1. Name of the medicinal product

Vildagliptin/Metformin Hydrochloride Tablets 50mg/500mg Taj Pharma
Vildagliptin/Metformin Hydrochloride Tablets 50mg/850mg Taj Pharma
Vildagliptin/Metformin Hydrochloride Tablets 50mg/1000mg Taj Pharma

  1. Qualitative and quantitative composition

a) Vildagliptin/Metformin Hydrochloride Tablets 50mg/500mg Taj Pharma
Each film-coated tablet contains:
Vildagliptin 50mg
Metformin HCl 500mg
Colours: Titanium Dioxide, Iron oxide yellow and Iron Oxide Red

b) Vildagliptin/Metformin Hydrochloride Tablets 50mg/850mg Taj Pharma
Each film-coated tablet contains:
Vildagliptin 50mg
Metformin HCl 850mg
Colours: Titanium Dioxide, Iron oxide yellow and Iron Oxide Red

c) Vildagliptin/Metformin Hydrochloride Tablets 50mg/1000mg Taj Pharma
Each film-coated tablet contains:
Vildagliptin 50mg
Metformin HCl 1000mg
Colours: Titanium Dioxide, Iron oxide yellow and Iron Oxide Red

For the full list of excipients, see section 6.1.

  1. Pharmaceutical form

Film-coated tablet.
Dark yellow, ovaloid film-coated tablet,

  1. Clinical particulars
  • Therapeutic indications

Vildagliptin/Metformin Hydrochloride Taj Pharma is indicated in the treatment of type 2 diabetes mellitus:

  • Vildagliptin/Metformin Hydrochloride Taj Pharma is indicated in the treatment of adult patients who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone or who are already treated with the combination of vildagliptin and metformin as separate tablets.
  • Vildagliptin/Metformin Hydrochloride Taj Pharma is indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled with metformin and a sulphonylurea.
  • Vildagliptin/Metformin Hydrochloride Taj Pharma is indicated in triple combination therapy with insulin as an adjunct to diet and exercise to improve glycaemic control in adult patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control.

Posology and method of administration

Posology

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

The dose of antihyperglycaemic therapy with Vildagliptin/Metformin Hydrochloride Taj Pharma should be individualised on the basis of the patient’s current regimen, effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100mg vildagliptin. Vildagliptin/Metformin Hydrochloride Taj Pharma may be initiated at either the 50mg/850mg or 50mg/1000mg tablet strength twice daily, one tablet in the morning and the other in the evening.

  • For patients inadequately controlled at their maximal tolerated dose of metformin monotherapy:

The starting dose of Vildagliptin/Metformin Hydrochloride Taj Pharma should provide vildagliptin as 50mg twice daily (100mg total daily dose) plus the dose of metformin already being taken.

  • For patients switching from co-administration of vildagliptin and metformin as separate tablets:

Vildagliptin/Metformin Hydrochloride Taj Pharma should be initiated at the dose of vildagliptin and metformin already being taken.

  • For patients inadequately controlled on dual combination with metformin and a sulphonylurea:

The doses of Vildagliptin/Metformin Hydrochloride Taj Pharma should provide vildagliptin as 50mg twice daily (100mg total daily dose) and a dose of metformin similar to the dose already being taken. When Vildagliptin/Metformin Hydrochloride Taj Pharma is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.

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

The dose of Vildagliptin/Metformin Hydrochloride Taj Pharma should provide vildagliptin dosed as 50mg twice daily (100mg total daily dose) and a dose of metformin similar to the dose already being taken.

The safety and efficacy of vildagliptin and metformin as triple oral therapy in combination with a thiazolidinedione have not been established.

Special populations

Elderly (≥ 65 years)

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Vildagliptin/Metformin Hydrochloride Taj Pharma should have their renal function monitored regularly (see sections 4.4 and 5.2).

Renal impairment

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 Vildagliptin/Metformin Hydrochloride Taj Pharma is available, individual monocomponents should be used instead of the fixed dose combination.

GFR ml/minMetforminVildagliptin
60-89Maximum daily dose is 3000mg.

Dose reduction may be considered in relation to declining renal function.

No dose adjustment.
45-59Maximum daily dose is 2000mg.

The starting dose is at most half of the maximum dose.

Maximal daily dose is 50mg.
30-44Maximum daily dose is 1000mg.

The starting dose is at most half of the maximum dose.

<30Metformin is contraindicated.

Hepatic impairment

Vildagliptin/Metformin Hydrochloride Taj Pharma should not be used in patients with hepatic impairment, including those with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN) (see sections 4.3, 4.4 and 4.8).

Paediatric population

Vildagliptin/Metformin Hydrochloride Taj Pharma is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of Vildagliptin/Metformin Hydrochloride Taj Pharma in children and adolescents (< 18 years) have not been established. No data are available.

Method of administration

Oral use.

Taking Vildagliptin/Metformin Hydrochloride Taj Pharma with or just after food may reduce gastrointestinal symptoms associated with metformin (see also section 5.2).

