||See TERMINOLOGY & ABBREVIATIONS ||
Vildagliptin with Metformin HCl.
mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg film-coated tablet contains vildagliptin 50 mg and metformin HCl 500 mg, 850 mg and 1000 mg,
|Indication(s)||Adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus whose diabetes is not adequately controlled on metformin HCl or vildagliptin alone or who are already treated with the combination of vildagliptin and metformin HCl, as separate tablets.|
|Dosage||Adults: Based on the patient's current dose of vildagliptin and/or metformin, This combination may be
initiated at either the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily, 1 tablet in the morning and the other in the evening. The
recommended daily dose is vildagliptin 100 mg plus metformin HCl 2000 mg.
Patients receiving vildagliptin and metformin from separate tablets may be switched to This combination containing the same doses of each component.
In treatment-naive patients, This combination may be initiated at 50 mg/500 mg once daily and gradually titrated to a maximum dose of 50 mg/1000 mg twice daily after assessing adequacy of therapeutic response.
Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the healthcare provider.
Doses >100 mg of vildagliptin are not recommended. There is no clinical experience of vildagliptin and metformin in triple combination with other antidiabetic agents.
The use of antihyperglycaemic therapy in the management of type 2 diabetes should be individualized on the basis of effectiveness and tolerability. The recommended starting dose of This combination should be based on the patient's current regimen of vildagliptin and/or metformin HCl.
Administration: Taking This combination with or just after food may reduce gastrointestinal symptoms associated with metformin.
|Administration||Should be taken with food.: Take w/ or immediately after meals to reduce GI discomfort.|
|Overdose||Vildagliptin: In healthy subjects
(7-14 subjects/treatment group), vildagliptin was administered in once-daily doses of 25 mg, 50 mg, 100 mg, 200 mg, 400 mg and 600 mg for up to 10
consecutive days. Doses up to 200 mg were well tolerated. At 400 mg, there were 3 cases of muscle pain and individual cases of mild and transient
paraesthesia, fever, oedema and transient increase in lipase levels [2x upper limit of normal (ULN)]. At 600 mg, 1 subject experienced 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. Three additional subjects in this dose group presented with oedema of both feet, accompanied by paraesthesia in 2 cases. All symptoms and
laboratory abnormalities resolved after This combination discontinuation. Vildagliptin is not dialyzable, however the major hydrolysis metabolite (LAY151)
can be removed by haemodialysis.
Metformin HCl: Overdose of metformin HCl has occurred, including ingestion of amounts >50 g. Hypoglycaemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin HCl overdose cases. Metformin HCl is dialyzable with a clearance of up to 170 mL/min under good haemodynamic conditions. Therefore, haemodialysis may be useful for removal of accumulated drug from patients in whom metformin HCl overdosage is suspected. In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.
|Contraindications||Known hypersensitivity to vildagliptin or metformin HCl or to any of the excipients of
Patients with renal disease or dysfunction [eg, as suggested by serum creatinine levels â‰¥1.5 mg/dL (>135 micromol/L) in males and â‰¥1.4 mg/dL (>110 micromol/L) in females or abnormal creatinine clearance] which may also result from conditions eg, cardiovascular collapse (shock), acute myocardial infarction and septicaemia (see Precautions).
Patients with congestive heart failure requiring pharmacologic treatment (see Precautions).
Patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
This combination 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 (see Precautions).
Galvus tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take This combination.
This combination should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Use in lactation: No studies have been conducted with the combined components of This combination. As it is not known whether vildagliptin and/or metformin HCl is excreted in human milk, This combination should not be administered to breastfeeding women.
|Special Precautions||This combination is not a substitute for insulin in insulin-requiring patients. Vildagliptin: Hepatic Impairment: Vildagliptin is not
recommended in patients with hepatic impairment, including patients with a pre-treatment alanine aminotransferase (ALT) or aspartate amiotransferase (AST)
>2.5x the upper limit of normal.
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 This combination. This combination is not recommended in patients with a pre-treatment ALT or AST >2.5x the upper limit of normal. LFTs should be monitored during This combination treatment at 3-month intervals during the 1st year and periodically thereafter. Patients who develop increased transaminase levels should be monitored with a 2nd liver function evaluation to confirm the finding and be followed thereafter with frequent LFTs until the abnomality(ies) return to normal. Should an increase in AST or ALT of â‰¥3x upper limit of normal persist, withdrawal of therapy with This combination is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue This combination and contact the physician immediately. Following withdrawal of treatment with This combination and LFT normalisation, This combination should not be reinitiated.
