Metplitin Co 50 mg/850 mg/1000 mg Tablets

• METPLITIN CO 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.
• METPLITIN CO 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 agents: Metformin, sitagliptin or a sulphonylurea.

Posology

General

The dosage of antihyperglycaemic therapy with METPLITIN CO 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. METPLITIN CO 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 METPLITIN CO should be based on the patientu2019s current regimen. METPLITIN CO should be given twice daily with meals. The following doses are available:

• 50 mg sitagliptin/850 mg metformin hydrochloride
• 50 mg sitagliptin/1000 mg metformin hydrochloride

For patients switching from co-administration of sitagliptin and metformin

For patients switching from co-administration of sitagliptin and metformin, METPLITIN CO 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 agents: Sitagliptin, metformin or a sulphonylurea

The usual starting dose of METPLITIN CO 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 4.4).

No studies have been performed specifically examining the safety and efficacy of METPLITIN CO, in patients previously treated with other oral antihyperglycaemic agents and switched to METPLITIN CO. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring, as changes in glycaemic control can occur.

Special populations

Patients with Renal Insufficiency

METPLITIN CO should not be used in patients with renal failure or renal dysfunction e.g., serum creatinine levels u2265 133 micromol/l [males], u2265 124 micromol/l [females] or abnormal creatinine clearance (see section 4.3).

Elderly

As metformin and sitagliptin are excreted by the kidneys, METPLITIN CO 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 4.4)

Paediatric Population

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

Method of administration

METPLITIN CO is for oral use.

METPLITIN CO (sitagliptin hydrochloride monohydrate/metformin hydrochloride) is contraindicated in patients with:

• Known hypersensitivity to sitagliptin hydrochloride, metformin hydrochloride or any other component of METPLITIN CO (see section 6.1).
• Severe renal failure (GFR < 30 mL/min) (see section 4.4).
• Acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma.
• 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.
• Diabetic pre-coma.
• Hepatic impairment.
• Acute alcohol intoxication, alcoholism.
• Breastfeeding.

Acute pancreatitis

In post-marketing experience there have been reports of acute pancreatitis, including fatal and non-fatal haemorrhagic or necrotising pancreatitis in patients taking sitagliptin. 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. If pancreatitis is suspected, METPLITIN CO and other potentially suspect medicinal products should be discontinued immediately.

Hypersensitivity Reactions

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of METPLITIN CO. 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 METPLITIN CO immediately, and institute an alternative class of medicines for treatment for diabetes.

Use in the elderly

As metformin and sitagliptin are excreted by the kidneys, METPLITIN CO 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.

METPLITIN CO 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 METPLITIN CO. In patients with advanced age, 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 METPLITIN CO 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 METPLITIN CO discontinued if evidence of renal impairment is present.

Hypoglycaemia in combination with a sulphonylurea

When sitagliptin, a component of METPLITIN CO was used in combination with metformin and a sulphonylurea, a medication known to cause hypoglycaemia, the incidence of sulphonylurea-induced hypoglycaemia was increased 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). The use of METPLITIN CO in combination with insulin has not been studied.

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

METPLITIN CO 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 (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 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 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 anti-hyperglycaemic medicine should be adjusted during therapy with the other medicine and on its discontinuation.

Sitagliptin hydrochloride

In medicine interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of the following: Metformin, rosiglitazone, glyburide, simvastatin, warfarin and oral contraceptives. Based on these data, sitagliptin does not inhibit CYP isoenzymes CYP3A4, 2C8 or 2C9. Based on in vitro data, sitagliptin is also not expected to inhibit CYP2D6, 1A2, 2C19 or 2B6 or to induce CYP3A4.

Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on sitagliptin pharmacokinetics. Medications assessed were those that are commonly administered to patients with type 2 diabetes including cholesterol-lowering agents (e.g. statins, fibrates, ezetimibe), anti-platelet agents (e.g. clopidogrel), antihypertensives (e.g. ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory agents (e.g. naproxen, diclofenac, celecoxib), anti-depressants (e.g. bupropion, fluoxetine, sertraline), antihistamines (e.g. cetirizine), proton-pump inhibitors (e.g. omeprazole, lansoprozole), and medications for erectile dysfunction (e.g. sildenafil).

