS); acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotising pancreatitis (see WARNINGS AND SPECIAL PRECAUTIONS, Pancreatitis); worsening renal function, including acute renal failure (sometimes requiring dialysis); vomiting, headache, constipation, nasopharyngitis, upper respiratory tract infection, arthralgia, myalgia, pain in extremity, back pain.

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. RISTABEN is not dialysable. In clinical studies, only about 13,5 % of the dose was removed over a 3 to 4 hour haemodialysis session. It is not known if RISTABEN is dialysable by peritoneal dialysis.