VYSOV-M Tablets (Vildagliptin + Metformin hydrochloride )

Table of Content

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by high blood glucose levels. Globally, 425 million are affected with diabetes and almost 73 million of these patients reside in India. As per ICMR-INDIAB study, around 70% of individuals with type 2 diabetes do not have adequate glycaemic control (HbA1c <7%).

Current guidelines by major diabetes organizations recommend metformin as a first line therapy for management of T2DM along with lifestyle modifications. Dipeptidyl peptidase 4 (DPP-4) inhibitors is a newer oral antihyperglycaemic drug class that helps in achieving glucose control without increasing the risk of hypoglycaemia. They inhibit the degradation of gut hormones viz. glucagon-like peptide 1 and glucose-dependent insulinotropic peptide, thus increasing insulin secretion and inhibiting glucagon secretion. Both these actions occur only during hyperglycaemia, thus reducing the risk of hypoglycaemia.

Vildagliptin is one of the earliest DPP-4 inhibitors that has shown sustained efficacy and tolerability in clinical trials as well as real-world studies. It has proven efficacy and safety data as an add-on in patients uncontrolled on monotherapy, as a component of dual therapy as well as add-on to insulin therapy. Due to its proven safety profile, it is also considered as an effective type 2 diabetes drug choice in elderly, those with renal impairment and those who fast for long periods (such as during Ramadan).

Vildagliptin and metformin have a complementary mode of action and thus the combination is expected to provide stronger glycaemic control. Indeed, vildagliptin / metformin combination has demonstrated strong HbA1c reduction with a tolerability profile consistent with previously reported risks associated with the two drugs.

Vysov® (Vildagliptin 50 mg tablets) is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus. It is indicated as monotherapy, in dual combination (with metformin/ sulphonylurea/ thiazolidinedione), in triple combination (with metformin and sulphonylurea) as well as with insulin. The management of antihyperglycaemic therapy should be individualized. The recommended dose of Vysov® is 50 mg once or twice daily. The maximum daily dose of Vysov® is 100 mg.

Vysov-M® (Vildagliptin 50 mg + Metformin HCl 500mg/1000mg tablets) is indicated as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus inadequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets. Vysov-M® is also indicated in triple combination (with metformin and sulphonylurea) and in combination with insulin. Vysov-M® is also indicated for the treatment of type 2 diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone. The therapy needs to be individualized on the basis of effectiveness and tolerability. When using Vysov-M® do not exceed the maximum daily dose of vildagliptin (100 mg).

May 2019

 

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

 

Qualitative and Quantitative Composition

VYSOV-M 50mg/ 500mg

Each tablet contains:

Vildagliptin ………………………………………50 mg

Metformin Hydrochloride HCl IP………………500 mg

VYSOV-M 50 mg/ 850 mg

Each tablet contains:

Vildagliptin ……………………………………....50 mg

Metformin hydrochloride HCl IP……………….850 mg

VYSOV-M 50 mg/ 1000 mg

Each tablet contains:

Vildagliptin.…………………………………. 50 mg

Metformin hydrochloride HCl IP…………….1000 mg

Dosage Form and Strength

Oral tablet

Clinical Particulars

Therapeutic Indications

For patients of age 18 years and above with type 2 diabetes mellitus (T2DM):

VYSOV-M is indicated as an adjunct to diet and exercise to improve glycemic control in patients whose diabetes is not adequately controlled on metformin hydrochloride or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin hydrochloride, as separate tablets.

VYSOV-M is indicated in combination with a sulfonylurea (SU) (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformin and a sulfonylurea.

VYSOV-M is indicated as add-on to insulin as an adjunct to diet and exercise to improve glycemic control in patients when stable doses of insulin and metformin alone do not provide adequate glycemic control.

VYSOV-M is also indicated for the treatment of type 2 diabetes mellitus having HbA1c > 8% where diabetes is not adequately controlled by diet and exercise alone.