Metformin HCl: 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 eg, poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia (see Contraindications and Interactions).
Diagnosis of Lactic Acidosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels >5 mmol/L and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment with the This combination should be discontinued and the patient hospitalised immediately (see Overdosage).
Monitoring of Renal Function: Metformin HCl is known to be substantially excreted by the kidney and the risk of metformin HCl 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 This combination. Since advancing age is associated with reduced renal function, This combination should be carefully titrated 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 eg, when initiating antihypertensive or diuretic therapy or when starting treatment with an nonsteroidal anti-inflammatory drug (NSAID). Renal function should be assessed and verified as normal before the initiation of This combination, then at least once a year in patients with normal renal function and at least 2-4 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. This combination should be discontinued if evidence of renal impairment is present.
Concomitant Medications that may Affect Renal Function or Metformin HCl Disposition: Concomitant medications that may affect renal function, result in significant haemodynamic change or interfere with the disposition of metformin HCl, eg cationic drugs that are eliminated by renal tubular secretion should be used with caution (see Interactions).
Administration of Intravascular Iodinated Contrast Materials: This combination 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, This combination should be temporarily discontinued at the time of or prior to the procedure, withheld for 48 hrs 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 azotemia. If such events occur in patients receiving This combination therapy, This combination should be promptly discontinued.
Surgical Procedures: Use of This combination 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 HCl on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving This combination.
Impaired Hepatic Function: Since impaired hepatic function has been associated with some cases of lactic acidosis, a risk associated with metformin HCl, This combination should generally be avoided in patients with clinical or laboratory evidence of hepatic disease including patients with a pre-treatment ALT or AST >2.5x the upper limit of normal.
This combination is not recommended in patients with hepatic impairment.
Vitamin B12 Levels: The metformin component of This combination 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 HCl and/or vitamin B12 supplementation. Measurement of haematological parameters on at least an annual basis is advised for patients receiving This combination and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (eg, 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 2- to 3-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 This combination 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, This combination must be stopped immediately and appropriate measures initiated.
Hypoglycaemia: Hypoglycaemia does not usually occur in patients receiving This combination 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 Î²-adrenergic blocking drugs.
Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress eg, fever, trauma, infection, surgery, a temporary loss of glycaemic control may occur. At such times, it may be necessary to withhold This combination and temporarily administer insulin. This combination may be reinstituted after the acute episode is resolved.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness should therefore avoid driving vehicles or using machines.
Use in pregnancy: Fertility studies have been performed with vildagliptin in rats at doses producing exposures equivalent to up to 200 times the human dose and have revealed no evidence of impaired fertility or early embryonic development due to vildagliptin. Embryofoetal development (teratology) studies have been conducted in rats and rabbits with the combination of vildagliptin and metformin HCl in a 1:10 ratio and produced no evidence of teratogenicity in either species. There are, however, no adequate and well-controlled studies in pregnant women and therefore, This combination should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. Animal studies are not always predictive of human response.
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.
Use in children: Safety and effectiveness of This combination in paediatric patients have not been established. Therefore, This combination is not recommended for use in children <18 years.
Use in the elderly: As metformin is excreted via the kidney and elderly patients have a tendency to decreased renal function, elderly patients taking This combination should have their renal function monitored regularly. This combination should only be used in elderly patients with normal renal function (see Contraindications).
|Adverse Drug Reaction(s)||There have been no therapeutic
clinical trials conducted with This combination. However, bioequivalence of this combination with co-administered vildagliptin and metformin has been
demonstrated (see Pharmacokinetics under Actions). The data presented as follows relate to the co-administration of vildagliptin and metformin, where
vildagliptin has been added to metformin. There have been no studies of metformin added to vildagliptin.
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. In data from controlled monotherapy and add-on therapy trials up to 24 weeks in duration, the incidence of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations â‰¥3x upper limit of normal (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, nonprogressive in nature and not associated with cholestasis or jaundice.
In clinical trials 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 trials, the incidence of hypoglycaemia 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 diarrhoea and nausea are known to occur very commonly during the introduction of metformin HCl. In the vildagliptin monotherapy clinical program (n=2264) where vildagliptin was administered 50 mg once daily, 50 mg twice daily or 100 mg once daily, the rate of diarrhoea 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 HCl 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 HCl compared to 18.1% of patients treated with metformin HCl alone.