  • Contraindications
  • Hypersensitivity to the active substances or to any of the excipients listed in section 6.1
  • 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:
  • dehydration,
  • severe infection,
  • shock,
  • intravascular administration of iodinated contrast agents (see section 4.4).
  • cardiac or respiratory failure,
  • recent myocardial infarction,
  • Acute or chronic disease which may cause tissue hypoxia, such as:
  • Hepatic impairment (see sections 4.2, 4.4 and 4.8)
  • Acute alcohol intoxication, alcoholism
  • Breast-feeding (see section 4.6)

Special warnings and precautions for use

General

Vildagliptin/Metformin Hydrochloride Taj Pharma is not a substitute for insulin in insulin-requiring patients and should not be used in patients with type 1 diabetes.

Lactic acidosis

Lactic acidosis, a very 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 diarrhoea or vomiting, 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 care-givers 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.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast-induced nephropathy, resulting in metformin accumulation and increased risk of lactic acidosis. 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 re-evaluated and found to be stable (see sections 4.2 and 4.5).

Renal function

GFR should be assessed before treatment initiation and regularly thereafter (see section 4.2). Metformin is contraindicated in patients with GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see section 4.3).

Hepatic impairment

Patients with hepatic impairment, including those with pre-treatment ALT or AST > 3x ULN, should not be treated with Vildagliptin/Metformin Hydrochloride Taj Pharma (see sections 4.2, 4.3 and 4.8).

Liver enzyme monitoring

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed prior to the initiation of treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma in order to know the patient’s baseline value. Liver function should be monitored during treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma at three-month intervals during the first year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent LFTs until the abnormality(ies) return(s) to normal. Should an increase in AST or in ALT of 3x ULN or greater persist, withdrawal of Vildagliptin/Metformin Hydrochloride Taj Pharma therapy is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Vildagliptin/Metformin Hydrochloride Taj Pharma.

Following withdrawal of treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma and LFT normalisation, treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma should not be re-initiated.

Skin disorders

Skin lesions, including blistering and ulceration have been reported with vildagliptin in extremities of monkeys in non-clinical toxicology studies (see section 5.3). Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.

Acute pancreatitis

Use of vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis.

If pancreatitis is suspected, vildagliptin should be discontinued; if acute pancreatitis is confirmed, vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.

Hypoglycaemia

Sulphonylureas are known to cause hypoglycaemia. Patients receiving vildagliptin in combination with a sulphonylurea may be at risk for hypoglycaemia. Therefore, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycaemia.

Surgery

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.

  • Interaction with other medicinal products and other forms of interaction

There have been no formal interaction studies for Vildagliptin/Metformin Hydrochloride Taj Pharma. The following statements reflect the information available on the individual active substances.

Vildagliptin

Vildagliptin has a low potential for interactions with co-administered medicinal products. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.

Results from clinical trials conducted with the oral antidiabetics pioglitazone, metformin and glyburide in combination with vildagliptin have shown no clinically relevant pharmacokinetic interactions in the target population.

Drug-drug interaction studies with digoxin (P-glycoprotein substrate) and warfarin (CYP2C9 substrate) in healthy subjects have shown no clinically relevant pharmacokinetic interactions after co-administration with vildagliptin.

Drug-drug interaction studies in healthy subjects were conducted with amlodipine, ramipril, valsartan and simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with vildagliptin. However, this has not been established in the target population.

Combination with ACE inhibitors

There may be an increased risk of angioedema in patients concomitantly taking ACE inhibitors.(see section 4.8).

As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.

Metformin

Combinations 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

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 (see sections 4.2 and 4.4).

Cationic active substances

Cationic active substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems and hence delay the elimination of metformin, which may increase the risk of lactic acidosis. A study in healthy volunteers showed that cimetidine, administered as 400mg twice daily, increased metformin systemic exposure (AUC) by 50%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered (see section 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.

Glucocorticoids, 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. If necessary, the dosage of Vildagliptin/Metformin Hydrochloride Taj Pharma may need to be adjusted during concomitant therapy and on its discontinuation.

Angiotensin converting enzyme (ACE) inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

  • Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Vildagliptin/Metformin Hydrochloride Taj Pharma in pregnant women. For vildagliptin studies in animals have shown reproductive toxicity at high doses. For metformin, studies in animals have not shown reproductive toxicity. Studies in animals performed with vildagliptin and metformin have not shown evidence of teratogenicity, but foetotoxic effects at maternotoxic doses (see section 5.3). The potential risk for humans is unknown. Vildagliptin/Metformin Hydrochloride Taj Pharma should not be used during pregnancy.

Breast-feeding

Studies in animals have shown excretion of both metformin and vildagliptin in milk. It is unknown whether vildagliptin is excreted in human milk, but metformin is excreted in human milk in low amounts. Due to both the potential risk of neonate hypoglycaemia related to metformin and the lack of human data with vildagliptin, Vildagliptin/Metformin Hydrochloride Taj Pharma should not be used during breast-feeding (see section 4.3).

Fertility

No studies on the effect on human fertility have been conducted for Vildagliptin/Metformin Hydrochloride Taj Pharma (see section 5.3).

  • Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness as an adverse reaction should avoid driving vehicles or using machines.

  • Undesirable effects

There have been no therapeutic clinical trials conducted with Vildagliptin/Metformin Hydrochloride Taj Pharma. However, bioequivalence of Vildagliptin/Metformin Hydrochloride Taj Pharma with co-administered vildagliptin and metformin has been demonstrated (see section 5.2). The data presented here relate to the co-administration of vildagliptin and metformin, where vildagliptin has been added to metformin. There have been no studies of metformin added to vildagliptin.