Posology and Method of Administration

General

The use of antihyperglycemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. When using VYSOV-M do not exceed the maximum daily dose of vildagliptin (100 mg). The recommended starting dose of VYSOV-M should be based on the patient’s condition and/or current regimen of vildagliptin and/or metformin hydrochloride.

Starting dose for patients inadequately controlled on vildagliptin monotherapy

Based on the usual starting doses of metformin hydrochloride (500 mg twice daily or 850 mg once daily), VYSOV-M may be initiated at the 50 mg/500 mg tablet strength twice daily and gradually titrated after assessing the adequacy of therapeutic response.

Starting dose for patients inadequately controlled on metformin hydrochloride monotherapy

Based on the patient’s current dose of metformin hydrochloride, VYSOV-M may be initiated at either the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1,000 mg tablet strength twice daily.

Starting dose for patients switching from combination therapy of vildagliptin plus metformin hydrochloride as separate tablets

VYSOV-M may be initiated with either the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1,000 mg tablet strength based on the dose of vildagliptin or metformin already being taken.

Starting dose for treatment naïve patients

In treatment naïve patients, VYSOV-M may be initiated at 50 mg/500 mg once daily and gradually titrated to a maximum dose of 50mg/1000 mg twice daily after assessing the adequacy of therapeutic response.

Use in combination with sulphonylurea or with insulin

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

For oral use, VYSOV-M should be given with meals to reduce the gastrointestinal side effects associated with metformin hydrochloride. If a dose of VYSOV-M is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

Special Populations

Patients with Renal Impairment

A GFR should be assessed before initiation of treatment with metformin-containing products (such as VYSOV-M) 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 to 6 months.

The maximum daily dose of metformin should preferably be divided into 2 to 3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products (such as VYSOV-M) in patients with GFR<60 ml/min. VYSOV-M is contraindicated in patients with GFR <30 ml/min because of its metformin component.

The following dosing recommendations apply to metformin and vildagliptin, used separately or in combination, in patients with renal impairment. If no adequate strength of VYSOV-M is available, individual components should be used instead of the fixed dose combination.

Table 1: Dose adjustments in patients with renal impairment

GFR ml/min

Metformin

Vildagliptin

60‑89

Maximum daily dose is 3000 mg*.

Dose reduction may be considered if renal function declines.

Maximum daily dose is 100 mg.

45‑59

Starting dose should not be more than 1000mg with a maximum daily dose of 2000 mg*.

Maximum daily dose is 50 mg.

30‑44

Starting dose should not be more than 500mg with a maximum daily dose of 1000 mg.

<30

Metformin is contraindicated.

*If metformin doses higher than those achievable with VYSOV-M alone are considered necessary.

Patients with Hepatic Impairment

VYSOV-M is not recommended in patients with clinical or laboratory evidence of hepatic impairment including patients with a pre-treatment ALT or AST >2.5x the ULN (upper limit of normal).

Pediatric Patients (below 18 years)

The safety and effectiveness of vildagliptin in pediatric patients have not been established. Therefore, VYSOV-M is not recommended for use in children below 18 years of age.

Elderly Patients (65 years or above)

As metformin is excreted via the kidneys, and elderly patients tend to exhibit decreased renal function, elderly patients taking metformin-containing products (such as VYSOV-M) should have their renal function monitored regularly. The dosage of VYSOV-M for elderly patients should be adjusted based on renal function.

Contraindications

Hypersensitivity

VYSOV-M is contraindicated in patients with known hypersensitivity to vildagliptin or metformin hydrochloride or to any of the excipients.

Patients with renal impairment

VYSOV-M is contraindicated in patients with severe renal impairment (GFR <30 ml/min).

Congestive heart failure 

VYSOV-M is contraindicated in patients with congestive heart failure requiring pharmacological treatment.

