Sitagliptin /Metformin 500 mg/850 mg/1000 mg Film-Coated Tablets

SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus, already being treated with sitagliptin and metformin given separately.

SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA is also indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in patients with type 2 diabetes mellitus, inadequately controlled with any two of the three medicines: Metformin, sitagliptin or a sulphonylurea.

General

The dosage of antihyperglycaemic therapy with sitagliptin and metformin should be individualised on the basis of the patientu2019s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin.

The combination of sitagliptin and metformin should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects associated with metformin.

Dosing Recommendations

The starting dose of sitagliptin and metformin should be based on the patientu2019s current regimen. The combination of Sitagliptin and metformin should be given twice daily with meals. The following doses are available:

• 50 mg sitagliptin/500 mg metformin hydrochloride
• 50 mg sitagliptin/850 mg metformin hydrochloride
• 50 mg sitagliptin/1 000 mg metformin hydrochloride

For patients switching from co-administration of sitagliptin and metformin, SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA may be initiated at the dose of sitagliptin and metformin already being taken.

For patients inadequately controlled on dual combination therapy with any two of the following three antihyperglycaemic medicines: Sitagliptin, metformin or a sulphonylurea. The usual starting dose of sitagliptin and metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose). In determining the starting dose of the metformin component, the patientu2019s level of glycaemic control and current dose of metformin should be considered. Gradual dose escalation to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients currently on or initiating a sulphonylurea may require lower sulphonylurea doses to reduce the risk of sulphonylurea-induced hypoglycaemia (see section 4.8).

Sitagliptin/metformin hydrochloride combination is contraindicated in patients with:

• Known hypersensitivity to sitagliptin, metformin hydrochloride or any other component of SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA (see section 4.4 and 4.8).
• Renal disease or renal dysfunction e.g. as suggested by serum creatinine levels u2265 133 micromol/l [males], u2265 124 micromol/l [females], or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicaemia.
• Acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma.
• Acute or chronic disease which may cause tissue hypoxia such as:
• cardiac or respiratory failure,
• recent myocardial infarction,
• shock;
• Acute conditions with the potential to alter renal function such as:
• dehydration,
• severe infection,
• shock
• Hepatic impairment;
• Acute alcohol intoxication, alcoholism
• Breast-feeding.
• Severe renal failure (GFR < 30 mL/min) (see section 4.4)
• Diabetic pre-coma

The combination of sitagliptin and metformin should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because the use of such products may result in acute alteration of renal function (see section 4.4 and 4.8).

A history of severe hypersensitivity reaction, such as anaphylaxis or angioedema to the combination of sitagliptin and metformin or any other gliptins (DPP-4).

Hypersensitivity Reactions: There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA. 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 combination of sitagliptin and metformin immediately, and institute an alternative class of medicines for treatment for diabetes (see section 4.3 and 4.8).

Pancreatitis: In post-marketing experience there have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis (see section 4.8) in patients taking sitagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis: Persistent, severe abdominal pain. Resolution of pancreatitis has been reported after discontinuation of sitagliptin. If pancreatitis is suspected, combination of sitagliptin/metformin and other potentially suspect medicinal products should be discontinued immediately.

Use in the elderly: As metformin and sitagliptin are excreted by the kidneys, combination of sitagliptin and 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 section 4.8).

Special Precautions: The combination of sitagliptin and metformin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Monitoring of renal function: Metformin and sitagliptin are known to be substantially excreted by the kidneys. The risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive the combination of sitagliptin and metformin. In patients with advanced age, the combination of sitagliptin and metformin should be carefully titrated to establish the minimum dose for adequate glycaemic effect, because aging can be associated with reduced renal function. In elderly patients, particularly those 80 years of age or older, renal function should be monitored regularly.

Before initiation of therapy with the combination of sitagliptin /metformin and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and the combination of sitagliptin and metformin is contraindicated in patients with GFR < 30 mL/min and should be discontinued if evidence of renal impairment is present.

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 re-evaluated and found to be stable.

Hypoglycaemia in combination with a sulphonylurea: When sitagliptin, a component of SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA was used in combination with metformin and a sulphonylurea, a medication known to cause hypoglycaemia, the incidence of sulphonylurea-induced hypoglycaemia was reported to increase over that of placebo in combination with metformin and a sulphonylurea. Therefore, to reduce the risk of sulphonylurea-induced hypoglycaemia, a lower dose of sulphonylurea may be considered (see section 4.2).

Pharmacokinetic medicine interaction with the combination of sitagliptin and metformin have not been reported; however such interactions have been reported with the individual components of SITAGLIPTIN/METFORMIN 50/50; 50/850; 50/1000 SUN PHARMA, sitagliptin and metformin.

