Sitagliptin Zydus 25/50/100 25 mg, 50 mg, 100 mg TABLET

Monotherapy

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

Combination therapy

SITAGLIPTIN ZYDUS is also indicated in patients with type 2 diabetes mellitus to improve glycaemic control in combination with metformin or a peroxisome proliferator-activated receptor gamma PPAR u03b3 agonist (e.g. thiazolidinedione) when diet and exercise, plus the single medicine do not provide adequate glycaemic control. The combination of SITAGLIPTIN ZYDUS and sulphonylureas has not been adequately studied.

Posology

The dose of SITAGLIPTIN ZYDUS in combination with metformin or a PPAR y agonist is 100 mg once daily. The dosage of metformin or PPAR y agonist should be maintained, and SITAGLIPTIN ZYDUS administered concomitantly. If a dose of SITAGLIPTIN ZYDUS is missed, it should be taken as soon as the patient remembers. A double dose of SITAGLIPTIN ZYDUS 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/L in men and u2264 133 u03bcmol/L in women), no dosage adjustment for SITAGLIPTIN ZYDUS is required.

For patients with moderate renal insufficiency (CrCl u2265 30 to u2264 50 mL/min, approximately corresponding to serum creatinine levels of > 150 u03bcmol/L to 133 u03bcmol/L to not < 221 u03bcmol/L in women), the dose of SITAGLIPTIN ZYDUS 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 u03bcmol/L in men and > 221 u03bcmol/L in women) or with end-stage renal disease requiring haemodialysis, the dose of SITAGLIPTIN ZYDUS is 25 mg once daily. SITAGLIPTIN ZYDUS 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 ZYDUS has not been studied in patients with severe hepatic insufficiency (see section 4.3).

Elderly patients: No dosage adjustment is necessary for elderly patients.

Paediatric population: There are no data available on the use of SITAGLIPTIN ZYDUS in patients younger than 18 years of age. Therefore, use of SITAGLIPTIN ZYDUS in paediatric patients is not recommended.

Method of administration

Oral use. SITAGLIPTIN ZYDUS can be taken with or without food.

• Hypersensitivity to sitagliptin or to any of the excipients listed in section 6.1;
• A history of severe hypersensitivity reaction, such as anaphylaxis or angioedema to SITAGLIPTIN ZYDUS or any other gliptins (DPP-4) (see section 4.4);
• SITAGLIPTIN ZYDUS has not been studied in patients with severe hepatic insufficiency (see section 5.2).

Hypersensitivity reactions

Post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin 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 some reports occurring after the first dose. If a hypersensitivity reaction is suspected, SITAGLIPTIN ZYDUS should be discontinued immediately. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated (see section 4.3).

Diabetes

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

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 ZYDUS (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported (see section 4.8). If pancreatitis is suspected, SITAGLIPTIN ZYDUS and other potentially suspect medicines should be discontinued; if acute pancreatitis is confirmed, SITAGLIPTIN ZYDUS 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 ZYDUS 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 ZYDUS is renally excreted. A dosage adjustment is recommended in patients with moderate or severe renal impairment, and in patients with end-stage renal disease requiring haemodialysis or peritoneal dialysis. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower doses of SITAGLIPTIN ZYDUS are recommended in patients with glomerular filtration rate (GFR) < 45 mL/min, as well as in end stage renal disease (ESRD) patients requiring haemodialysis or peritoneal dialysis (see section 4.2 and 5.2). When considering the use of SITAGLIPTIN ZYDUS in combination with another anti-diabetic medicine, its conditions for use in patients with renal impairment should be checked.

Bullous pemphigoid

There have been reports of bullous pemphigoid in patients taking DPP-4 inhibitors including sitagliptin. SITAGLIPTIN ZYDUS should be discontinued if bullous pemphigoid is suspected.