Adverse reactions reported in patients who received vildagliptin in double-blind studies as add-on to metformin and as monotherapy, are listed as follows, for each indication, by system organ class and absolute frequency. Frequencies are defined as: Very common (â‰¥1/10); common (â‰¥1/100, <1/10); uncommon (â‰¥1/1000, <1/100); rare (â‰¥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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.
Adverse Reactions Reported in Patients Who Received Galvus 100 mg Daily in Combination with Metformin in Double-Blind Studies (n=208): Galvus in Dual Oral Therapy with Metformin: Nervous System Disorders: Common: Tremor, dizziness, headache. Uncommon: Fatigue.
Gastrointestinal Disorders: Common: Nausea.
Metabolism and Nutrition Disorders: Common: Hypoglycaemia.
Vildagliptin: Adverse reactions for vildagliptin component from monotherapy double blind studies are presented as follows.
Adverse Reactions Reported in Patients Who Received Vildagliptin 50 mg Once Daily (n=409) or 50 mg Twice Daily (n=1373) as Monotherapy in Double-Blind Studies: Nervous System Disorders: Common: Dizziness. Uncommon: Headache.
Gastrointestinal Disorders: Uncommon: Constipation.
General Disorders and Administration Site Conditions: Uncommon: Peripheral oedema.
Adverse Reactions Reported in Patients Who Received Galvus 50 mg, 100 mg Daily as Monotherapy in Double-Blind Studies (n=1855): Nervous System Disorders: Common: Dizziness. Uncommon: Headache.
Gastrointestinal Disorders: Uncommon: Constipation.
Skin and Subcutaneous Tissue Disorders: Uncommon: Skin rash.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Arthralgia.
Metabolism and Nutrition Disorders: Uncommon: Hypoglycaemia.
Infections and Infestations: Very Rare: Upper respiratory tract infection, nasopharyngitis.
Vascular Disorders: Uncommon: Peripheral oedema.
None of the adverse reactions reported for the vildagliptin monotherapy were observed at clinically significant higher rates when vildagliptin was administered concomitantly with metformin.
The overall incidence of withdrawals from monotherapy trials 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, hypoglycaemia was uncommon reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1373) of patients treated with vildagliptin 50 mg twice daily compared to 0.2% (2 of 1082) 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 trials of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin.
Post-Marketing Experience: During post-marketing experience the following additional adverse drug reactions have been reported (frequency not known): Urticaria, pancreatitis.
Metformin HCl: Known adverse reactions for metformin component are summarized as follows.
Metabolism and Nutrition Disorders: Very Rare: Decrease of vitamin B12absorption*, lactic acidosis.
Nervous System Disorders: Common: Metallic taste.
Gastrointestinal Disorders: Very Common: Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite.
Hepatobiliary Disorders: Very Rare: Liver function tests abnormalities, hepatitis**.
Skin and Subcutaneous Tissue Disorders: Very Rare: Skin reactions eg, erythema, pruritus, urticaria.
*A decrease of vitamin B12 absorption with decrease of serum levels has been observed very rarely in patients treated long-term with metformin and appears generally to be without clinical significance. Consideration of such aetiology is recommended if a patient presents with megaloblastic anaemia.
**Isolated cases of LFT 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.
|Drug Interactions||No clinically relevant pharmacokinetic interaction was observed when vildagliptin (100 mg once daily) was co-administered with metformin
HCl (1000 mg once daily). Drug interactions for each component of This combination has been extensively studied. However, the concomitant use of vildagliptin
and metfromin HCl 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 drug interactions. Since vildagliptin is not a CYP450 enzyme substrate nor does it inhibit nor induces CYP450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes.
Furthermore, vildagliptin does not affect metabolic clearance of co-medications metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5. Drug-drug interaction studies were conducted with commonly co-prescribed medications for patients with type 2 diabetes or medications with a narrow therapeutic window. As a result of these studies, no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin HCl), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin.
Metformin HCl: The following is known for metformin component: Furosemide: Furosemide increased peak plasma concentration (Cmax) and blood area under the concentration-time curve (AUC) of metformin with no change in renal clearance of metformin. Metformin decreased Cmax, blood AUC of furosemide, with no change in renal clearance of furosemide.
Nifedipine: Nifedipine increased absorption, Cmax and AUC of metformin and increased excretion of metformin in urine. Metformin had minimal effects on nifedipine.
Glyburide: Glyburide produced no changes in metformin pharmacokinetic/pharmacodynamic parameters. Decreased in Cmax, blood AUC of glyburide were observed, but were highly variable. Therefore, the clinical significance of this finding was unclear.
