4.1. Therapeutic indications

For adult patients with type 2 diabetes mellitus:

Sitagliptin/Metformin is indicated as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin.

Sitagliptin/Metformin is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea.

Sitagliptin/Metformin is indicated as triple combination therapy with a peroxisome proliferatoractivated receptor gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.

Sitagliptin/Metformin is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycaemic control.

4.2. Posology and method of administration

Posology

The dose of antihyperglycaemic therapy with Sitagliptin/Metformin should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.

Adults with normal renal function (GFR ≥ 90 ml/min)

For patients inadequately controlled on maximal tolerated dose of metformin monotherapy

For patients not adequately controlled on metformin alone, the usual starting dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken.

For patients switching from co-administration of sitagliptin and metformin

For patients switching from co-administration of sitagliptin and metformin, Sitagliptin/Metformin should be initiated at the dose of sitagliptin and metformin already being taken.

For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When sitagliptin/metformin is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).

For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a PPARγ agonist

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken.

For patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose of metformin

The dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. When sitagliptin/metformin is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).

For the different doses on metformin, the combination of sitagliptin and metformin may also be available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1000 metformin hydrochloride.

All patients should continue their recommended diet with an adequate distribution of carbohydrate intake during the day.

Special populations

Renal impairment

No dose adjustment is needed for patients with mild renal impairment (glomerular filtration rate [GFR] ≥ 60 ml/min). A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see section 4.4) should be reviewed before considering initiation of metformin in patients with GFR < 60 ml/min.

If no adequate strength of Sitagliptin/Metformin is available, individual monocomponents should be used instead of the fixed-dose combination.

GFR ml/min

Metformin

Sitagliptin

60 - 89

Maximum daily dose is 3000 mg. Dose reduction may be considered in relation to declining renal function.

Maximum daily dose is 100 mg.

45 - 59

Maximum daily dose is 2000 mg. The starting dose is at most half of the maximum dose.

Maximum daily dose is 100 mg.

30 - 44

Maximum daily dose is 1000 mg. The starting dose is at most half of the maximum dose.

Maximum daily dose is 50 mg.

< 30

Metformin is contraindicated.

Maximum daily dose is 25 mg.

Hepatic impairment

Sitagliptin/metformin must not be used in patients with hepatic impairment (see section 5.2).

Elderly

As metformin and sitagliptin are excreted by the kidney, sitagliptin/metformin should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see sections 4.3 and 4.4).

Paediatric population

Sitagliptin/Metformin 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/Methformin has not been studied in paediatric patients under 10 years of age.

Method of administration

Sitagliptin/Metformin should be given twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.

4.3. Contraindications

Sitagliptin/metformin is contraindicated in patients with:

• hypersensitivity to the active substances or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8)

• any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

• diabetic pre-coma

• severe renal failure (GFR < 30 ml/min) (see section 4.4)

• acute conditions with the potential to alter renal function such as:

o dehydration

o severe infection

o shock

o intravascular administration of iodinated contrast agents (see section 4.4)

• acute or chronic disease which may cause tissue hypoxia such as:

o cardiac or respiratory failure

o recent myocardial infarction o shock

• hepatic impairment

• acute alcohol intoxication, alcoholism

• breast-feeding

4.4. Special warnings and precautions for use

General

Sitagliptin/metformin should not be used in patients with type 1 diabetes and must not be used 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/metformin and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, sitagliptin/metformin should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Lactic acidosis

Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (> 5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Sitagliptin/metformin is contraindicated in patients with GFR < 30 ml/min and should be temporarily discontinued during conditions with the potential to alter renal function (see section 4.3).

Hypoglycaemia

Patients receiving sitagliptin/metformin in combination with a sulphonylurea or with insulin may be at risk for hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.

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 sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, sitagliptin/metformin should be discontinued, other potential causes of the event should be assessed, and alternative treatment for diabetes should be instituted (see section 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/metformin should be discontinued.

Surgery

Sitagliptin/metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia. Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided, that renal function has been reevaluated and found to be stable.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Sitagliptin/metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been reevaluated and found to be stable (see sections 4.3 and 4.5).

Change in clinical status of patients with previously controlled type 2 diabetes

A patient with type 2 diabetes previously well controlled on sitagliptin/metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, treatment must be stopped immediately and other appropriate corrective measures initiated.

Vitamin B12

Metformin may reduce vitamin B12 serum levels. The risk of low vitamin B12 levels increases with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

Pharmacokinetic drug interaction studies with sitagliptin/metformin have not been performed; however, such studies have been conducted with the individual active substances, sitagliptin and metformin.

Concomitant use not recommended

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Sitagliptin/metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been reevaluated and found to be stable (see sections 4.3 and 4.4).

Combinations requiring precautions for use

Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when such products are co-administered.