There was a slight increase in the area under the curve (AUC 11 %) and mean peak medicine concentration (C max 18 %) of digoxin with the co-administration of sitagliptin. These increases are not considered to be clinically meaningful. Patients receiving digoxin should be monitored appropriately. The AUC and C max of sitagliptin were increased approximately 29 % and 68 % respectively, in subjects with co-administration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of ciclosporin, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered to be clinically meaningful.

Metformin hydrochloride

Glyburide: In a single-dose interaction study in type 2 diabetes patients, co-administration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and C max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, make the clinical significance of this interaction uncertain.

Furosemide: A single-dose, metformin-furosemide medicine interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. Furosemide increased the metformin plasma and blood C max by 22 % and blood AUC by 15 %, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31 % and 12 % smaller respectively, than when administered alone, and the terminal half-life was decreased by 32 %, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when co-administered chronically.

Nifedipine: A single-dose, metformin-nifedipine medicine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C max and AUC by 20 % and 9 % respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

Cationic medicines: Cationic medicines (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim or vancomycin) that are eliminated by renal tubular secretion, theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine, has been observed in normal healthy volunteers in both single- and multiple-dose metformin-cimetidine medicine interaction studies, with a 60 % increase in peak metformin plasma and whole blood concentrations, and a 40 % increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of METPLITIN CO and/or the interfering medicine is recommended in patients who are taking cationic medications, that are excreted via the proximal renal tubular secretory system.

Other: Certain medicines tend to produce hyperglycaemia and may lead to loss of glycaemic control. These medicines include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking medicines and isoniazid. When such medicines are administered to a patient receiving METPLITIN CO, the patient should be closely observed to maintain adequate glycaemic control. In healthy volunteers the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when co-administered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein-bound medicines such as salicylates, sulphonamides, chloramphenicol and probenecid, as compared to the sulphonylureas, which are extensively bound to serum proteins.

Pregnancy

There are no adequate and well-controlled studies in pregnant women with METPLITIN CO or its individual components; therefore, the safety of METPLITIN CO in pregnant women is not known. METPLITIN CO is not recommended for use in pregnancy.

Breastfeeding

No studies in lactating animals have been conducted with the combined components of METPLITIN CO. METPLITIN CO should not be used by a woman who is breastfeeding an infant.

Fertility

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

METPLITIN CO 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 METPLITIN CO 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. Hypoglycaemia has been reported in combination with sulphonylurea (13,8 %) and insulin (10,9 %).

Sitagliptin and metformin

Tabulated summary of adverse reactions

Adverse drug reactions are classified by system organ class and frequency; within each frequency grouping, and listed in the table below.

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 Less frequent

Immune system disorders hypersensitivity reactions including anaphylactic responses *, u2020 Frequency not known

Metabolism and nutrition disorders hypoglycaemia u2020 Frequent

Nervous system disorders somnolence Less frequent

Respiratory, thoracic and mediastinal disorders interstitial lung disease * Frequency not known

Gastrointestinal disorders nausea, vomiting, flatulence Frequent

diarrhoea, constipation, upper abdominal pain Less frequent

acute pancreatitis *,u2020,u2021 , fatal and non-fatal haemorrhagic and necrotising pancreatitis *,u2020 Frequency not known

Skin and subcutaneous tissue disorders pruritus * Less frequent

angioedema *,u2020 , rash *,u2020 , urticaria *,u2020 , cutaneous vasculitis *,u2020 , exfoliative skin conditions including Stevens-Johnson syndrome *,u2020 , bullous pemphigoid * Frequency not known

Musculoskeletal and connective tissue disorders arthralgia * , myalgia * , pain in extremity * , back pain * , arthropathy * Frequency not known

Renal and urinary disorders impaired renal function * , acute renal failure * Frequency not known

*Adverse reactions were identified through post-marketing surveillance.

u2020 See section 4.4.

u2021 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 post-marketing 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 the combination of sitagliptin/metformin 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 u2265 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 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.

Sitagliptin hydrochloride

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin (see section 5.1, PHARMACOLOGICAL ACTION, Pharmacodynamics, Cardiac electrophysiology). There is no experience with doses above 800 mg in humans. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed 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. 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.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycaemia was reported in approximately 10 % of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32 % of metformin overdose cases (see section 4.4, Metformin hydrochloride). 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.