Cationic Drugs: Cationic drugs (eg, 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 pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful monitoring of patients and doses of metformin and such medications are recommended.
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, sympathomimetics, calcium-channel blocking drugs and isoniazid. 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 insufficiency) due to the metformin active substance of This combination. Avoid consumption of alcohol and medicinal products containing alcohol. (See Precautions.)
|Pharmacology||Pharmacodynamics: This product combines 2 antihyperglycemic agents with different mechanisms of action
to improve glycaemic control in patients with type 2 diabetes: Vildagliptin, a member of the dipeptidyl-peptidase-4 (DPP-4) inhibitor class and metformin
HCl, a member of the biguanide class.
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 HCl therapy.
In a double-blind, placebo-controlled trial in patients with type 2 diabetes whose hyperglycaemia was inadequately controlled on a maximal dose of metformin HCl alone, the addition of vildagliptin (50 mg once daily or 100 mg in divided doses) for 24 weeks led to statistically significant reductions in HbA1c and increased the proportion of patients achieving at least a 0.7% reduction in HbA1c when compared to patients who were continued on metformin HCl alone. Group mean baseline HbA1c (%) ranged from 8.3% (placebo plus metformin HCl) to 8.4% (in both vildagliptin plus metformin HCl groups). Vildagliptin combined with metformin HCl resulted in additional statistically significant mean reductions in HbA1c compared to placebo (between group differences of -0.7% to -1.1% for vildagliptin 50 mg and 100 mg, respectively). The proportion of patients who achieved a clinically meaningful and robust decrease in HbA1c (defined as a decrease â‰¥0.7% from baseline) was statistically significantly higher in both vildagliptin plus metformin HCl groups (46% and 60%, respectively) versus the metformin HCl plus placebo group (20%). Patients on the combination of vildagliptin plus metformin HCl did not experience a meaningful change in body weight compared to baseline. After 24 weeks, there was a decrease from baseline for both systolic and diastolic blood pressure in the vildagliptin treatment groups combined with metformin HCl. Mean changes from baseline were -2/0.8 mm Hg, -3.5/-2.2 mm Hg and -0.8/-0.1 mm Hg, in patients receiving metformin HCl combined with vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily or placebo, respectively. The incidence of gastrointestinal side effects ranged from 10-15% in the vildagliptin plus metformin HCl groups as compared to 18% in the metformin HCl plus placebo group.
The effect of vildagliptin in combination with metformin HCl was evaluated in another double-blind, placebo-controlled clinical trial of 52 weeks total duration (12-week core study plus a 40-week extension) involving 132 patients with type 2 diabetes on stable doses of metformin HCl (1500-3000 mg daily). The addition of vildagliptin (50 mg once daily) to metformin HCl resulted in an additional statistically significant reduction in mean HbA1c (-0.6%) from baseline compared to placebo plus metformin HCl (+0.1%) at the end of the 12-week study interval (mean baseline HbA1c of 7.7% and 7.9%, respectively). Of these patients, 71 continued add-on treatment with vildagliptin or placebo for an additional 40 weeks (placebo-controlled, double-blind extension). At 52 weeks, mean change from baseline in HbA1c was statistically significantly greater and sustained with vildagliptin (50 mg) plus metformin HCl versus patients continued on metformin HCl alone (between group difference of -1.1%) indicating a durable effect on glycaemic control. In contrast, glycaemic control in the metformin HCl plus placebo group deteriorated over the course of the study.
In a 24-week trial (LAF2354) vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin. Mean reductions from baseline 8.4% HbA1c were -0.9% with vildagliptin added to metformin and -1% with pioglitazone added to metformin. The decrease in HbA1c from baseline >9% was greater (-1.5%) in both treatment groups. Patients receiving pioglitazone in addition to metformin experienced an increase in weight of 1.9 kg. Patients receiving vildagliptin in addition to metformin experienced an increase in weight of 0.3 kg. In a 28-week extension, HbA1c reductions were similar between treatment groups and the body weight differences further increased.
In a long-term trial of up to >2 years (LAF2308), vildagliptin (100 mg/day) was compared to glimepiride (up to 6 mg/day) in patients treated with metformin. After 1 year, mean reductions in HbA1c were -0.4% with vildagliptin added to metformin and -0.5% with glimepiride added to metformin. Body weight change with vildagliptin was -0.2 kg versus +1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycemia differences were maintained.
