Janumet 50 mg/1,000 mg film-coated tablets

Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin hydrochloride.

For a full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Capsule-shaped, red film-coated tablet with “577” debossed on one side.

For patients with type 2 diabetes mellitus:

Janumet 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.

Janumet 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.

Janumet is indicated as triple combination therapy with a peroxisome proliferator-activated 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.

Janumet 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.

Posology

The dose of antihyperglycaemic therapy with Janumet 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.

For patients inadequately controlled on maximal tolerated dose of metformin monotherapy

For patients not adequately controlled on metformin alone, the usual starting dose of Janumet 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, Janumet 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 of Janumet 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 Janumet 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 of Janumet 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 of Janumet 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 Janumet 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, Janumet is available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.

All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

Special populations

Renal impairment

Janumet should not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min) (see sections 4.3 and 4.4).

Hepatic impairment

Janumet should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).

Elderly

As metformin and sitagliptin are excreted by the kidney, Janumet 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). Limited safety data on sitagliptin is available in patients > 75 years of age and care should be exercised.

Paediatric population

Janumet is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy in this population.

Method of administration

Janumet should be given twice daily with meals to reduce the gastrointestinal undesirable effects associated with metformin.

Janumet is contraindicated in patients with:

- hypersensitivity to the active substances or to any of the excipients (see sections 4.4 and 4.8);

- diabetic ketoacidosis, diabetic pre-coma;

- moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);

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

      - dehydration,

      - severe infection,

      - shock,

      - intravascular administration of iodinated contrast agents (see section 4.4);

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

      - cardiac or respiratory failure,

      - recent myocardial infarction,

      - shock;

- hepatic impairment;

- acute alcohol intoxication, alcoholism;

- lactation.

General

Janumet should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis.

Pancreatitis

In post-marketing experience there have been spontaneously reported adverse reactions of 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 necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Janumet and other potentially suspect medicinal products should be discontinued.

Lactic acidosis

Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.

Diagnosis

Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately (see section 4.9).

Renal function

Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin-related lactic acidosis increases with the degree of impairment of renal function, therefore, serum creatinine concentrations should be determined regularly:

- at least once a year in patients with normal renal function

- at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients.

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).

Hypoglycaemia

Patients receiving Janumet 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

Postmarketing 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, discontinue Janumet, assess for other potential causes of the event, and institute alternative treatment for diabetes (see section 4.8).

Surgery

As Janumet contains metformin hydrochloride, the treatment should be discontinued 48 hours before elective surgery with general, spinal or epidural anaesthesia. Janumet should not usually be resumed earlier than 48 hours afterwards and only after renal function has been re-eva luated and found to be normal.

Administration of iodinated contrast agent

The intravascular administration of iodinated contrast agents in radiological studies can lead to renal failure which has been associated with lactic acidosis in patients receiving metformin. Therefore, Janumet should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal (see section 4.5).

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

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

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 Janumet have not been performed; however, such studies have been conducted with the individual active substances of Janumet, sitagliptin and metformin.

There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Janumet (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.

Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50 % and C_max by 81 %. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic agents that are eliminated by renal tubular secretion are co-administered.

The intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Janumet should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-eva luated and found to be normal (see section 4.4).

Combination requiring precautions for use

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

Clinical data described below suggest that the risk for clinically meaningful interactions following co-administration of other medicinal products is low.

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 and a single 600 mg oral dose of ciclosporin increased the AUC and C_max 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.

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 phamacokinetics of sitagliptin in patients with severe renal impairment or ESRD. The effects of p