Summary of the safety profile

The majority of adverse reactions were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose.

Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations ≥ 3x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%, 0.3% and 0.2% for vildagliptin 50mg once daily, vildagliptin 50mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

Rare cases of angioedema have been reported on vildagliptin at a similar rate to controls. A greater proportion of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.

Tabulated list of adverse reactions

Adverse reactions reported in patients who received vildagliptin in double-blind studies as monotherapy and add-on therapies are listed below by system organ class and absolute frequency. Adverse reactions listed in Table 5 are based on information available from the metformin Summary of Product Characteristics available in the EU. 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported in patients who received vildagliptin 100mg daily as add-on therapy to metformin compared to placebo plus metformin in double-blind studies (N=208)

Metabolism and nutrition disorders
CommonHypoglycaemia
Nervous system disorders
CommonTremor
CommonHeadache
CommonDizziness
UncommonFatigue
Gastrointestinal disorders
CommonNausea

Description of selected adverse reactions

In controlled clinical trials with the combination of vildagliptin 100mg daily plus metformin, no withdrawal due to adverse reactions was reported in either the vildagliptin 100mg daily plus metformin or the placebo plus metformin treatment groups.

In clinical trials, the incidence of hypoglycaemia was common in patients receiving vildagliptin in combination with metformin (1%) and uncommon in patients receiving placebo + metformin (0.4%). No severe hypoglycaemic events were reported in the vildagliptin arms.

In clinical trials, weight did not change from baseline when vildagliptin 100mg daily was added to metformin (+0.2 kg and -1.0 kg for vildagliptin and placebo, respectively).

Clinical trials of up to more than 2 years’ duration did not show any additional safety signals or unforeseen risks when vildagliptin was added on to metformin.

Combination with a sulphonylurea

Table 2 Adverse reactions reported in patients who received vildagliptin 50mg twice daily in combination with metformin and a sulphonylurea (N=157)

Metabolism and nutritional disorders
CommonHypoglycaemia
Nervous system disorders
CommonDizziness, tremor
Skin and subcutaneous tissue disorders
CommonHyperhidrosis
General disorders and administration site conditions
CommonAsthenia

Description of selected adverse reactions

There were no withdrawals due to adverse reactions reported in the vildagliptin + metformin + glimepiride treatment group versus 0.6% in the placebo + metformin + glimepiride treatment group.

The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride group versus 1.9% for the placebo + metformin + glimepiride group). One severe hypoglycaemic event was reported in the vildagliptin group.

At the end of the study, effect on mean body weight was neutral (+0.6 kg in the vildagliptin group and -0.1 kg in the placebo group).

Combination with insulin

Table 3 Adverse reactions reported in patients who received vildagliptin 100mg daily in combination with insulin (with or without metformin) in double-blind studies (N=371)

Metabolism and nutrition disorders
CommonDecreased blood glucose
Nervous system disorders
CommonHeadache, chills
Gastrointestinal disorders
CommonNausea, gastro-oesophageal reflux disease
UncommonDiarrhoea, flatulence

Description of selected adverse reactions

In controlled clinical trials using vildagliptin 50mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence of withdrawals due to adverse reactions was 0.3% in the vildagliptin treatment group and there were no withdrawals in the placebo group.

The incidence of hypoglycaemia was similar in both treatment groups (14.0% in the vildagliptin group vs 16.4% in the placebo group). Two patients reported severe hypoglycaemic events in the vildagliptin group, and 6 patients in the placebo group.

At the end of the study, effect on mean body weight was neutral (+0.6 kg change from baseline in the vildagliptin group and no weight change in the placebo group).

Additional information on the individual active substances of the fixed combination

Vildagliptin

Table 4 Adverse reactions reported in patients who received vildagliptin 100mg daily as monotherapy in double-blind studies (N=1855)

Infections and infestations
Very rareUpper respiratory tract infection
Very rareNasopharyngitis
Metabolism and nutrition disorders
UncommonHypoglycaemia
Nervous system disorders
CommonDizziness
UncommonHeadache
Vascular disorders
UncommonOedema peripheral
Gastrointestinal disorders
UncommonConstipation
Musculoskeletal and connective tissue disorders
UncommonArthralgia

Description of selected adverse reactions

The overall incidence of withdrawals from controlled monotherapy trials due to adverse reactions was no greater for patients treated with vildagliptin at doses of 100mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).

In comparative controlled monotherapy studies, hypoglycaemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with vildagliptin 100mg daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.

In clinical trials, the weight did not change from baseline when vildagliptin 100mg daily was administered as monotherapy (-0.3 kg and -1.3 kg for vildagliptin and placebo, respectively).

Clinical trials of up to 2 years’ duration did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Metformin

Table 5 Adverse reactions for metformin component

Metabolism and nutrition disorders
Very rareDecrease of vitamin B12 absorption and lactic acidosis*
Nervous system disorders
CommonMetallic taste
Gastrointestinal disorders
Very commonNausea, vomiting, diarrhoea, abdominal pain and loss of appetite
Hepatobiliary disorders
Very rareLiver function test abnormalities or hepatitis**
Skin and subcutaneous tissue disorders
Very rareSkin reactions such as erythema, pruritus and urticaria
*A decrease in vitamin B12 absorption with decrease in serum levels has been very rarely observed in patients treated long-term with metformin. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.