Metabolic acidosis

VYSOV-M is contraindicated in patients with acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Special Warnings and Precautions for Use

VYSOV-M is not a substitute for insulin in patients requiring insulin. VYSOV-M should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Drug Interactions

No clinically relevant pharmacokinetic interactions have been observed when vildagliptin (100 mg once daily) was co-administered with metformin hydrochloride (1,000 mg once daily). Drug interactions for each component of vildagliptin and metformin has been extensively studied. However, the concomitant use of the active substances in patients in clinical studies and in widespread clinical use has not resulted in any unexpected interactions.

The following statements reflect the information available on the individual active substances (vildagliptin and metformin).

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 coadministration 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.

As with other oral antidiabetic medicinal products the hypoglycemic 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.

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 400 mg twice daily, increased metformin systemic exposure (AUC) by 50%. Therefore, close monitoring of glycemic 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.

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 hyperglycemic activity. The patient should be informed, and more frequent blood glucose monitoring performed, especially at the beginning of treatment. If necessary, the dosage of VYSOV-M 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 antihyperglycemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Use in Special Population

Patients with Renal impairment

GFR should be assessed before treatment initiation and regularly thereafter. Metformin-containing products (such as VYSOV-M) are contraindicated in patients with GFR <30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function. Metformin hydrochloride is known to be substantially excreted by the kidneys, and the risk of metformin hydrochloride accumulation and lactic acidosis increases with the degree of renal function impairment. Since advancing age is associated with reduced renal function, metformin-containing products (such as VYSOV-M) should be carefully titrated in the elderly to establish the minimum dose for adequate glycemic effect, and renal function should be monitored regularly.

Patients with Hepatic impairment

Vildagliptin is not recommended in patients with hepatic impairment, including patients with pre-treatment ALT or AST >2.5x the ULN.

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 VYSOV-M. LFTs should be monitored during VYSOV-M treatment 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 up thereafter with frequent liver function tests until the abnormality/abnormalities return to normal. Should an increase in AST or ALT of 3x the ULN or greater persist, withdrawal of therapy with VYSOV-M is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue VYSOV-M and contact their physician immediately. Following withdrawal of treatment with VYSOV-M and LFT normalization, VYSOV-M should not be reinitiated.

VYSOV-M is not recommended in patients with hepatic impairment.

Since impaired hepatic function has been associated with some cases of lactic acidosis, a risk associated with metformin hydrochloride, metformin-containing products (such as VYSOV-M) should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

Pregnant Women

There is insufficient experience with vildagliptin in pregnant women. Embryo-fetal development (teratology) studies have been conducted in rats and rabbits with the combination of vildagliptin and metformin hydrochloride in a 1:10 ratio and produced no evidence of teratogenicity in either species. VYSOV-M should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Animal studies are not always predictive of human response.

Lactating Women

No studies have been conducted with the combined components of vildagliptin/metformin. Metformin is excreted into human breast milk. It is not known whether vildagliptin is excreted in human milk or not. VYSOV-M should not be administered to breast-feeding women.

Heart Failure

A clinical study of vildagliptin in patients with New York Heart Association (NYHA) functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive. There is no experience of vildagliptin use in clinical studies in patients with NYHA functional class IV and therefore use is not recommended in these patients.

Lactic Acidosis

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

In case of dehydration (e.g. due to severe diarrhea or vomiting, fever or reduced fluid intake), the patient should stop taking metformin-containing products (such as VYSOV-M) and seek immediate medical attention.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in patients treated with metformin-containing products (such as VYSOV-M). Other risk factors for lactic acidosis are excessive alcohol intake, hepatic impairment, 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.

Diagnosis of lactic acidosis

Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. If suspected symptoms occur, the patient should stop taking metformin -containing products (such as VYSOV-M) 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. If metabolic acidosis is suspected, treatment with metformin-containing products (such as VYSOV-M) should be discontinued and the patient should be immediately hospitalized.

Hypoxic States

Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. If such events occur in patients receiving metformin-containing products (such as VYSOV-M), the medication should be promptly discontinued.

