Vildagluse Plus Tablet

Vildagluse Plus  ( generic ) is the local alternative for  Galvus Met ( brand) .Manufactured in Egypt by DBK Pharmaceutical Industries for Inspire Pharmaceutical Company (IPC Pharma).

This medicine available in Egyptian pharmacies, the price of the package 30 tablets ( 3 strips ) is 104 Egyptian pounds( around 6 USD ).

A10BD08#Vildagluse Plus 5000 Tablet#Inspire
A10BD08#Vildagluse Plus 5000 Tablet#Inspire

Vildagliptin – Metformln 50mg/1000mg Film-Coated Tablets .

NAME OF THE MEDICINAL PRODUCT

Vildagluse Plus 50/1000 mg film-coated tablets.

QUAUTATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet of Vildagluse Plus 50/1000 mg contains:

 50 mg vildagliptin and 1000 mg  metformin hydrochloride.

PHARMACETICAL FORM

Film-coated tablets.

CLINICAL PARTICULARS

 Therapeutic Indications

For patients with Type 2 diabetes mellitus (T2DM);

Vildagluse Plus is indicated as an adjunct to diet and exercises to improve glycaemic control in patients whose diabetes is not adequately controlled on metformin alone or who are already treated with the combination of vildagliptin and metformin, as separate tablets. Treatment should not be initiated with this fixed-dose combination.

Vildagluse Plus is indicated in combination with a sulfonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled with metformln and a sulfonylurea.

Vildagluse Plus is indicated as add-on to insulin as an adjunct to diet and exercise to improve glycaemic control in patients when stab le dose of insulin and metformin alone do not provide adequate glycaemic control.

Posology and method of administration

Posology

life threatening lactic acidosis can occur due to accumulation of metformin. The main risk factor is renal impairment. Other risk factors  include old age associated with reduced renal function and high doses of metformin above 2 g per day.

To minimise the risk of lactic acidosis, only one strength of Vildagluse Plus should be prescribed and used at any one time. Patients should also be advised to discard their previous metformin medication when initiated on Vildagluse Plus.

Adults

The use of antihyperglycaemic  therapy in the management of T2D should be individualized on the basis of effectiveness and tolerability.

 The recommended starting dose of Vildagluse Plus should be based on the patient’s current regimen of vildagliptin and/or metformin.

 Vildagluse Plus should be given with meals to reduce the gastrointestinal side effects associated with metformin.

 When using Vildagluse Plus, the maximum daily dose of vildagliptin (100 mg) should not be exceeded

Starting dose for patients inadequately controlled on metformin monotherapy:

Based on the patient’s current dose of metformin, Vildagluse Plus may be initiated at either the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily

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

Vildagluse Plus  may be initiated with either the 50 mg/500 mg, 50mg/850 mg or 50 mg/1000 mg tablet strength based on the dose of vildagliptin or metformin already being taken.

Use in combination with a sulfonylurea or with Insulin:

The dose of Vildagluse Plus 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.

Special populations

Elderly

Vildagluse Plus treatment should not be initiated in patients  ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function Is not reduced.

Renal impairment

Vildagliptin: No dosage adjustment is required in patients with mild renal impairment. The use of vildagliptin is not recommended in patients with moderate or severe renal impairment or in patients with ESRD on haemodialysis.

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

Hepatic impairment

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 upper limlt of normal.

Metformin : No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

 Paediatric population

The safety and effectiveness of Vildagluse Plus in paediatric patients have not been established. Therefore, Vildagluse Plus is not recommended for use in children below 18 years of age .

Method of administration

Oral use : Taking Vildagluse Plus with or just after food may reduce gastrointestinal symptoms associated with metformin .

 Contraindications

Hypersensitivity

Vildagluse Plus  is contraindicated in patients with known hypersensitivity to vildagliptin or metformin or to any of the excipients.