**Isolated cases of liver function test abnormalities or hepatitis resolving upon metformin discontinuation have been reported.

Gastrointestinal adverse reactions occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 daily doses during or after meals. A slow increase in the dose may also improve gastrointestinal tolerability.

Post-marketing experience

Table 6 Post-marketing adverse reactions

Gastrointestinal disorders
Not knownPancreatitis
Hepatobiliary disorders
Not knownHepatitis (reversible upon discontinuation of the medicinal product)

Abnormal liver function tests (reversible upon discontinuation of the medicinal product)

Musculoskeletal and connective tissue disorders
Not knownMyalgia
Skin and subcutaneous tissue disorders
Not knownUrticaria

Exfoliative and bullous skin lesions, including bullous pemphigoid

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.

  • Overdose

No data are available with regard to overdose of Vildagliptin/Metformin Hydrochloride Taj Pharma.

Vildagliptin

Information regarding overdose with vildagliptin is limited.

Symptoms

Information on the likely symptoms of overdose with vildagliptin was taken from a rising dose tolerability study in healthy subjects given vildagliptin for 10 days. At 400mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, oedema and a transient increase in lipase levels. At 600mg, one subject experienced oedema of the feet and hands, and increases in creatine phosphokinase (CPK), AST, C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced oedema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.

Metformin

A large overdose of metformin (or co-existing risk of lactic acidosis) may lead to lactic acidosis, which is a medical emergency and must be treated in hospital.

Management

The most effective method of removing metformin is haemodialysis. However, vildagliptin cannot be removed by haemodialysis, although the major hydrolysis metabolite (LAY 151) can. Supportive management is recommended.

  1. Pharmacological properties
    • Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs,

Mechanism of action

Vildagliptin/Metformin Hydrochloride Taj Pharma combines two antihyperglycaemic agents with complimentary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: vildagliptin, a member of the islet enhancer class, and metformin hydrochloride, a member of the biguanide class.

Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor. Metformin acts primarily by decreasing endogenous hepatic glucose production.

Pharmacodynamic effects

Vildagliptin

Vildagliptin acts primarily by inhibiting DPP-4, the enzyme responsible for the degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide).

The administration of vildagliptin results in a rapid and complete inhibition of DPP-4 activity resulting in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 and GIP.

By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with vildagliptin 50-100mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment–β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.

The enhanced increase in the insulin/glucagon ratio during hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia.

The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment.

Metformin

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia or increased weight gain.

Metformin may exert its glucose-lowering effect via three mechanisms:

  • by reduction of hepatic glucose production through inhibition of gluconeogenesis and glycogenolysis;
  • in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation;
  • by delaying intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase and increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

In humans, independently of its action on glycaemia, metformin has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin reduces serum levels of total cholesterol, LDL cholesterol and triglycerides.

The prospective randomised UKPDS (UK Prospective Diabetes Study) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin after failure of diet alone showed:

  • a significant reduction in the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034;
  • a significant reduction in the absolute risk of diabetes-related mortality: metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017;
  • a significant reduction in the absolute risk of overall mortality: metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021);
  • a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years (p=0.01).

Clinical efficacy and safety

Vildagliptin added to patients whose glycaemic control was not satisfactory despite treatment with metformin monotherapy resulted after 6-month treatment in additional statistically significant mean reductions in HbA1c compared to placebo (between group differences of -0.7% to -1.1% for vildagliptin 50mg and 100mg, respectively). The proportion of patients who achieved a decrease in HbA1c of ≥ 0.7% from baseline was statistically significantly higher in both vildagliptin plus metformin groups (46% and 60%, respectively) versus the metformin plus placebo group (20%).

In a 24-week trial, vildagliptin (50mg twice daily) was compared to pioglitazone (30mg once daily) in patients inadequately controlled with metformin (mean daily dose: 2020mg). Mean reductions from baseline HbA1c of 8.4% were -0.9% with vildagliptin added to metformin and -1.0% with pioglitazone added to metformin. A mean weight gain of +1.9 kg was observed in patients receiving pioglitazone added to metformin compared to +0.3 kg in those receiving vildagliptin added to metformin.

In a clinical trial of 2 years’ duration, vildagliptin (50mg twice daily) was compared to glimepiride (up to 6mg/day – mean dose at 2 years: 4.6mg) in patients treated with metformin (mean daily dose: 1894mg). After 1 year mean reductions in HbA1c were -0.4% with vildagliptin added to metformin and -0.5% with glimepiride added to metformin, from a mean baseline HbA1c of 7.3%. Body weight change with vildagliptin was -0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycaemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycaemia differences were maintained.

In a 52-week trial, vildagliptin (50mg twice daily) was compared to gliclazide (mean daily dose: 229.5mg) in patients inadequately controlled with metformin (metformin dose at baseline 1928mg/day). After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin added to metformin (mean baseline HbA1c 8.4%) and -0.85% with gliclazide added to metformin (mean baseline HbA1c 8.5%); statistical non-inferiority was achieved (95% CI -0.11 – 0.20). Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.

