Dibestor 25, 50 & 100 mg FC tablet

Monotherapy
DIBESTOR is indicated as an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus.
Combination Therapy
DIBESTOR is indicated in patients with type 2 diabetes mellitus to improve glycaemic control in combination with metformin or a PPAR u03b3 (peroxisome proliferator-activated receptor gamma) agonist (e.g. thiazolidinedione) when diet and exercise, plus the single agent do not provide adequate glycaemic control. The combination of sitagliptin and sulphonylureas has not been adequately studied.

Posology
The dose is 100 mg once daily when taken in combination with metformin or a PPAR u03b3 agonist. The dosage of metformin or PPAR u03b3 agonist should be maintained, and DIBESTOR administered concomitantly.
If a dose of DIBESTOR is missed, it should be taken as soon as the patient remembers. A double dose of DIBESTOR should not be taken on the same day.
Special populations
Patients with renal insufficiency
No dosage adjustment for DIBESTOR is required for patients with mild renal insufficiency. Mild renal insufficiency is defined as 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. The dose of DIBESTOR is 50 mg once daily 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). This dose should be decreased if CrCl decreases to < 30ml/min. The dose of DIBESTOR is 25 mg once daily 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. DIBESTOR may be administered without regard to the timing of haemodialysis.
Patients with hepatic insufficiency
Sitagliptin has not been studied in patients with severe hepatic insufficiency. No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency.
Elderly
No dosage adjustment is necessary for elderly patients.
Paediatric population
The safety and efficacy of DIBESTOR in children aged under 18 years has not yet been established. Therefore, use of DIBESTOR in paediatric patients is not recommended.
Method of administration
For oral use. DIBESTOR may be taken with or without food.

Hypersensitivity to sitagliptin, other gliptins or to any of the excipients (see section 6.1)

General
DIBESTOR should not be used for the treatment of diabetic ketoacidosis or in patients with type 1 diabetes.
Acute pancreatitis
Patients should be told of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. A risk of developing acute pancreatitis has been associated with the use of DPP-4 inhibitors. After discontinuation of sitagliptin a resolution of pancreatitis has been observed (with or without supportive treatment). Cases of haemorrhagic or necrotising pancreatitis and/or death have been reported. DIBESTOR and other potentially suspect medicines should be discontinued if pancreatitis is suspected. If acute pancreatitis is confirmed, DIBESTOR should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Hypersensitivity reactions
There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. 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 sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue DIBESTOR immediately and institute an alternative class of medicines for treatment for diabetes (see sections 4.3 and 4.8).
Hypoglycaemia when used in combination with other anti-hyperglycaemic medicines
Hypoglycaemia has been observed when sitagliptin was used in combination with sulphonylurea or insulin. Clinical trials have indicated sitagliptin as monotherapy and as part of combination therapy with medicines not known to cause hypoglycaemia (i.e. PPARu03b3 agonist and/or metformin), rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo. 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. Lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see sections 4.2 and 5.2) to achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function. Conditions for use in patients with renal impairment should be checked, when considering the use of sitagliptin in combination with another anti-diabetic medicine.
Bullous pemphigoid
There have been reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. DIBESTOR should be discontinued if bullous pemphigoid is suspected.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium freeu2019.

