SITAGLIPTIN SANDOZ 100 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Sitagliptin Sandoz 100 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains sitagliptin hydrochloride monohydrate equivalent to 100 mg sitagliptin.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Light brown, round, biconvex film-coated tablet debossed with “ST 100” on one side; diameter 9.7 – 10.6 mm.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For adult patients with type 2 diabetes mellitus, Sitagliptin is indicated to improve glycaemic control: as monotherapy

in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance.

as dual oral therapy in combination with

metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control.

a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance.

a peroxisome proliferator-activated receptor gamma (PPAR ) agonist (i.e. a thiazolidinedione) when use of a PPARD agonist is appropriate and when diet and exercise plus the PPARD agonist alone do not provide adequate glycaemic control.

as triple oral therapy in combination with

a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.

a PPARD agonist and metformin when use of a PPARD agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control.

Sitagliptin is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycaemic control.

4.2 Posology and method of administration

Posology

The dose is 100 mg sitagliptin once daily. When used in combination with metformin and/or a PPAR agonist, the dose of metformin and/or PPAR agonist should be maintained, and sitagliptin administered concomitantly. When sitagliptin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see section 4.4).

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

Special populations

Renal impairment

When considering the use of sitagliptin in combination with another antidiabetic medicinal product, its conditions for use in patients with renal impairment should be checked.

For patients with mild renal impairment (glomerular filtration rate [GFR] □ 60 to < 90 ml/min), no dose adjustment is required.

For patients with moderate renal impairment (GFR □ 45 to < 60 mL/min), no dose adjustment is required.

For patients with moderate renal impairment (GFR □ 30 to < 45 mL/min), the dose of sitagliptin is 50 mg once daily.

For patients with severe renal impairment (GFR > 15 to <30 mL/min) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring haemodialysis or peritoneal dialysis, the dose of sitagliptin is 25 mg once daily. Treatment may be administered without regard to the timing of dialysis.

Because there is a dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of sitagliptin and periodically thereafter.

Hepatic impairment

No dose adjustment is necessary for patients with mild to moderate hepatic impairment. Sitagliptin has not been studied in patients with severe hepatic impairment and care should be exercised (see section 5.2).

However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Elderly

No dose adjustment is necessary based on age.

Paediatric population

Sitagliptin should not be used in children and adolescents 10 to 17 years of age because of insufficient efficacy. Currently available data are described in sections 4.8, 5.1, and 5.2. Sitagliptin has not been studied in paediatric patients under 10 years of age.

Method of administration

Sitagliptin can be taken with or without food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4 and 4.8).

4.4 Special warnings and precautions for use

General

Sitagliptin 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 (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Sitagliptin and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Sitagliptin should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Hypoglycaemia when used in combination with other anti-hyperglycaemic medicinal products In clinical trials of sitagliptin as monotherapy and as part of combination therapy with medicinal products not known to cause hypoglycaemia (i.e. metformin and/or a PPAR 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 doses are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis (see section 4.2 and 5.2).

When considering the use of sitagliptin in combination with another antidiabetic medicinal product, its conditions for use in patients with renal impairment should be checked.

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 should be discontinued. Other potential causes for the event should be assessed, and alternative treatment for diabetes initiated.

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 should be discontinued.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sitagliptin

Clinical data described below suggest that the risk for clinically meaningful interactions by co-administered medicinal products 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. 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. Coadministration 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 medicinal products

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 Cmaxon 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of sitagliptin 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 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. Sitagliptin should not be used during breast-feeding.

Fertility

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

4.7 Effects on ability to drive and use machines

Sitagliptin 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 sitagliptin is used in combination with a sulphonylurea or with insulin.

4.8 Undesirable effects

Summary of the safety profile

Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (4.7 %-13.8 %) and insulin (9.6 %) (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions are listed below (Table 1) by system organ class and frequency. Frequencies are

defined as: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).

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

*T^            7            n 7–7– rTt 1      :      1 7 Ti

Adverse reactions were identified through post-marketing surveillance.

t See section 4.4.

See TECOS Cardiovascular Safety Study below.

Description of selected adverse reactions

In addition to the drug-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 sitagliptin 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 sitagliptin (not reaching the 5 % level, but occurring with an incidence of > 0.5 % higher with sitagliptin 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 with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).