In a 24-week trial the efficacy of the fixed dose combination of vildagliptin and metformin (gradually titrated to a dose of 50mg/500mg twice daily or 50mg/1000mg twice daily) as initial therapy in drug-naïve patients was evaluated. Vildagliptin/metformin 50mg/1000mg twice daily reduced HbA1c by -1.82% ,vildagliptin/metformin 50mg/500mg twice daily by -1.61%, metformin 1000mg twice daily by -1.36% and vildagliptin 50mg twice daily by -1.09% from a mean baseline HbA1c of 8.6%. The decrease in HbA1c observed in patients with a baseline ≥10.0% was greater.

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50mg twice daily) in combination with metformin (≥1500mg daily) and glimepiride (≥4mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo. The placebo-adjusted mean reduction from a mean baseline HbA1c of 8.8% was -0.76%.

A 24-week randomised, double-blind, placebo-controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 units), with concomitant use of metformin (N=276) or without concomitant metformin (N=173). Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo. In the overall population, the placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycaemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Patients receiving vildagliptin experienced no weight gain (+0.2 kg) while those receiving placebo experienced weight reduction (-0.7 kg).

In another 24-week study in patients with more advanced type 2 diabetes not adequately controlled on insulin (short and longer acting, average insulin dose 80 IU/day), the mean reduction in HbA1c when vildagliptin (50mg twice daily) was added to insulin was statistically significantly greater than with placebo plus insulin (0.5% vs. 0.2%). The incidence of hypoglycaemia was lower in the vildagliptin group than in the placebo group (22.9% vs. 29.6%).

Cardiovascular risk

A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV monotherapy and combination therapy clinical studies of up to more than 2 years duration (mean exposure 50 weeks for vildagliptin and 49 weeks for comparators) was performed and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk versus comparators. The composite endpoint of adjudicated major adverse cardiovascular events (MACE) including acute myocardial infarction, stroke or cardiovascular death was similar for vildagliptin versus combined active and placebo comparators [Mantel–Haenszel risk ratio (M-H RR) 0.82 (95% CI 0.61-1.11)]. A MACE occurred in 83 out of 9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator-treated patients. Assessment of each individual MACE component showed no increased risk (similar M-H RR). Confirmed heart failure (HF) events defined as HF requiring hospitalisation or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients with M-H RR 1.08 (95% CI 0.68-1.70).

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with vildagliptin in combination with metformin in all subsets of the paediatric population with type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

  • Pharmacokinetic properties

Vildagliptin/Metformin Hydrochloride Taj Pharma

Absorption

Bioequivalence has been demonstrated between Vildagliptin/Metformin Hydrochloride Taj Pharma at three dose strengths (50mg/500mg, 50mg/850mg and 50mg/1000mg) versus free combination of vildagliptin and metformin hydrochloride tablets at the corresponding doses.

Food does not affect the extent and rate of absorption of vildagliptin from Vildagliptin/Metformin Hydrochloride Taj Pharma. The rate and extent of absorption of metformin from Vildagliptin/Metformin Hydrochloride Taj Pharma 50mg/1000mg were decreased when given with food as reflected by the decrease in Cmax by 26%, AUC by 7% and delayed Tmax (2.0 to 4.0 h).

The following statements reflect the pharmacokinetic properties of the individual active substances of Vildagliptin/Metformin Hydrochloride Taj Pharma.

Vildagliptin

Absorption

Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of vildagliptin with food resulted in a decreased Cmax (19%) compared to dosing in the fasting state. However, the magnitude of change is not clinically significant, so that vildagliptin can be given with or without food. The absolute bioavailability is 85%.

Distribution

The plasma protein binding of vildagliptin is low (9.3%) and vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady-state after intravenous administration (Vss) is 71 litres, suggesting extravascular distribution.

Biotransformation

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis product (4% of dose). DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent, and accordingly the metabolic clearance of vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, vildagliptin is not likely to affect metabolic clearance of co-medications metabolised by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.

Elimination

Following oral administration of [14C] vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose was recovered in the faeces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13 l/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.

Linearity/non-linearity

The Cmax for vildagliptin and the area under the plasma concentrations versus time curves (AUC) increased in an approximately dose proportional manner over the therapeutic dose range.

Characteristics in patients

Gender: No clinically relevant differences in the pharmacokinetics of vildagliptin were observed between male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin is not affected by gender.

Age: In healthy elderly subjects (≥ 70 years), the overall exposure of vildagliptin (100mg once daily) was increased by 32%, with an 18% increase in peak plasma concentration as compared to young healthy subjects (18-40 years). These changes are not considered to be clinically relevant, however. DPP-4 inhibition by vildagliptin is not affected by age.

Hepatic impairment: In subjects with mild, moderate or severe hepatic impairment (Child-Pugh A-C) there were no clinically significant changes (maximum ~30%) in exposure to vildagliptin.

Renal impairment: In subjects with mild, moderate, or severe renal impairment, systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) and total body clearance was reduced compared to subjects with normal renal function.

Ethnic group: Limited data suggest that race does not have any major influence on vildagliptin pharmacokinetics.

Metformin

Absorption

After an oral dose of metformin, the maximum plasma concentration (Cmax) is achieved after about 2.5 h. Absolute bioavailability of a 500mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption are non-linear. At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/ml. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 µg/ml, even at maximum doses.