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

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 medicines: 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 re-evaluated and found to be stable.

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 medicines 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 coadministered.

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 anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Sitagliptin: Sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: Metformin, rosiglitazone, glyburide, simvastatin, warfarin and oral contraceptives. Sitagliptin has not been reported to inhibit CYP isoenzymes CYP3A4, 2C8 or 2C9. Sitagliptin is also not expected to inhibit CYP2D6, 1A2, 2C19 or 2B6 or to induce CYP3A4.

It has been reported that, concomitant medications that are commonly administered to patients with type 2 diabetes including cholesterol-lowering medicines (e.g. statins, fibrates, ezetimibe), anti-platelet medicines (e.g. clopidogrel), antihypertensives (e.g. ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory medicines (e.g. naproxen, diclofenac, celecoxib), anti-depressants (e.g. bupropion, fluoxetine, sertraline), antihistamines (e.g. cetirizine), proton-pump inhibitors (e.g. omeprazole, lansoprazole), and medications for erectile dysfunction (e.g. sildenafil), did not have a clinically meaningful effect on sitagliptin pharmacokinetics.

Pregnancy: There are no adequate and well-controlled reported studies in pregnant women with the combination of sitagliptin and metformin; therefore, the safety of the combination of sitagliptin and metformin in pregnant women is not known. Sitagliptin/metformin is not recommended for use in pregnancy. A limited amount of reported data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Reported animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development.

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.

Lactation: No studies in lactating animals have been reported with the combination of sitagliptin and metformin. Combination of sitagliptin and metformin should not be used by a woman who is breastfeeding an infant. In studies reported 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.

Fertility: Reported animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

No studies of the effects of sitagliptin/metformin on the ability to drive and use machines have been reported. However, sitagliptin/metformin is not expected to affect the ability to drive and use machines.

Although, 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.

Table: The adverse reaction reported in patients receiving sitagliptin in combination with metformin

Sitagliptin with Metformin

Sitagliptin with Metformin and a Sulphonylurea

System organ class

Frequent

Less frequent

Frequent

Less frequent

Investigations

Decreased blood glucose levels

Nervous system disorders

Somnolence

Gastrointestinal disorders

Nausea

Diarrhoea, Upper abdominal pain

Constipation

Metabolism and nutrition disorders

Hypoglycaemia

Table: The frequency of adverse reactions identified from reported 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

Less frequent

Immune system disorders

hypersensitivity reactions including anaphylactic responses

Less frequent

Metabolism and nutrition disorders

hypoglycaemia

frequent

Nervous system disorders

somnolence

Less frequent

Respiratory, thoracic and mediastinal disorders

interstitial lung disease

Less frequent

Gastrointestinal disorders

diarrhoea

Less frequent

nausea

frequent

flatulence

frequent

constipation

Less frequent

upper abdominal pain

Less frequent

vomiting

frequent

acute pancreatitis

Less frequent

fatal and non-fatal haemorrhagic and necrotizing pancreatitis

Less frequent

Skin and subcutaneous tissue disorders

pruritus

Less frequent

angioedema

Less frequent

rash

Less frequent

urticaria

Less frequent

cutaneous vasculitis

Less frequent

exfoliative skin conditions including Stevens - Johnson syndrome

Less frequent

bullous pemphigoid

Less frequent

Musculoskeletal and connective tissue disorders

arthralgia

Less frequent

myalgia

Less frequent

pain in extremity

Less frequent

back pain

Less frequent

arthropathy

Less frequent

Renal and urinary disorders

impaired renal function

Less frequent

acute renal failure

Less frequent

Sitagliptin: Single doses of up to 800 mg sitagliptin has been reported to be generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, has been reported at a dose of 800 mg sitagliptin (see section 5). There is no reported data with doses above 800 mg in humans. In reported Phase I multiple-dose studies, there were no dose-related clinical adverse reactions reported with sitagliptin with doses of up to 600 mg per day for 10 days and 400 mg per day for periods of up to 28 days. 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 is modestly dialysable. Approximately 13.5 % of the dose has been reported to be 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.

Metformin hydrochloride: Overdose of metformin hydrochloride has been reported, including ingestion of amounts greater than 50 grams. Hypoglycaemia has been reported in approximately 10 % of cases, but no causal association with metformin hydrochloride has been reported. Lactic acidosis has been reported in approximately 32 % of metformin overdose cases (see section 4.4). Metformin is dialysable with a clearance of up to 170 ml/min under good haemodynamic conditions. Therefore, haemodialysis may be useful for removal of accumulated medicine from patients in whom metformin overdosage is suspected.