Paediatric population

In clinical trials with sitagliptin in paediatric patients with type 2 diabetes mellitus aged 10 to17 years, the profile of adverse reactions was comparable to that observed in adults.

TECOS Cardiovascular Safety Study

The Trial Evaluating Cardiovascular Outcomes with sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was > 30 and

< 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population.

Both treatments were added to usual care targeting regional standards for HbAic and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo. In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7 % in sitagliptin-treated patients and 2.5 % in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0 % in sitagliptin-treated patients and 0.7 % in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3 % in sitagliptin-treated patients and 0.2 % in placebo-treated patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Absorption

Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose, mean plasma AUC of sitagliptin was 8.52 LiVhlir, Cmax was 950 nM. The absolute bioavailability of sitagliptin is approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics, sitagliptin may be administered with or without food.

Plasma AUC of sitagliptin increased in a dose-proportional manner. Doseproportionality was not established for Cmax and C24hr(Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than doseproportional manner).

Distribution

The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound to plasma proteins is low (38 %).

Biotransformation

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79 % of sitagliptin is excreted unchanged in the urine.

Following a [14C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.

Elimination

Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100 % of the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of dosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was approximately 350 ml/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2 transporters. In vitro, sitagliptin did not inhibit OAT3 (IC50=160 |iM) or p-glycoprotein (up to 250 iiM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.

Characteristics in patients

The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.

Renal impairment

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with mild, moderate, and severe renal impairment, as well as patients with ESRD on haemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild, moderate, or severe renal impairment (including ESRD) were assessed using population pharmacokinetic analyses.

Compared to normal healthy control subjects, plasma AUC of sitagliptin was increased by approximately 1.2-fold and 1.6-fold in patients with mild renal impairment (GFR > 60 to

< 90 mL/min) and patients with moderate renal impairment (GFR > 45 to < 60 mL/min), respectively.

Because increases of this magnitude are not clinically relevant, dose adjustment in these patients is not necessary.

Plasma AUC of sitagliptin was increased approximately 2-fold in patients with moderate renal impairment (GFR > 30 to < 45 mL/min), and approximately 4-fold in patients with severe renal impairment (GFR < 30 mL/min), including in patients with ESRD on haemodialysis. Sitagliptin was modestly removed by haemodialysis (13.5 % over a 3– to 4-hour haemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower doses are recommended in patients with GFR < 45 mL/min (see section 4.2).

Hepatic impairment

No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment

(Child-Pugh score D9). There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the pharmacokinetics of sitagliptin.

Elderly

No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of sitagliptin compared to younger subjects.

Paediatric population

The pharmacokinetics of sitagliptin (single dose of 50 mg, 100 mg or 200 mg) were investigated in paediatric patients (10 to 17 years of age) with type 2 diabetes. In this population, the dose-adjusted AUC of sitagliptin in plasma was approximately 18 % lower compared to adult patients with type 2 diabetes for a 100 mg dose. This is not considered to be a clinically meaningful difference compared to adult patients based on the flat PK/PD relationship between the dose of 50 mg and 100 mg. No studies with sitagliptin have been performed in paediatric patients with age <10 years.

Other patient characteristics

No dose adjustment is necessary based on gender, race, or body mass index (BMI). These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

5.3 Preclinical safety data

Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these findings for humans is unknown. Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.

Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumours in rats was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans.

No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.

In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.

Reproductive toxicity studies showed a slight treatment-related increased incidence of foetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels. Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/plasma ratio: 4:1).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Calcium hydrogen phosphate (E341)

Cellulose, microcrystalline (E460)

Croscarmellose sodium (E468) Magnesium stearate (E470b) Sodium stearyl fumarate

Coating:

Hypromellose (E464)

Hydroxypropyl­cellulose (E463)

Macrogol (E1521)

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Iron oxide, black (E172)

Talc (E553b)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

OPA/Al/PVCAl blisters

Transparent PVC/PE/PVDCA1 blisters

28, 30, 50, 56, 60, 84, 90, 98, 100, 105, 108, 110, 112, 120, 168, 180, 196, 198 or 200 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Sandoz Limited

Park View, Riverside Way

Watchmoor Park

Camberley, Surrey

GU15 3YL

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 04416/1583

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/03/2021