Real Disease

Vildagluse Plus is contraindicated In patients with renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/Dl (>135 µmol/L) in males and ≥ 1.4 mg/dl (> 110 µmol/L)in females or abnormal creatinine clearance), which may also result from conditions  such as cardiovascular collapse (shock), acute myocardial infarction, and septicaemia.

 Congestive heart failure

Vildagluse Plus is contraindicated in patients with congestive heart failure requiring pharmacologic treatment.

 Metabolic acidosis

Vildagluse Plus is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Radiologic studies

Vildagluse Plus should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function .

Special warnings and precautions for use

General

Vildagluse Plus is not a substitute for insulin in insulin-requiring patients. Vildagluse Plus should not be used in patients with T1D or for the treatment of diabetic ketoacidosis.

Renal impairment

Vildagluse Plus should not be used In patients with renal failure or renal dysfunction, e.g serum creatinine levels ≥ 1.5 mg/dL(>135 µmol/L) in males and ≥ 1.4 mg/dl (> 110 µmol/L)in females

 Monitoring of renal function

Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of renal function impairment. Patients with serum creatinine levels above the upper limit of normal for their age should not receive Vildagluse Plus. Since advancing age is associated with reduced renal function, Vildagluse Plus should be carefully titrate in the elderly to establish the minimum dose for adequate glycaemic effect, and renal function should be monitored regularly.

 Also, special caution should be exercised where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a NSAID.

 Renal function should be assessed and verified as normal before the initiation of Vildagluse Plus, then at least once a year in patients with normal renal function and at least two to four times a year in patients with serum creatinine levels at the upper limit of normal.

Additionally, patients in whom renal dysfunction is anticipated should have their renal function assessed more frequently.

Vildagluse Plus should be discontinued if evidence of renal impairment is present.

Concomitant medications that may affect renal function or metformin disposition

Concomitant medications that may affect renal function, result in significant haemodynamic change or interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

Cardiac failure

Vildagluse Plus is contraindicated in patients with congestive heart failure requiring pharmacologic treatment, which may potentially Interact with metformin .

Vildagliptin in patients with 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 CHF versus placebo. 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 patients with NYHA functional class IV and therefore use is not recommended in these patients.

Hepatic impairment

Vildagliptin, and hence Vildagluse Plus, 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 upper limit of normal.

Since impaired hepatic function has been associated with some cases of lactic acidosis (a risk associated with Metformin), Vildagluse Plus should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.

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 Vildagluse Plus.

Vildagluse Plus is not recommended in patients with a pre-treatment ALT or AST >2.5x the upper limit of normal.

LFTs should be monitored during Vildagluse Plus 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 thereafter with frequent liver function tests until the abnormality (ies) return to normal.

 Should an increase in AST or ALT of 3x upper limit of normal or greater persist, withdrawal of therapy with Vildagluse Plus is recommended.

 Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Vildagluse Plus and contact their physician immediately.

 Following withdrawal of treatment with Vildagluse Plus and LFT normalisation, Vildagluse Plus should not be reinitiated.

 Vildagluse Plus is not recommended in patients with hepatic impairment.

Lactic Acidosis

Lactic acidosis is a very rare but serious metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure.

 The incidence of lactic acidosis can and should be reduced by also assessing other associated  risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.

lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate/pyruvate ratio.

 If metabolic acidosis is suspected, treatment with the medicinal product should be discontinued and the patient hospitalised immediately .

Paediatric use

The safety and effectiveness of Vildagluse Plus in paediatric patients have not been established. Therefore, Vildagluse Plus is not recommended for use in children below 18 years of age.

 Use in the elderly  ( 65 Years)

As metformin is excreted via the kidney, and elderly patients have a tendency to decreased renal function, elderly patients taking Vildagluse Plus should have their renal function monitored regularly.

Vildagluse Plus should only be used in elderly patients with normal renal function .

Effects on skin

In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at all oral doses administered (5 to 160 mg/kg/day). These were consistently located on the extremities (hands, feet, ears and tail) and  included flaking skin ; peeling skin, scabs, tail sores and blisters.

At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), lesions were reversible despite continued treatment.