Food slightly delays and decreases the extent of the absorption of metformin. Following administration of a dose of 850mg, the plasma peak concentration was 40% lower, AUC was decreased by 25% and time to peak plasma concentration was prolonged by 35 minutes. The clinical relevance of this decrease is unknown.

Distribution

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The mean volume of distribution (Vd) ranged between 63-276 litres.

Biotransformation

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

Elimination

Metformin is eliminated by renal excretion. Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

  • Preclinical safety data

Animal studies of up to 13-week duration have been conducted with the combined substances in Vildagliptin/Metformin Hydrochloride Taj Pharma. No new toxicities associated with the combination were identified. The following data are findings from studies performed with vildagliptin or metformin individually.

Vildagliptin

Intra-cardiac impulse conduction delays were observed in dogs with a no-effect dose of 15mg/kg (7-fold human exposure based on Cmax).

Accumulation of foamy alveolar macrophages in the lung was observed in rats and mice. The no-effect dose in rats was 25mg/kg (5-fold human exposure based on AUC) and in mice 750mg/kg (142-fold human exposure).

Gastrointestinal symptoms, particularly soft faeces, mucoid faeces, diarrhoea and, at higher doses, faecal blood were observed in dogs. A no-effect level was not established.

Vildagliptin was not mutagenic in conventional in vitro and in vivo tests for genotoxicity.

A fertility and early embryonic development study in rats revealed no evidence of impaired fertility, reproductive performance or early embryonic development due to vildagliptin. Embryofoetal toxicity was evaluated in rats and rabbits. An increased incidence of wavy ribs was observed in rats in association with reduced maternal body weight parameters, with a no-effect dose of 75mg/kg (10-fold human exposure). In rabbits, decreased foetal weight and skeletal variations indicative of developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect dose of 50mg/kg (9-fold human exposure). A pre- and postnatal development study was performed in rats. Findings were only observed in association with maternal toxicity at ≥ 150mg/kg and included a transient decrease in body weight and reduced motor activity in the F1 generation.

A two-year carcinogenicity study was conducted in rats at oral doses up to 900mg/kg (approximately 200 times human exposure at the maximum recommended dose). No increases in tumour incidence attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in mice at oral doses up to 1000mg/kg. An increased incidence of mammary adenocarcinomas and haemangiosarcomas was observed with a no-effect dose of 500mg/kg (59-fold human exposure) and 100mg/kg (16-fold human exposure), respectively. The increased incidence of these tumours in mice is considered not to represent a significant risk to humans based on the lack of genotoxicity of vildagliptin and its principal metabolite, the occurrence of tumours only in one species, and the high systemic exposure ratios at which tumours were observed.

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥ 5mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5mg/kg/day (approximately equivalent to human AUC exposure at the 100mg dose), only blisters were observed. They were reversible despite continued treatment and were not associated with histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses ≥ 20mg/kg/day (approximately 3 times human AUC exposure at the 100mg dose). Necrotic lesions of the tail were observed at ≥ 80mg/kg/day. Skin lesions were not reversible in the monkeys treated at 160mg/kg/day during a 4-week recovery period.

Metformin

Non-clinical data on metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

  1. Pharmaceutical particulars
  • List of excipients

Tablet core

Hydroxypropylcellulose

Magnesium stearate

Film-coating

Hypromellose

Titanium dioxide

Iron oxide, yellow

Macrogol 4000

Talc

  • Incompatibilities

Not applicable.

  • Shelf life

PA/Alu/PVC/Alu 2 years

PCTFE/PVC/Alu 18 months

  • Special precautions for storage

Do not store above 30°C.

Store in the original package (blister) in order to protect from moisture.

  • Nature and contents of container

Aluminium/Aluminium (PA/Alu/PVC/Alu) blister

Pack Size:

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is available in packs containing 10, 30, 60, 120, 180, 360 and 500 film-coated tablets and in multipacks containing 120 (2×60), 180 (3×60) or 360 (6×60) film-coated tablets.

Not all pack sizes and tablet strengths may be available in your country.

  • Special precautions for disposal and other handling

No special requirements.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Vildagliptin/Metformin Hydrochloride Tablet 50mg/1000mg Taj Pharma

Package leaflet: Information for the user

Vildagliptin/Metformin Hydrochloride Taj Pharma,

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor, pharmacist or nurse.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

  1. What Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is and what it is used for
  2. What you need to know before you take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma
  3. How to take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma
  4. Possible side effects
  5. How to store Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma
  6. Contents of the pack and other information

1. What Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is and what it is used for

The active substances of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma, vildagliptin and metformin, belong to a group of medicines called “oral antidiabetics”.

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is used to treat adult patients with type 2 diabetes. This type of diabetes is also known as noninsulin-dependent diabetes mellitus. Type 2 diabetes develops if the body does not make enough insulin or if the insulin that the body makes does not work as well as it should. It can also develop if the body produces too much glucagon.

Both insulin and glucagon are made in the pancreas. Insulin helps to lower the level of sugar in the blood, especially after meals. Glucagon triggers the liver to make sugar, causing the blood sugar level to rise.

How Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma works

Both active substances, vildagliptin and metformin, help to control the level of sugar in the blood. The substance vildagliptin works by making the pancreas produce more insulin and less glucagon. The substance metformin works by helping the body to make better use of insulin. This medicine has been shown to reduce blood sugar, which may help to prevent complications from your diabetes.