In a 52-week trial (LAF237A2338), vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day) in patients inadequately controlled with metformin. After 1 year, mean reductions in HbA1c were -0.81% with vildagliptin added to metformin (mean baseline 8.4% HbA1c) and -0.85% with gliclazide added to metformin (mean baseline 8.5% HbA1c); statistical non-inferiority was achieved. Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide.
Vildagliptin: Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor that improves glycaemic control.
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-hr period. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous levels of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of Î²-cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with 50-100 mg daily in patients with type 2 diabetes significantly improved markers of Î²-cell function. The degree of improvement in Î²-cell function is dependent on the initial degree of impairment; in nondiabetic (normal glycaemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of Î±-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.
More than 15,000 patients with type 2 diabetes participated in double-blind, placebo- or active-controlled clinical trials of up to >2 years treatment duration. In these studies, vildagliptin was administered to >9000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5000 male and 4000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1900 patients receiving vildagliptin 50 mg once daily or 100 mg daily were â‰¥65 years. In these trials, vildagliptin was administered as monotherapy in drug-naive patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products.
Overall, vildagliptin improved glycaemic control when given as monotherapy or when used in combination with metformin HCl, as measured by clinically relevant reductions in HbA1c and fasting plasma glucose from baseline at study endpoint. When given as monotherapy or in combination with metformin HCl in studies of up to 52 weeks duration, these improvements in glucose homeostasis were durable.
Metformin HCl: Metformin HCl improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin HCl decreases hepatic glucose production, decrease intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin HCl does not produce hypoglycaemia in either patients with type 2 diabetes or normal subjects (except in special circumstances) and does not cause hyperinsulinaemia. With metformin HCl therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Metformin HCl 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).
In humans, independently of its action on glycaemia, metformin HCl has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin HCl reduces total cholesterol, low-density lipoprotein cholesterol (LDLc) and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin HCl after failure of diet alone showed: A significant reduction of the absolute risk of any diabetes-related complication in the metformin HCl group (29.8 events/1000 patient-years) versus diet alone (43.3 events/1000 patient-years), p=0.0023 and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p=0.0034; a significant reduction of the absolute risk of diabetes-related mortality: Metformin HCl 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p=0.017; a significant reduction of the absolute risk of overall mortality: Metformin HCl 13.5 events/1000 patient-years versus diet alone 20.6 events/1000 patient-years (p=0.011) and versus the combined sulphonylurea and insulin monotherapy groups 18.9 events/1000 patient-years (p=0.021) and a significant reduction in the absolute risk of myocardial infarction: Metformin HCl 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p=0.01).
Pharmacokinetics: Absorption: In the bioequivalence studies at 2 dose strengths (50 mg/850 mg and 50 mg/1000 mg), versus free combination of vildagliptin and metformin HCl tablets at the corresponding doses, the area under the curve (AUC) and maximum concentration (Cmax) of both the vildagliptin and the metformin HCl component of the This 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 from This combination. The Cmax and AUC of the metformin HCl component from This combination were decreased by 26% and 7%, respectively, when given with food. The absorption of metformin HCl was also delayed as reflected by the time to peak plasma concentration (Tmax) (2-4 hrs) when given with food. These changes in Cmax and AUC are consistent but lower than those observed when metformin HCl when given alone under fed conditions. The effects of food on the pharmacokinetics of both the vildagliptin component and metformin HCl component of This combination were similar to the pharmacokinetics of vildagliptin and metformin HCl 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 hrs. 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 hrs. There is no change in the extent of absorption and food does not alter the overall exposure (AUC).
Metformin HCl: The absolute bioavailability of metformin HCl 500-mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of metformin HCl tablets 500-1500 mg and 850-2550 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 HCl, as shown by approximately a 40% lower mean Cmax, a 25% lower AUC and a 35-min prolongation of Tmax following administration of a single 850-mg tablet of metformin HCl with food, compared to the same tablet strength administered fasting. The clinical relevance of these decrease is unknown.
Linearity: Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. Peak plasma concentrations for vildagliptin and the AUC increased in an approximately dose-proportional manner over the therapeutic dose range.
Distribution: Vildagliptin: The plasma protein-binding of vildagliptin is low (9.3%) and it distributes equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady state after IV administration (Vss) is 71 L, suggesting extravascular distribution.