 Necrotic lesions of the tail were observed at ≥ 80 mg/kg/day (18 times human AUC exposure at the maximum recommended clinical dose).

 Skin lesions were not reversible in monkeys treated at 160 mg/kg/day (35 times human AUC exposure) during a 4-week recovery period. Skin lesions have not been observed in other animal species and no excess of skin lesions with vildagliptin treatment relative to comparator treatments have been observed Iin the clinical trial programme.

 Administration of intravascular iodinated contrast materials

Vildagluse Plus should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function and increase the risk of lactic acidosis.

In patients undergoing such studies, Vildagluse Plus should be temporarily discontinued at the time of or prior to the procedure, with held for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal .

Hypoxic States

Cardiovascular collapse (shock). acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxaemia have been associated with lactic acidosis and may also cause pre-renal azotmeia.

lf such events occur in patients receiving Vildagluse Plus therapy, the medication should be promptly discontinued.

Surgical procedures

Use of Vildagluse Plus should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.

Alcohol  intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving Vildagluse Plus.

Vitamin B12 levels

The metformin has been associated with a decrease in serum vitamin B12 levels without clinical manifestations in approximately 7% of patients. Such decrease is very rarely associated with anaemia and appears to be rapidly reversible with discontinuation of metformin and/or Vitamin B12 supplementation.

 Measurement of haematological parameters on at least an annual basis is advised for patients receiving Vildagluse Plus 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 T2DM

A patient With T2DM previously well-controlled on Vildagluse Plus 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, Vildagluse Plus must be stopped immediately and appropriate measures initiated.

Hypoglycaemia

Hypoglycaemia  does not usually occur in patients receiving Vildagluse Plus 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 hypoglycaemic effects.

Hypoglycaemia 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 glycaemic control may occur. At such times, It may be necessary to withhold Vildagluse Plus and temporarily administer insulin.

Vildagluse Plus may be reinstituted after the acute episode is resolved.

Interaction with other medicinal products and other forms of interaction

No clinically relevant pharmacokinetic Interaction was observed when vildagliptin (100 mg once daily) was co-administered with metformin (1000 mg once daily).

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

 Vildagliptin

Vildagliptin has a low potential for drug interactions. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it Inhibit nor induce CYP 450 enzymes, it is not likely to Interact with co-medications that are substrates, inhibitors or lnducers of these enzymes.

Furthermore, vildagliptin does not affect metabolic clearance of co-medications metabolised by CYP lA2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2El, and CYP 3A4/5.

No relevant Interactions with other oral antidiabetics (glibenclamide, ploglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan orwarfann were observed after co-administraticn with vildagliptin.

Metformin

1-Furosemide:  Increased C-max and blood AUC of metformin with no change in renal clearance of metformin. Metformin decreased C-max blood AUC of furosemide, with no change in renal clearance of furosemide.

2-Nifedipine : Nifedlpine increased absorption, C-max and AUC of metformin, and Increased excretion of metformln in urine. Metformin had minimal effects on nifedipine.

3-Glyburide :Glyburide produced no changesin metformin PK/PD parameters. Decreases in C-max, blood AUC of glyburide were observed, but were highly variable. Therefore, the clinical significance of this finding was unclear.

4-cattonic drugs :Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide ,quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Thus, with cimetidine increases in metformin plasma/blood concentration and AUC were observed to be 60 and 40 respectively. Metformin had no effect on cimetidine PK. Although such interactions remain theoretical (except for cimetidine), careful monitoring of patients and doses of metformin and such medications are recommended.

5-Other :Certain drugs tend to produce hyperglycaemia and may lead to loss of glycaemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, svmpathomirnettcs, calcium channel blocking drugs, and isomand. Close monitoring of glycaemic control and metformin dose adjustments are recommended when such drugs are administered or withdrawn for these patients.

There is an increased risk of lactic acidosis in acute alcohol intoxication  (particularly in the case of fasting, malnutrition or hepatic Impairment) due to the metformin. Consumption of alcohol and medicinal products containing alcohol should be avoided .