Surgical Procedures

Metformin-containing products (such as VYSOV-M) must be discontinued at the time of surgery under general, spinal or epidural anesthesia (except minor procedures not associated with restricted intake of food and fluids) and may be restarted no earlier than 48 hours following surgery or until the patient’s oral nutrition has resumed and renal function has been re-evaluated and found to be stable.

Alcohol Intake

Alcohol is known to potentiate the effect of metformin hydrochloride on lactate metabolism.  Patients should be warned against excessive alcohol intake while receiving metformin-containing products (such as VYSOV-M). Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

Vitamin B12 Levels

Metformin has been associated with a decrease in serum vitamin B12 levels without clinical manifestations, in approximately 7% of patients. Such a decrease is very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride and/or vitamin B12 supplementation.  Measurement of hematological parameters on at least an annual basis is advised for patients receiving metformin-containing products (such as VYSOV-M) and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (e.g. those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at minimally two-to-three-year intervals may be useful.

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

A patient with type 2 diabetes previously well-controlled on VYSOV-M who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should promptly be evaluated for ketoacidosis and/or lactic acidosis. If acidosis of either form occurs, VYSOV-M must be stopped immediately, and appropriate measures initiated.

Hypoglycemia

Hypoglycemia does not usually occur in patients receiving VYSOV-M alone, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or ethanol use. Elderly debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people taking beta-adrenergic blocking drugs.

Loss of control of blood glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, surgery, etc., a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold VYSOV-M and temporarily administer insulin. VYSOV-M may be reinstituted after the acute episode is resolved.

Effects of Ability to Drive and Use Machines

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

Undesirable Effects

The data presented here relate to the administration of vildagliptin and metformin as a free or fixed dose combination.

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.

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. In data from controlled monotherapy and add-on therapy studies lasting up to 24 weeks, 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 50 mg daily, vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.

In clinical studies with the combination of vildagliptin + metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg twice daily + metformin or the placebo + metformin treatment groups.

In clinical studies, the incidence of hypoglycemia was uncommon in patients receiving vildagliptin 50 mg once daily in combination with metformin (0.9%), patients receiving vildagliptin 50 mg twice daily in combination with metformin (0.5%) and in patients receiving placebo and metformin (0.4%). No severe hypoglycemic events were reported in the vildagliptin arms.

Vildagliptin is weight neutral when administered in combination with metformin.

Gastrointestinal adverse reactions including diarrhea and nausea, are known to occur very commonly during the introduction of metformin hydrochloride. In the vildagliptin monotherapy clinical program (n =2,264) where vildagliptin was administered 50 mg once daily, 50 mg twice daily, or 100 mg once daily, the rate of diarrhea was 1.2%, 3.5% and 0.8 %, respectively, and the rate of nausea was 1.7%, 3.7% and 1.7%, respectively, as compared to 2.9% for both in the placebo group (n = 347) and 26.2% and 10.3%, respectively, in the metformin hydrochloride group (n = 252).

Overall, gastrointestinal symptoms were reported in 13.2% (50 mg once daily or twice daily) of patients treated with the combination of vildagliptin and metformin hydrochloride compared to 18.1% of patients treated with metformin hydrochloride alone.

Summary of adverse drug reactions from clinical studies

Adverse reactions reported in patients who received vildagliptin in double-blind studies as an add-on to metformin and as monotherapy are listed below for each indication, by MedDRA system organ class and absolute frequency. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Table 2: Other adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=233) or 50 mg twice daily (n=183) as add-on therapy to metformin compared to placebo plus metformin in double-blind studies

Nervous system disorders

 

Common

Tremor, dizziness, headache

Long-term clinical studies of up to more than 2 years in duration, did not show any additional safety signals or unforeseen risks when vildagliptin was added on to metformin.

When vildagliptin was studied as an initial combination therapy with metformin, no additional safety signals or unforeseen risks were observed.

Combination with insulin

In controlled clinical studies using vildagliptin 50 mg 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 cases of withdrawal in the placebo group.

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

At the end of the study, the 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).