Metformin HCl: The apparent volume of distribution (V/F) of metformin HCl following single oral doses of 850 mg averaged 654Â±358 L. Metformin HCl is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are >90% protein bound. Metformin HCl partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin HCl, steady-state plasma concentrations of metformin HCl are reached within 24-48 hrs and are generally <1 mcg/mL. During controlled clinical trials of metformin HCl, maximum metformin HCl plasma levels did not exceed 5 mcg/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 P-450 (CYP450) enzymes to any quantifiable extent. In vitro studies demonstrated that vildagliptin does not inhibit or induce CYP450 enzymes.
Excretion and 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 IV administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 L/hr and 13 L/hr, respectively. The mean elimination tÂ½ after IV administration is approximately 2 hrs. The elimination tÂ½ after oral administration is approximately 3 hrs and is independent of dose.
Metformin HCl: IV single-dose studies in normal subjects demonstrate that metformin HCl 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 hrs, with a plasma elimination tÂ½ of approximately 6.2 hrs. In blood, the elimination tÂ½ is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: 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.
Metformin HCl: Metformin HCl 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 antihyperglycaemic effect of metformin HCl was comparable in males and females.
Obesity: Vildagliptin: Body mass index 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 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 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 approximately 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5x the upper limit of normal.
Metformin HCl: No pharmacokinetic studies of metformin HCl have been conducted in subjects with hepatic insufficiency.
Renal Impairment: Vildagliptin: In subjects with mild, moderate and severe renal impairment and end-stage renal disease (ESRD) patients on haemodialysis, systemic exposure to vildagliptin was increased (Cmax 8-66%; AUC 32-134%) 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).
This combination should not be used in patients with renal failure or renal dysfunction eg, serum creatinine levels â‰¥1.5 mg/dL (>135 micromol/L) in males and â‰¥1.4 mg/dL (>110 micromol/L) in females (see Contraindications and Precautions).
Metformin HCl: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood tÂ½ of metformin HCl is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Elderly: Vildagliptin: In otherwise healthy elderly subjects (â‰¥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 (18-40 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.
Metformin HCl: Limited data from controlled pharmacokinetic studies of metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin HCl is decreased, the tÂ½ is prolonged and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin HCl pharmacokinetics with aging is primarily accounted for by a change in renal function.
This combination treatment should not be initiated in patients â‰¥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Paediatric: No pharmacokinetic data available.
Ethnic Group: Vildagliptin: There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.
Metformin HCl: No studies of metformin HCl pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin HCl in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51) and Hispanics (n=24).
Toxicology: Preclinical Safety Data: Animal studies of up to 13-week duration have been conducted with combined substances in This combination. No new toxicities associated with the combination were identified. The following data are findings from studies performed with vildagliptin or metformin individually.
Vildagliptin: A 2-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose). No increases in tumour incidence attributable to vildagliptin were observed. A 2-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). Mammary tumour incidence was increased in female mice at approximately 150 times the maximum anticipated human exposure to vildagliptin; it was not increased at approximately 60 times the maximum human exposure. The incidence of haemangiosarcoma was increased in male mice treated at 42-240 times the maximum human exposure to vildagliptin and in female mice at 150 times the maximum human exposure. No significant increases in haemangiosarcoma incidences were observed at approximately 16 times the maximum human exposure to vildagliptin in males and approximately 60 times the maximum human exposure in females.
Vildagliptin was not mutagenic in a variety of mutagenicity tests including a bacterial reverse mutation Ames assay and a human lymphocyte chromosomal aberration assay. Oral bone marrow micronucleus tests in both rats and mice did not reveal clastogenic or aneugenic potential up to 2000 mg/kg or approximately 400 times the maximum human exposure. An in vivomouse liver comet assay using the same dose was also negative.
In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses â‰¥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 and peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses â‰¥20 mg/kg/day (approximately 3 times human AUC exposure at the 100-mg dose). Necrotic lesions of the tail were observed at â‰¥80 mg/kg/day. It should be noted that vildagliptin exhibits a significantly higher pharmacological potency in monkeys compared with humans. Skin lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period. Skin lesions have not been observed in other animal species or in humans treated with vildagliptin.
Metformin HCl: Preclinical 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.
Long-term carcinogenicity studies with metformin HCl have been performed in rats (dosing duration 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin HCl was found in either male or female mice. Similarly, there was no tumourigenic potential observed with metformin HCl in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of mutagenic potential of metformin HCl in the following in vitro tests: Ames tests (S. typhimurium) and gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
|ATC Classification||A10BD08 - metformin and vildagliptin; Belongs to the class of combinations of oral blood glucose lowering drugs.|