Fertility, pregnancy and lactation

Pregnancy (Category C)

There are no adequate data in pregnant women. Therefore, Vildagluse Plus should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.

Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Breast-feeding

There is no available data on the combined components of Vildagluse Plus.

 Metformin is excreted into human breast milk.

 It is not known whether vildagliptin is excreted in human milk or not.

 Vildagluse Plus should not be administered to breast-feeding women.

Fertility

There is no available data on vildagliptin and metformin in combination to evaluate potential effects on fertility.

 Effects on ability to drive and use machines

There is no available data on the effects on the ability to drive and use machines. Patients who may 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 angiotensin converting enzyme inhibitor (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. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice. Vildagliptin is weight neutral when administered in combination with metformin.

Adverse reactions reported in patients who received vildagliptin are listed in Table 1 for each indication, by system organ class and absolute frequency. Frequencies are defined as; very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥  1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare(< 1/10,000), including isolated reports

 Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Other adverse reactions reported in patients who received vildagliptln 50 mg once daily or 50 mg twice daily as add-on therapy to metformin compared to placebo plus metformin

Nervous system disorders
Common Tremor
Common Headache
Common dizziness

Combination with Insulin

Table 2: Adverse effects reported in patients who received vildagliptln 50 mg twice daily  vs  placebo in combination with insulin (with or without metformin)

Metabolism and nutrition disorders
Common Decreased blood glucose
Nervous system disorders
Common Headache, chills
Gastrointestinal disorder
Common Nausea ;gastro-oesophageal reflux disease
Uncommon Diarrhea ,flatulence

Combination With sulfonylurea

Table 3: Adverse reactions reported in patients who received vildagliptin 50 mg twice daily in cembination with metformin and sulfonylurea

Metabolism and nutritional disorders
Common Hvpoglycemia
Nervous system disarders
Common Dizziness, tremor
Skin and subcutaneous tissue disorders
Common Hyperhidrosis
General disorders and administration site conditions
Common Asthenia

Vildagliptin

Table 4; Adverse reactions reported in patients who recived vildagliptin 50 mg once daily 0r 50 mg twice daily as monotherapy

Nervous system disarders
Common Dizziness
Uncommon Headache
GastroIntestinal disorders
Uncommen Constipation
General disorders and administration site condltions
Uncommon Oedema peripheral

Post-marketing experience with vildagliptin

During post-marketing experience, the following additional adverse drug reaction has-been reported:

  • Rare cases of hepatitis reversible upon drug discontinuation. Frequency not known.
  • Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid.
  • Arthralgia sometimes severe.

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”.

Metformin

Known adverse reactions for metformin are summarized in Table 5.

Table 5: known adverse reactions for metformin

Metabolism and nutrition disorders

 

Very rare Decrease of vitamin B12 absorption, lactic acidosis
Nervous system disorders
Common Metallic taste
Gastrointestinal disorders
Very common Flatulence,nausea,vomiting  ,diarrhea,abdominal pain,.loss of appetite
Hepatobillary disorders
Very rare liver function test abnormalities, hepatitiis
Skin and subcutaneous tissue disorders
Very rare Skin reactions such as erythema. pruritus.urticaria

A decrease of vitamin B12 absorption with decrease of serum levels has been very rarely observed in patients treated long-term with metformin and appears generally to be without clinical significance. Consideration af 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 undesirable effects 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.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system to Egyptian Pharmacovigilance center e-mail: pv.center@eda.mohealth.gov.eg or to Inspire Pharmaceutical Companye-mail:safety@inspirephanna.com.

Overdose

Accidental overdose resulting from the continuance of previously prescribed products may occur.

 To avoid accidental overdose, patients should be advised to discard their previous metformin medication when prescribed with Vildagluse Plus.