Table 3: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with insulin (with or without metformin (n= 371)

Nervous system disorders

 

Common

Headache

Gastrointestinal disorders

 

Common

Nausea, gastroesophageal reflux disease

 

Uncommon

Diarrhea, flatulence

General disorders and administration site conditions

 

Common

Chills

Investigations

 

Common

Blood glucose decreased

Combination with SU

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

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

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

Table 4: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in combination with metformin and SU (n=157)

Nervous system disorders

 

Common

Dizziness, tremor

General disorders and administration site condition

 

Common

Asthenia

Metabolism and nutritional disorders

 

Common

Hypoglycemia

Skin and subcutaneous tissue disorders

 

Common

Hyperhidrosis

Vildagliptin

Adverse reactions for vildagliptin component from monotherapy double blind studies are presented in Table 5.

Table 5: Adverse reactions reported in patients who received vildagliptin 50 mg once daily (n=409) or 50 mg twice daily (n=1,373) as monotherapy in double-blind studies

Nervous system disorders

 

Common

Dizziness

 

Uncommon

Headache

Gastrointestinal disorders

 

Uncommon

Constipation

General disorders and administration site conditions

 

Uncommon

Edema peripheral

 

None of the adverse reactions reported for the vildagliptin monotherapy were observed at clinically significantly higher rates when vildagliptin was administered concomitantly with metformin.

The overall incidence of withdrawal from monotherapy studies due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg once daily (0.2%) or vildagliptin at a dose of 50 mg twice daily (0.1%) than for placebo (0.6%) or comparators (0.5%).

In monotherapy studies, hypoglycemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1,373) of patients treated with vildagliptin 50 mg twice 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. Vildagliptin is weight neutral when administered as monotherapy.

Long term clinical studies of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.

Adverse drug reactions from spontaneous reports and literature cases - post-marketing experience (frequency not known)

The following adverse drug reactions have been derived from post-marketing experience with vildagliptin/metformin combination via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.

  • Hepatitis, reversible upon drug discontinuation
  • Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid
  • Pancreatitis
  • Arthralgia, sometimes severe

Metformin Hydrochloride

Known adverse reactions for the metformin component are summarized in Table 6.

Table 6: Known adverse reactions for metformin

Metabolism and Nutrition disorders

 

Very common

Decreased appetite

 

Very Rare

Lactic acidosis

Nervous system disorders

 

Common

Dysgeusia

Gastrointestinal disorders

 

Very Common

Flatulence, nausea, vomiting, diarrhea, abdominal pain

Hepatobiliary disorders

 

Very Rare

Hepatitis**

Skin and subcutaneous tissue disorders

 

Very rare

Skin reactions such as erythema, pruritus, urticaria

Investigations

 

Very rare

Decrease of vitamin B12 absorption*, Liver function test abnormal

*A decrease of vitamin B12 absorption with decrease of serum levels has very rarely been observed in patients treated long-term with metformin and appears to generally not be of clinical significance. Consideration of such etiology is recommended if a patient presents with megaloblastic anemia.

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

         

Gastrointestinal adverse effects occur most frequently during initiation of therapy and resolve spontaneously in most cases.

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdosage

Vildagliptin

In healthy subjects (seven to fourteen subjects per treatment group), vildagliptin was administered in once-daily doses of 25, 50, 100, 200, 400, and 600 mg for up to 10 consecutive days. Doses up to 200 mg were well tolerated. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paresthesia, fever, edema and transient increase in lipase levels (2x ULN). At 600 mg, one subject experienced edema of the hands and feet, and an excessive increase in creatine phosphokinase (CPK) levels, accompanied by elevations of aspartate aminotransferase (AST), C-reactive protein, and myoglobin. Three additional subjects in this dose group presented with edema of both feet, accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after study drug discontinuation. Vildagliptin is not dialyzable, however the major hydrolysis metabolite (LAY151) can be removed by hemodialysis.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia 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 hydrochloride overdose cases. Metformin hydrochloride is dialyzable with a clearance of up to 170 ml/min under good hemodynamic conditions.  Therefore, hemodialysis may be useful for removal of the accumulated drug from patients in whom metformin hydrochloride overdosage is suspected. In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

Pharmacological Properties

Mechanism of Action

VYSOV-M combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the DPP-4 (dipeptidyl-peptidase-4) inhibitor 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 that improves glycemic control. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).

Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase and increase the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

Pharmacodynamic Properties

The efficacy and safety of the separate components have been previously established and the co-administration of the separate components have been evaluated for efficacy and safety in clinical studies. These clinical studies established an added benefit of vildagliptin in patients with inadequately controlled type 2 diabetes while on metformin hydrochloride therapy.

Vildagliptin

The administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. In patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period.

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 50 to 100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function.  The degree of improvement in beta-cell function is dependent on the initial degree of impairment; in non-diabetic (normal glycemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.

By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion. The reduction in inappropriate glucagon during meals in turn attenuates insulin resistance.

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

The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment. In addition, a reduction in postprandial lipemia that is not associated with vildagliptin’s incretin mediated effect to improve islet function, has been observed.

Metformin Hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin hydrochloride does not cause hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances) and does not cause hyperinsulinemia. With metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

In humans, metformin hydrochloride has favorable effects on lipid metabolism, independent of its action on glycemia. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, low-density lipoprotein cholesterol (LDLc) and triglyceride levels.

Pharmacokinetic Properties

Absorption

In the bioequivalence studies of vildagliptin and metformin at three dose strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1,000 mg), versus free combination of vildagliptin and metformin hydrochloride tablets at the corresponding doses, the area under the curve (AUC) and maximum concentration (Cmax) of both the vildagliptin component and the metformin hydrochloride component of the vildagliptin/metformin combination tablets were demonstrated to be bioequivalent to that of free combination tablets.

Food does not affect the extent and rate of absorption of vildagliptin. The Cmax and AUC of the metformin hydrochloride were decreased by 26% and 7%, respectively when given with food. The absorption of metformin hydrochloride was also delayed as reflected by the Tmax (2.0 to 4.0 hours) when given with food.  These changes in Cmax and AUC are consistent but lower than those observed when metformin hydrochloride was given alone under fed conditions. The effects of food on the pharmacokinetics of both the vildagliptin component and metformin hydrochloride component of combination were similar to the pharmacokinetics of vildagliptin and metformin hydrochloride when given alone with food.

Vildagliptin

Following oral administration in the fasting state, vildagliptin is rapidly absorbed with an absolute bioavailability of 85%. Peak plasma concentrations for vildagliptin and the area under the plasma concentration versus time curve (AUC) increased in an approximately dose-proportional manner over the therapeutic dose range. Peak plasma concentrations for vildagliptin was observed at 1.75 hours. Co-administration with food slightly decreases the rate of absorption of vildagliptin, as characterized by a 19% decrease in peak concentrations, and a delay in the time to peak plasma concentration to 2.5 hours. There is no change in the extent of absorption, and food does not alter the overall exposure (AUC).

Metformin Hydrochloride

The absolute bioavailability of a 500mg metformin hydrochloride tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin hydrochloride, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of the time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered under fasting conditions. The clinical relevance of these decrease is unknown.

Distribution

Vildagliptin

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

Metformin Hydrochloride

The apparent volume of distribution (V/F) of metformin hydrochloride following single oral doses of 850 mg averaged 654 ± 358 liters. Metformin hydrochloride is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound.  Metformin hydrochloride partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin hydrochloride are reached within 24 to 48 hours and are generally <1 microgram/mL. During controlled clinical studies of metformin hydrochloride, maximum metformin hydrochloride plasma levels did not exceed 5 micrograms/mL, even at maximum doses.

Metabolism

Vildagliptin

Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite, LAY151, 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 the dose). DPP-4 contributes partially to the hydrolysis of vildagliptin as shown in an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by cytochrome P450 enzymes to any quantifiable extent. In vitro studies demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes.