  1. What you need to know before you take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

Do not take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

  • if you are allergic to vildagliptin, metformin or any of the other ingredients of this medicine (listed in section 6). If you think you may be allergic to any of these, talk to your doctor before taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma.
  • if you have uncontrolled diabetes, with, for example, severe hyperglycaemia (high blood glucose), nausea, vomiting, diarrhoea, rapid weight loss, lactic acidosis (see “Risk of lactic acidosis” below) or ketoacidosis. Ketoacidosis is a condition in which substances called ketone bodies accumulate in the blood and which can lead to diabetic pre-coma. Symptoms include stomach pain, fast and deep breathing, sleepiness or your breath developing an unusual fruity smell.
  • if you have recently had a heart attack or if you have heart failure or serious problems with your blood circulation or difficulties in breathing which could be a sign of heart problems.
  • if you have severely reduced kidney function.
  • if you have a severe infection or are seriously dehydrated (have lost a lot of water from your body).
  • if you are going to have a contrast x-ray (a specific type of x-ray involving an injectable dye).

Please also see information about this in section “Warnings and precautions”.

  • if you have liver problems.
  • if you drink alcohol excessively (whether every day or only from time to time).
  • if you are breast-feeding (see also “Pregnancy and breast-feeding”).

Warnings and precautions

Risk of lactic acidosis

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma may cause a very rare, but very serious side effect called lactic acidosis, particularly if your kidneys are not working properly. The risk of developing lactic acidosis is also increased with uncontrolled diabetes, serious infections, prolonged fasting or alcohol intake, dehydration (see further information below), liver problems and any medical conditions in which a part of the body has a reduced supply of oxygen (such as acute severe heart disease).

If any of the above apply to you, talk to your doctor for further instructions.

Stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma for a short time if you have a condition that may be associated with dehydration (significant loss of body fluids) such as severe vomiting, diarrhoea, fever, exposure to heat or if you drink less fluid than normal. Talk to your doctor for further instructions.

Stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma and contact a doctor or the nearest hospital immediately if you experience some of the symptoms of lactic acidosis, as this condition may lead to coma.

Symptoms of lactic acidosis include:

  • vomiting
  • stomach ache (abdominal pain)
  • muscle cramps
  • a general feeling of not being well with severe tiredness
  • difficulty in breathing
  • reduced body temperature and heartbeat

Lactic acidosis is a medical emergency and must be treated in a hospital.

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is not a substitute for insulin. Therefore, you should not receive Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma for the treatment of type 1 diabetes.

Talk to your doctor, pharmacist or nurse before taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma if you have or have had a disease of the pancreas.

Talk to your doctor, pharmacist or nurse before taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma if you are taking an anti-diabetic medicine known as a sulphonylurea. Your doctor may want to reduce your dose of the sulphonylurea when you take it together with Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma in order to avoid low blood glucose (hypoglycaemia).

If you have previously taken vildagliptin but had to stop taking it because of liver disease, you should not take this medicine.

Diabetic skin lesions are a common complication of diabetes. You are advised to follow the

recommendations for skin and foot care that you are given by your doctor or nurse. You are also

advised to pay particular attention to new onset of blisters or ulcers while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma. Should these occur, you should promptly consult your doctor.

If you need to have major surgery you must stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma during and for some time after the  procedure. Your doctor will decide when you must stop and when to restart your treatment with

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma.

A test to determine your liver function will be performed before the start of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma treatment, at three-month intervals for the first year and periodically thereafter. This is so that signs of increased

liver enzymes can be detected as early as possible.

During treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma, your doctor will check your kidney function at least once a year or more frequently if you are elderly and/or have worsening renal function.

Your doctor will test your blood and urine for sugar regularly.

Children and adolescents

The use of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma in children and adolescents up to 18 years of age is not recommended.

Other medicines and Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

If you need to have an injection of a contrast medium that contains iodine into your bloodstream, for example in the context of an X-ray or scan, you must stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma before or at the time of the injection. Your doctor will decide when you must stop and when to restart your treatment with Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma.

Tell your doctor if you are taking, have recently taken or might take any other medicines. You may need more frequent blood glucose and kidney function tests, or your doctor may need to adjust the dosage of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma. It is especially important to mention the following:

  • glucocorticoids generally used to treat inflammation
  • beta-2 agonists generally used to treat respiratory disorders
  • other medicines used to treat diabetes
  • medicines which increase urine production (diuretics)
  • medicines used to treat pain and inflammation (NSAID and COX-2-inhibitors, such as ibuprofen and celecoxib)
  • certain medicines for the treatment of high blood pressure (ACE inhibitors and angiotensin II receptor antagonists)
  • certain medicines affecting the thyroid, or
  • certain medicines affecting the nervous system.

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma with alcohol

Avoid excessive alcohol intake while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma since this may increase the risk of lactic acidosis (please see section “Warnings and precautions”).

Pregnancy and breast-feeding

  • If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will discuss with you the potential risk of taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma during pregnancy.
  • Do not use Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma if you are pregnant or breast-feeding (see also “Do not take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma”). Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

If you feel dizzy while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma, do not drive or use any tools or machines.

  1. How to take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

The amount of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma that people have to take varies depending on their condition. Your doctor will tell you exactly the dose of Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma to take.