Symptoms and treatment

Vildagliptin :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 muscle pain, and mild and transient paraesthesia, fever, oedema and transient increase in lipase levels (2x ULN). At 600 mg, oedema of the feet and hands, and an excessive increase in creatine phosphokinase (CPK) levels, accompanied by elevations of aspartate aminotransferase (AST), C-reactive protein and myoglobin. All symptoms and laboratory abnormalities resolved after study drug discontinuation.

Vildagliptin  is not dialyzable, however the major hydrolysis metabolite (LAY151) can be removed by haemodialysis.

 Metformin : Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycaemia was  reported in approximately 10 of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32 of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good haemodynamic condition.s. Therefore, haemodialysis may be useful for removal of accumulated drug from patients in whom  metformin overdosage is suspected.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

 PHARMACOLOGICAL PROPERTIES

Pharmacodynamic  properties

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

 ATC code: A10BD08

 Mechanism of action

Vildagluse Plus combines two antihyperglycaemic agents with different mechanisms of action to improve glycaemic control in patients with type 2 diabetes (T2D):

  1. vildagliptin, a member of the DPP-4 (dipeptidyl-peptidase-4) inhibitor class.
  2. metformin,a member of the biguanide class.

Vildagliptin : Vildagliptin, a member of the islet enhancer class, is a high affinity dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycaemic control.

The administration of vildagliptin results in rapid and near-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. 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).

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 dally in patients with T2D 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 glycaemic) 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 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 to delay gastric emptying  is not observed with vildagliptin treatment. In addition, a reduction in postprandial  lipaemia that is not associated with vildagliptin’s incretin mediated effect to improve islet function, has been observed.

 Metformin : Metformin improves glucose tolerance in patients with T2D, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucoseand improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycaemia in either patients with T2D or normal subjects (except in special circumstances), and does not cause hyperinsulinaemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

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

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

Pharmacokinetic properties

Absorption

The area under the curve (AUC) and maximum concentration (C-max) of both the vildagliptin component and the metformin component were demonstrated to be bioequivalent to that of free combination.

Food does not affect the extent and rate of absorption of vildagliptin from Vildagluse Plus.

 The C-max and AUC of the metformin component from Vildagluse Plus were decreased by 26% and 7% respectively when given with food. The absorption of metformin was also delayed as reflected by the T-max (2.0 to 4.0 hrs) when given with food. These changes in C-max and AUC are consistent but lower than those observed when metformin when given alone underfed conditions. The effects of food on the pharmacokinetics of both the vildagliptin component and metformin component of Vildagluse Plus were similar to the pharmacokinetics of vildagliptin and metformin when given alone with food.

Vildagliptin : Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations 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 : The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximate 50 to 60. Studies using single oral doses of metformin tablets 500 mg to 1500 mg, and 850 mg to 2550 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, as shown by approximately a 40% lower mean peak plasma concentration (C-max), a 25% lower area under the plasma concentration versus time curve, and a 35 minute prolongation of time to peak plasma concentration (T-max) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Vildagliptin :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 is 71 L, suggesting extravascular distribution.

Metformin :The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654 ± 358 L . Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 micrograrm/ml. During controlled clinical trials of metformin, maximum metformin 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: Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. In patients with significantly decreased renal function, the plasma half-life of metformin is prolonged and renal clearance is decreased.

Elimination

Vildagliptin : Following oral administration of (14C)-vildagliptin, approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the faeces. 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 L/hour and 13 L/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 do se.

Metfarmin : Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or 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.

linearity/non-linearity

Vildagliptin:Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. Peak plasma concentrations for vildagliptin and the area under the plasma concentration versus time curve increased in an approximately dose-proportional manner over the therapeutic dose range.

Metformin : Studies using single oral doses of metformin tablets indicate a lack of dose proportionality, due to increased absorption of metformin with Increasing doses.

Special populations

Elderly

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

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

Vildagluse Plus treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function Is not reduced .

Paediatric

No pharrnacokinetic data are available in children .

 Gender

Vildagliptin: 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.

Metfarmin : Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with T2D when analysed according to gender.