Sitagliptin does not have clinically meaningful effects on the pharmacokinetics of the following: simvastatin, metformin, warfarin, glyburide and oral contraceptives. Based on this, sitagliptin does not inhibit CYP isoenzymes CYP3A4, 2C8 or 2C9. According to in vitro data, sitagliptin is also not expected to induce CYP3A4 or to inhibit CYP2D6, 1A2, 2C19 or 2B6. There is limited information on multiple dose co-administration of these medicines. Although there was a slight increase in the mean peak medicine concentration (C max 18 %) and area under the curve (AUC 11 %) of digoxin with the co-administration of sitagliptin; these increases are not considered likely to be clinically significant. No dosage adjustment of digoxin or DIBESTOR is recommended. Patients receiving digoxin should be monitored appropriately. In subjects with co-administration of a single 100 mg oral dose of DIBESTOR and a single 600 mg oral dose of ciclosporin (a potent probe inhibitor of p-glycoprotein), the C max and AUC of DIBESTOR were increased approximately 68 % and 29 % respectively. No dosage adjustment for DIBESTOR is recommended when co-administered with ciclosporin or other p-glycoprotein inhibitors (e.g. ketoconazole), as the observed changes in DIBESTOR pharmacokinetics are not considered likely to be clinically significant. The risk for clinically meaningful interactions by co-administered medicines is low as described by the clinical data below. In vitro studies showed that CYP3A4 is the primary enzyme responsible for the limited metabolism of sitagliptin, with contribution from CYP2C8. Metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin, in patients with normal renal function. However, 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). Therefore, in patients with severe renal impairment or ESRD, it is possible that potent CYP3A4 inhibitors (i.e. itraconazole, ketoconazole, clarithromycin, ritonavir) could alter the pharmacokinetics of sitagliptin. A clinical study has not been assessed the effect of potent CYP3A4 inhibitors in the setting of renal impairment. In vitro transport studies showed that sitagliptin is a substrate for organic anion transporter-3 (OAT3) and p-glycoprotein. In vitro, Probenecid inhibited OAT3 mediated transport of sitagliptin. The risk of clinically significant interactions is low. In vivo, concomitant administration of OAT3 inhibitors has not been evaluated. Metformin: In patients with type 2 diabetes the co-administration with 50 mg sitagliptin and multiple twice-daily doses of 1,000 mg metformin did not meaningfully alter the pharmacokinetics of sitagliptin.

Pregnancy
DIBESTOR is not recommended for use in pregnancy as there are no studies in pregnant women.
Breastfeeding
DIBESTOR should not be used by a woman who are breastfeeding as it is not known whether DIBESTOR is excreted in human breast milk. Animal studies indicate sitagliptin is excreted in breast milk.
Fertility
Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

DIBESTOR may cause dizziness and somnolence, therefore patients taking DIBESTOR should not drive or use machines until their individual susceptibility to dizziness and somnolence is known.

MedDRA system organ class
Frequency
Adverse reactions
Blood and lymphatic system disorders
Less frequent
Thrombocytopenia
Immune system disorders
Frequency not known
hypersensitivity reactions including anaphylactic responses
Metabolism and nutrition disorders
Frequent
Hypoglycaemia (when taken with PPARu03b3 Agent)
Nervous system disorders
Frequent
Headache
Less Frequent
Dizziness, somnolence (when taken with Metformin)
Respiratory, thoracic and mediastinal disorders
Frequency not known
interstitial lung disease
Gastrointestinal disorders
Frequent
Nausea, flatulence (when taken with PPARu03b3 Agent)
Less Frequent
Diarrhoea, upper abdominal pain (when taken with Metformin), Constipation
Frequency not known
Vomiting, acute pancreatitis, fatal and non-fatal haemorrhagic and necrotizing pancreatitis
Skin and subcutaneous tissue disorders
Less Frequent
Pruritus
Frequency not known
Angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome, bullous pemphigoid
Musculoskeletal and connective tissue disorders
Frequency not known
Arthralgia, myalgia, back pain, arthropathy
Renal and urinary disorders
Frequency not known
Impaired renal function, acute renal failure
General disorders and administration site conditions
Frequent
Peripheral oedema (when taken with Metformin)
Investigations
Less frequent
Decreased blood glucose levels (when taken with Metformin)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

In the event of an overdose the usual supportive measures can be implemented e.g. employ clinical monitoring (including obtaining an electrocardiogram), remove unabsorbed material from the gastrointestinal tract and institute supportive therapy if required. Sitagliptin is dialysable and in clinical studies, approximately 13.5 % of the dose was removed over a 3-to-4-hour haemodialysis session. Therefore, prolonged haemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialysable by peritoneal dialysis. Single doses of up to 800 mg sitagliptin were generally well tolerated in controlled clinical studies in healthy subjects. At a dose of 800 mg minimal increases in QTc was observed and was found not be clinically relevant.