Effects of other medicines on SITAGLIPTIN ZYDUS

Clinical data suggest that the risk for clinically meaningful interactions by co-administered medicines discussed below is low. 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 ZYDUS. Metabolism may play a more significant role in the elimination of SITAGLIPTIN ZYDUS 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 ZYDUS 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 ZYDUS did not meaningfully alter the pharmacokinetics of SITAGLIPTIN ZYDUS 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 ZYDUS and a single 600 mg oral dose of ciclosporin increased the area under the curve (AUC) and peak concentration (C max) of SITAGLIPTIN ZYDUS by approximately 29 % and 68 %, respectively. These changes in SITAGLIPTIN ZYDUS pharmacokinetics were not considered to be clinically meaningful. The renal clearance of SITAGLIPTIN ZYDUS was not meaningfully altered. Therefore, meaningful interactions would not be expected with ciclosporin or other p-glycoprotein inhibitors (e.g. ketoconazole).

Effects of SITAGLIPTIN ZYDUS on other medicines

Digoxin

SITAGLIPTIN ZYDUS 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 area under the curve (AUC) of digoxin was increased on average by 11 %, and the plasma peak concentration (C max) on average by 18 %. No dose adjustment of digoxin or SITAGLIPTIN ZYDUS is recommended. However, patients at risk of digoxin toxicity should be monitored for this when SITAGLIPTIN ZYDUS and digoxin are administered concomitantly.

Other medicines

In vitro data suggest that SITAGLIPTIN ZYDUS does not inhibit nor induce CYP450 isoenzymes. In interaction 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 ZYDUS may be a mild inhibitor of p-glycoprotein in vivo. Based on in vitro data, SITAGLIPTIN ZYDUS is also not expected to inhibit CYP2D6, 1A2, C19 or 2B6, or to induce CYP3A4.

Pregnancy

There are no adequate data from the use of SITAGLIPTIN ZYDUS in pregnant women. SITAGLIPTIN ZYDUS should not be used during pregnancy.

Lactation

It is unknown whether SITAGLIPTIN ZYDUS is excreted in human breast milk. SITAGLIPTIN ZYDUS should not be used during breastfeeding.

Fertility

Animal data do not suggest an effect of SITAGLIPTIN ZYDUS on male and female fertility. Human data are lacking (see section 5.3).

SITAGLIPTIN ZYDUS 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 with the use of SITAGLIPTIN ZYDUS and caution is advised until the effects of SITAGLIPTIN ZYDUS are known. In addition, patients should be alerted to the risk of hypoglycaemia when SITAGLIPTIN ZYDUS 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 with the use of SITAGLIPTIN ZYDUS. Hypoglycaemia has been reported in combination with sulphonylurea (4.7 % - 13.8 %) and insulin (9.6 %) (see section 4.4).

Table 1: Adverse reactions of SITAGLIPTIN ZYDUS monotherapy

* Adverse reactions were identified post-marketing. # See section 4.4.

Description of selected adverse reactions

In addition to the adverse reactions described above, adverse reactions reported regardless of causal relationship to medicine and occurring in at least 5 % and more commonly in patients treated with SITAGLIPTIN ZYDUS included upper respiratory tract infection and nasopharyngitis. Additional adverse reactions reported regardless of causal relationship to medicine that occurred more frequently in patients treated with SITAGLIPTIN ZYDUS (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with SITAGLIPTIN ZYDUS than that in the control group) included osteoarthritis and pain in extremity. Some adverse reactions were observed more frequently in studies of combination use of SITAGLIPTIN ZYDUS with other antidiabetic medicines than in studies of SITAGLIPTIN ZYDUS monotherapy. These included hypoglycaemia (occurring frequently with the combination of sulphonylurea and metformin), influenza (occurring frequently with insulin (with or without metformin)), nausea and vomiting (occurring frequently with metformin), flatulence (occurring frequently with metformin or pioglitazone), constipation (occurring frequently with the combination of sulphonylurea and metformin), peripheral oedema (occurring frequently with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (occurring less frequently with metformin), and dry mouth (occurring less frequently with insulin (with or without metformin)).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of SITAGLIPTIN ZYDUS is important. It allows continued monitoring of the benefit/risk balance of SITAGLIPTIN ZYDUS. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

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 ZYDUS is modestly dialysable. Prolonged haemodialysis may be considered if clinically appropriate. It is not known if SITAGLIPTIN ZYDUS is dialysable by peritoneal dialysis.