Metformin Hydrochloride

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

Excretion

Vildagliptin

Following oral administration of - vildagliptin, approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of the unchanged vildagliptin accounts for 23% of the dose after oral administration. After an intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 liters/hour and 13 liters/hour, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours and is independent of the dose.

Metformin Hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin hydrochloride is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment

Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. The AUC of the metabolites LAY151 increased 1.6, 3.2 and 7.3-fold and that of BQS867 increased on average about 1.4, 2.7 and 7.3-fold in patients with mild, moderate and severe renal impairment, respectively, compared to healthy volunteers. Limited data from patients with end stage renal disease (ESRD) indicate that vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations in ESRD patients were approximately 2-3-fold higher than in patients with severe renal impairment. Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3-4-hour hemodialysis session starting 4 hours post dose).

In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin hydrochloride is prolonged, and the renal clearance is decreased in proportion to the decrease in creatinine clearance.

Hepatic Impairment

The effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment decreased (20% and 8%, respectively), while the exposure to vildagliptin for subjects with severe impairment increased by 22%. The maximum change (increase or decrease) in the exposure to vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of hepatic function impairment and changes in exposure to vildagliptin. The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5x the ULN.

No pharmacokinetic studies of metformin hydrochloride have been conducted in subjects with hepatic impairment.

Elderly

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

Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin hydrochloride is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.

VYSOV-M treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Pediatric

No pharmacokinetic data available.

Gender

No differences in the pharmacokinetics of vildagliptin were observed between male and female subjects with a diverse range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin was unaffected by gender.

Metformin hydrochloride pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride was comparable in males and females.

Obesity

BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI.

Ethnicity

There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.

No studies of metformin hydrochloride pharmacokinetic parameters according to race have been performed.  In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51) and Hispanics (n=24).

Nonclinical Properties

Animal Toxicology and Pharmacology

Animal studies of up to 13-week duration have been conducted with the combined substances in vildagliptin/metformin combination. 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 15 mg/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 25 mg/kg (5-fold human exposure based on AUC) and in mice 750 mg/kg (142-fold human exposure).

Gastrointestinal symptoms, particularly soft faeces, mucoid faeces, diarrhea 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. Embryo fetal 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 75 mg/kg (10-fold human exposure). In rabbits, decreased fetal weight and skeletal variations indicative of developmental delays were noted only in the presence of severe maternal toxicity, with a no-effect dose of 50 mg/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 ≥ 150 mg/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 900 mg/kg (approximately 200 times human exposure at the maximum recommended dose). No increases in tumor incidence attributable to vildagliptin were observed. Another two-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg. An increased incidence of mammary adenocarcinomas and hemangiosarcomas was observed with a no-effect dose of 500 mg/kg (59-fold human exposure) and 100 mg/kg (16-fold human exposure), respectively. The increased incidence of these tumors 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 ≥ 5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg 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 ≥ 20 mg/kg/day (approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day. Skin lesions were not reversible in the monkeys treated at 160 mg/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.

Description

VYSOV-M Tablets combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the DPP-4 inhibitor class and metformin hydrochloride, a member of the biguanide class.

Pharmaceutical Particulars

VYSOV-M 50mg/500mg tablets

Light Yellow, ovaloid bevelled edge, film coated tablet, plain on both sides

VYSOV-M 50mg/850mg tablets

Yellow, ovaloid bevelled edge, film coated tablet, plain on both sides

VYSOV-M 50mg/1000mg tablets

Dark Yellow, ovaloid bevelled edge, film coated tablet, plain on both sides

Incompatibilities

Not applicable

Shelf-Life

18 Months

Packaging Information

VYSOV-M 50 mg/ 500 mg: Strip of 15 tablets

VYSOV-M 50 mg/ 850 mg: Strip of 15 tablets

VYSOV-M 50 mg/ 1000 mg: Strip of 15 tablets

Storage and Handling Instructions

Store between 8°C – 25°C. Protect from moisture.