Obesity

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

 Hepatic impairment

Vildagliptin : The effect of impaired hepatic function on the pharmacokinetics ofvildagliptin 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 was decreased (20% and 8%, respectively), while the exposure to vildagliptin for subjects with severe impairment was 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 upper Limit of normal .

Metformin :No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.

Renal impairment

Vildagliptin:In subjects with mild, moderate and sever  renal impairment, and patients with end stage renal disease (ESRD) on haemodialysis, systemic exposure to vildagliptin was increased (C-max  8% to 66%; AUC 32% to 134%) compared to subjects with normal renal function. Exposure to the inactive metabolite (LAY151) increased with increasing severity of renal impairment (AUC 1.6 to 6.7-fold). Changes in exposure to vildagliptin did not correlate with severity of renal  impairment, whereas changes in exposure to the inactive metabolite did correlate. Elimination half-life of vildagliptin was not affected by renal impairment. Based on the evaluation of safety, tolerability and effectiveness of vildagliptin in patients enrolled in clinical triais whose GFR values were < 60 Ml/min, no dosage adjustment is required in patients with mild renal impairment. The use of vildagliptin is not recommended in patients with moderate or severe renal impairment or in patients with ESRD on haemodialysis .

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

Pharmaceutical Particulars

List of excipients

Tablet Core:

Hydroxypropylcellulose (klucel EF), Microcrystalline cellulose (avicel 102), Magnesium stearate.

Toblet Coat: Hydroxy propyl methyl cellulose(methoceIE5), Titanium dioxide, Yellow iron oxide, Poiyethyleneglycol6000 ,Talc powder.

Incompatibilities

 Not applicable.

Shelf life

2 years.

Special precautions for storage

Store at a temperature not exceeding 30°C, in a dry place.

Store in the original package in order to protect from moisture.

Keep out of reach of children.

Nature and contents of container

Carton box containing 1, 2 or 3 (Al/Al) blister contains 10 film coated tablets and an inner leaflet.

 MARKETING AUTHORISATION HOLDER

Manufactured by D B K Pharma for Inspire Pharmaceutical Company (IPC Pharma).

Brands and Generics in Egypt

Name Price in L.E.

Company

AR – Name
DIBAVALLY PLUS 50/1000 mg 14 TABS. 32 L.E. for 14 tablets AUG PHARMA ديبافالى بلس
GALVUS MET 50/1000mg 30 F.C. tabs. 147 L.E. for 30 tablets NOVARTIS جالفس مت
GLIPTUS PLUS 50/1000mg 30 TABLETS 104 L.E. for 30 tablets EVA PHARMA جليبتس بلس
ICANDRA PLUS 50/1000mg 30 F.C. Tabs. 114 L.E. for 30 tablets MASH PREMIERE إيكاندرا بلس
VILDAGLUSE PLUS 50/1000 mg 30 TABS. 104 L.E. for 30 tablets INSPIRE PHARMACEUTICAL COMPANY فيلداجلوز بلس
Other concentration
GALVUS MET 50/500mg 30 F.C. tabs. 147 L.E. for 30 tablets NOVARTIS جالفس مت
GALVUS MET 50/850mg 30 F.C. tabs. 147 L.E. for 30 tablets NOVARTIS جالفس مت
GLIPTUS PLUS 50/850mg 30 TABLETS 104 L.E. for 30 tablets EVA PHARMA جليبتيس بلس
SUGARLO PLUS 50/850mg 30 F.C. TABS. 81.90 L.E. for 30 tablets AL ESRAA PHARMACEUTICAL OPTIMA سيوجارلو بلس
VILGAT PLUS 50/500 mg 30 TABS. 104 L.E for 30 tablets FUTURE PHARMACEUTICAL INDUSTRIES (FPI) فيلجات بلس

Referances – EN

GLVUSMET  from news medical net.

Vildagliptin with metformin from nps.org.au.

American Diabetes Association.

Diabetes In Control.

Referance – AR

جالفس مت – فارماسيا.

فيداجليبتين – الصيدلية العربية .

فيلداغليبتين – موسوعة العلوم العربية .


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