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is one film-coated tablet of either 50mg/850mg or 50mg/1000mg taken twice a day

If you have reduced kidney function, your doctor may prescribe a lower dose. Also if you are taking an anti-diabetic medicine known as a sulphonylurea your doctor may prescribe a lower dose.

Your doctor may prescribe this medicine alone or with certain other medicines that lower the level of sugar in your blood.

When and how to take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

  • Swallow the tablets whole with a glass of water,
  • Take one tablet in the morning and the other in the evening with or just after food. Taking the tablet just after food will lower the risk of an upset stomach.

Continue to follow any advice about diet that your doctor has given you. In particular, if you are following a diabetic weight control diet, continue with this while you are taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma.

If you take more Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma than you should

If you take too many Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma tablets, or if someone else takes your tablets, talk to a doctor or pharmacist immediately. Medical attention may be necessary. If you have to go to a doctor or hospital, take the pack and this leaflet with you.

If you forget to take Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

If you forget to take a tablet, take it with your next meal unless you are due to take one then anyway.

Do not take a double dose (two tablets at once) to make up for a forgotten tablet.

If you stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma

Continue to take this medicine as long as your doctor prescribes it so that it can continue to control your blood sugar. Do not stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma unless your doctor tells you to. If you have any questions about how long to take this medicine, talk to your doctor.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You should stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma and see your doctor immediately if you experience the following side effects:

  • Lactic acidosis (very rare: may affect up to 1 user in 10,000):
  • Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma may cause a very rare, but very serious side effect called lactic acidosis (see section “Warnings and precautions”). If this happens you must stop taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma and contact a doctor or the nearest hospital immediately, as lactic acidosis may lead to coma.
  • Angioedema (rare: may affect up to 1 in 1,000 people): Symptoms include swollen face, tongue or throat, difficulty swallowing, difficulty breathing, sudden onset of rash or hives, which may indicate a reaction called “angioedema”.
  • Liver disease (hepatitis) (rare): Symptoms include yellow skin and eyes, nausea, loss of appetite or dark-coloured urine, which may indicate liver disease (hepatitis).
  • Inflammation of the pancreas (pancreatitis) (frequency not known): Symptoms include severe and persistent pain in the abdomen (stomach area), which might reach through to your back, as well as nausea and vomiting.

Other side effects

Some patients have experienced the following side effects while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma:

  • Very common (may affect more than 1 in 10 people): nausea, vomiting, diarrhoea, pain in and around the stomach (abdominal pain), loss of appetite.
  • Common (may affect up to 1 in 10 people): dizziness, headache, trembling that cannot be controlled, metallic taste, low blood glucose.
  • Uncommon (may affect up to 1 in 100 people): joint pain, tiredness, constipation, swollen hands, ankle or feet (oedema).
  • Very rare (may affect up to 1 in 10,000 people): sore throat, runny nose, fever; signs of a high level of lactic acid in the blood (known as lactic acidosis) such as drowsiness or dizziness, severe nausea or vomiting, abdominal pain, irregular heart beat or deep, rapid breathing; redness of the skin, itching; decreased vitamin B12 levels (paleness, tiredness, mental symptoms such as confusion or memory disturbances). Some patients have experienced the following side effects while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma and a sulphonylurea:
  • Common: dizziness, tremor, weakness, low blood glucose, excessive sweating. Some patients have had the following side effects while taking Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma and insulin:
  • Common: headache, chills, nausea (feeling sick), low blood glucose, heartburn.
  • Uncommon: diarrhoea, flatulence. Since this product has been marketed, the following side effects have also been reported:
  • Frequency not known (cannot be estimated from the available data): itchy rash, inflammation of the pancreas, localised peeling of skin or blisters, muscle pain.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

  1. How to store Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma
    • Keep this medicine out of the sight and reach of children.
    • Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. The expiry date refers to the last day of that month.
    • Do not store above 30C.
    • Store in the original package (blister) in order to protect from moisture.
  2. Contents of the pack and other information

What Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma contains

  • The active substances are vildagliptin and metformin hydrochloride.
  • Each Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma 50mg/850mg film-coated tablet contains 50mg vildagliptin and 850mg metformin hydrochloride (corresponding to 660mg of metformin).
  • Each Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma 50mg/1000mg film-coated tablet contains 50mg vildagliptin and 1000mg metformin hydrochloride (corresponding to 780mg of metformin).
  • The other ingredients are: Hydroxypropylcellulose, Magnesium Stearate, Hypromellose, Titanium Dioxide, Yellow Iron Oxide, Macrogol 4000 And Talc.

What Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma looks like and contents of the pack

Vildagliptin/Metformin Hydrochloride Tablets 50mg/500mg Taj Pharma

Vildagliptin/Metformin Hydrochloride Tablets 50mg/850mg Taj Pharma

Vildagliptin/Metformin Hydrochloride Tablets 50mg/1000mg Taj Pharma

Each strength tablet looks like, Dark yellow, ovaloid film-coated tablet,

Pack Size:

Vildagliptin/Metformin Hydrochloride Taj Pharma Taj Pharma is available in packs containing 10, 30, 60, 120, 180, 360 and 500 film-coated tablets and in multipacks containing 120 (2×60), 180 (3×60) or 360 (6×60) film-coated tablets.

Not all pack sizes and tablet strengths may be available in your country.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com