Patient Counseling Information

VYSOV-M 50 mg/500 mg tablets

VYSOV-M 50 mg/850 mg tablets

VYSOV-M 50 mg/1000 mg tablets

Vildagliptin/Metformin hydrochloride

Read all 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.

What is in this leaflet

  1. What VYSOV-M is and what it is used for
  2. What you need to know before you take VYSOV-M
  3. How to take VYSOV-M
  4. Possible side effects
  5. How to store VYSOV-M
  6. Contents of the pack and other information
  1. What VYSOV-M is and what it is used for

The active substances of VYSOV-M, vildagliptin and metformin, belong to a group of medicines called “oral antidiabetics”.

VYSOV-M 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 VYSOV-M 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 VYSOV-M

Do not take VYSOV-M

  • If you are allergic to vildagliptin, metformin or any of the other ingredients of this medicine. If you think you may be allergic to any of these, talk to your doctor before taking VYSOV-M.
  • 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

VYSOV-M 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, 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).

Stop taking VYSOV-M 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 VYSOV-M 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.

VYSOV-M is not a substitute for insulin. Therefore, you should not receive VYSOV-M for the treatment of type 1 diabetes.

Talk to your doctor, pharmacist or nurse before taking VYSOV-M if you have or have had a disease of the pancreas.

Talk to your doctor, pharmacist or nurse before taking VYSOV-M, 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 VYSOV-M 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 VYSOV-M. Should these occur, you should promptly consult your doctor.

If you need to have major surgery, you must stop taking VYSOV-M during and for some time after the procedure. Your doctor will decide when you must stop and when to restart your treatment with VYSOV-M.

A test to determine your liver function will be performed before the start of VYSOV-M 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 VYSOV-M, 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 VYSOV-M in children and adolescents up to 18 years of age is not recommended.

Other medicines and VYSOV-M

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 VYSOV-M before or at the time of the injection. Your doctor will decide when you must stop and when to restart your treatment with VYSOV-M

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 VYSOV-M. 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.

VYSOV-M with alcohol

Avoid excessive alcohol intake while taking VYSOV-M since this may increase the risk of lactic acidosis

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 VYSOV-M during pregnancy.
  • Do not use VYSOV-M if you are pregnant or breast-feeding

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

If you feel dizzy while taking VYSOV-M, do not drive or use any tools or machines.

  1. How to take VYSOV-M

The amount of VYSOV-M that people have to take varies depending on their condition. Your doctor will tell you exactly the dose of VYSOV-M 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 tablet of either 50mg/500mg, 50 mg/850 mg or 50 mg/1000 mg 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 VYSOV-M

  • 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 VYSOV-M.

If you take more VYSOV-M than you should

If you take too many VYSOV-M 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 VYSOV-M

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 VYSOV-M

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 VYSOV-M 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 VYSOV-M 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):

VYSOV-M may cause a very rare, but very serious side effect called lactic acidosis. If this happens you must stop taking VYSOV-M 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 VYSOV-M:

 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 VYSOV-M and a sulphonylurea:

 Common: dizziness, tremor, weakness, low blood glucose, excessive sweating.

Some patients have had the following side effects while taking VYSOV-M 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 experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

  1. How to store VYSOV-M
  • 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 in order to protect from moisture.
  1. Contents of the pack and other information

The active substances are vildagliptin and metformin hydrochloride.

  • Each VYSOV-M 50 mg/500 mg tablet contains 50 mg vildagliptin and 500 mg metformin hydrochloride
  • Each VYSOV-M 50 mg/850 mg tablet contains 50 mg vildagliptin and 850 mg metformin hydrochloride
  • Each VYSOV-M 50 mg/1000mg tablet contains 50 mg vildagliptin and 1000 mg metformin hydrochloride

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or Licence Number with Date

M.L. MNB/05/109

Date of Revision

July 2020