Glucocorticoids (given by systemic and local routes) beta-2-agonists and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Effects of other medicinal products on sitagliptin

In vitro and clinical data described below suggest that the risk for clinically meaningful interactions following co-administration of other 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 effects of potent CYP3A4 inhibitors in the setting of renal impairment have 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.

Ciclosporin

A study was conducted to assess the effect of ciclosporin, a potent inhibitor of pglycoprotein, on the pharmacokinetics of sitagliptin. Co-administration 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 Cmax 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 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 of sitagliptin (see section 5.3).

A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see also section 5.3).

Sitagliptin/metformin should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment should be discontinued and the patient switched to insulin treatment as soon as possible.

Breast-feeding

No studies in lactating animals have been conducted with the combined active substances of this medicinal product. In studies performed with the individual active substances, both sitagliptin and metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. Sitagliptin/metformin must therefore not be used in women who are breast-feeding (see section 4.3).

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/metformin 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 sitagliptin.

In addition, patients should be alerted to the risk of hypoglycaemia when sitagliptin/metformin is used in combination with a sulphonylurea or with insulin.

4.8. Undesirable effects

Summary of the safety profile

There have been no therapeutic clinical trials conducted with sitagliptin/metformin tablets, however bioequivalence of sitagliptin/metformin with co-administered sitagliptin and metformin has been demonstrated (see section 5.2). Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (13.8 %) and insulin (10.9 %).

Tabulated list of adverse reactions

Sitagliptin and metformin

Adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1).

In this section, frequencies of undesirable effects are defined as follows: 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 and metformin alone, and post-marketing experience

Adverse reaction

Frequency of adverse reaction

Blood and lymphatic system disorders

Thrombocytopenia

Rare

Immune system disorders

Hypersensitivity reactions including anaphylactic responses* †

Not known

Metabolism and nutrition disorders

Hypoglycaemia †

Common

Vitamin B12 decrease/deficiency (see section 4.4).

Common

Nervous system disorders

Somnolence

Uncommon

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease*

Not known

Gastrointestinal disorders

Nausea.

Common

Flatulence.

Common

Vomiting.

Common

Diarrhoea.

Uncommon

Constipation.

Uncommon

Upper abdominal pain.

Uncommon

Acute pancreatitis * † ‡

Not known

Fatal and non-fatal haemorrhagic and necrotizing pancreatitis * †

Not known

Skin and subcutaneous tissue disorders

Pruritus *

Uncommon

Angioedema *†

Not known

Rash *†

Not known

Urticaria *†

Not known

Cutaneous vasculitis *†

Not known

Exfoliative skin conditions including Stevens-Johnson syndrome

Not known

Bullous pemphigoid *

Not known

Musculoskeletal and connective tissue disorders

Arthralgia *

Not known

Myalgia *

Not known

Pain in extremity *

Not known

Back pain *

Not known

Arthropathy *

Not known

Renal and urinary disorders

Impaired renal function *

Not known

Acute renal failure *

Not known

* Adverse reactions were identified through post-marketing surveillance.

† See section 4.4.

‡ See TECOS Cardiovascular Safety Study below.

Description of selected adverse reactions

Some adverse reactions were observed more frequently in studies of combination use of sitagliptin and metformin with other anti-diabetic medicinal products than in studies of sitagliptin and metformin alone. These included hypoglycaemia (frequency very common with sulphonylurea or insulin), constipation (common with sulphonylurea), peripheral oedema (common with pioglitazone), and headache and dry mouth (uncommon with insulin).

Sitagliptin

In monotherapy studies of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions reported were headache, hypoglycaemia, constipation, and dizziness.

Among these patients, adverse events reported regardless of causal relationship to medicinal product occurring in at least 5 % included upper respiratory tract infection and nasopharyngitis. In addition, osteoarthritis and pain in extremity were reported with frequency uncommon (> 0.5 % higher among sitagliptin users than that in the control group).

Metformin

Gastrointestinal symptoms were reported very commonly in clinical studies and postmarketing use of metformin. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases. Additional adverse reactions associated with metformin include metallic taste (common); lactic acidosis, liver function disorders, hepatitis, urticaria, erythema, and pruritus (very rare). Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anaemia). Frequency categories are based on information available from metformin Summary of Product Characteristics available in the EU.

Paediatric population

In clinical trials with Janumet in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, the profile of adverse reactions was generally comparable to that observed in adults. In paediatric patients on or not on background insulin, sitagliptin was associated with an increased risk of hypoglycaemia.

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 HbA1c 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 sitagliptintreated 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no doserelated clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.

A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis, which is a medical emergency and must be treated in hospital. The most effective method to remove lactate and metformin is haemodialysis.

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 is dialysable by peritoneal dialysis.

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.