Vildagliptin, metformin hydrochloride.
Each 50 mg/500 mg tablet contains vildagliptin 50 mg and metformin HCl 500 mg.
Each 50 mg/850 mg tablet contains vildagliptin 50 mg and metformin HCl 850 mg.
Each 50 mg/1000 mg tablet contains vildagliptin 50 mg and metformin HCl 1000 mg.
ATC code: A10BD08.
Pharmacology: Pharmacodynamics: Mechanism of action: Galvus Met: Galvus Met combines two antihyperglycaemic agents with different mechanisms of action to improve glycaemic control in patients with type 2 diabetes: Vildagliptin is a DPP-4 (dipeptidyl-peptidase-4) inhibitor, and metformin is a member of the biguanide class.
Vildagliptin: Administration of vildagliptin inhibits DPP-4 activity, resulting 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 vildagliptin daily in patients with type 2 diabetes significantly improved markers of beta cell function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently employed meal tolerance test. In non-diabetic (normoglycaemic) 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 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.
Metformin: Mechanism of action: Metformin is an oral antidiabetic agent of the biguanide class, whose hypoglycaemic effect is based primarily on the overcoming of insulin resistance in liver and muscle. In the presence of insulin, it lowers both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion and, when used alone, does not produce hypoglycaemia.
The hypoglycaemic effect is based on three mechanisms: In the liver: Hepatic glucose production is largely responsible for hyperglycaemia in the fasting state. Metformin reduces hepatic glucose production activated by insulin resistance by inhibiting gluconeogenesis and glycogenolysis, thereby at the same time counteracting the hyperglycaemic effect of glucagon. By this mechanism, metformin reduces fasting hyperglycaemia.
In muscle: Impaired peripheral glucose uptake and storage are mainly responsible for postprandial hyperglycaemia. Metformin increases cellular sensitivity to insulin by stimulating insulin-receptor tyrosine kinase activity, thereby promoting cellular glucose uptake. Metformin increases the capacity of all cell-membrane glucose transporters (GLUTs). This effect of metformin is particularly marked in hyperglycaemic states. Intracellular glycogen synthesis is increased by stimulation of the key enzyme, glycogen synthase. By this mechanism, metformin reduces postprandial hyperglycaemia.
In the intestine: Metformin delays intestinal glucose absorption, thereby reducing postprandial glucose exposure.
Effects on lipid metabolism and fibrinolysis: Metformin also has a positive effect on human lipid metabolism, independently of its effect on blood glucose. Medium- and long-term controlled clinical studies have demonstrated that therapeutic doses of metformin reduce total cholesterol, LDL cholesterol and triglyceride levels. In addition, metformin was shown in some studies to increase HDL cholesterol levels.
Metformin also possesses fibrinolytic properties.
Clinical efficacy: Galvus Met: There have been no studies of the clinical efficacy of Galvus Met. The safety and efficacy of the separate components have already been established. Co-administration of the two components has been evaluated for safety and efficacy in two clinical studies. Both of these studies demonstrated an added benefit for vildagliptin in patients with inadequately controlled type 2 diabetes who had been treated with metformin.
In a 24-week, double-blind, placebo-controlled study in patients with type 2 diabetes whose glycaemia was inadequately controlled on metformin alone at doses ≥2000 mg, vildagliptin combined with metformin showed a statistically significantly greater reduction in HbA1c than that achieved in the group using metformin and placebo (the mean difference was -0.7% in the group using 50 mg vildagliptin once daily and -1.1% in the group using 50 mg vildagliptin twice daily).
The efficacy of vildagliptin in combination with 1000 mg metformin was evaluated in another double-blind, placebo-controlled clinical study of 52 weeks' total duration (12-week core study [n = 132] plus a 40-week extension [n = 71]). The addition of vildagliptin (50 mg once daily) to metformin resulted in an additional and statistically significant reduction in mean HbA1c from baseline (0.55%), compared with the group using metformin plus placebo (+0.1%), at the end of the first 12 weeks of the study (mean baseline HbA1c of 7.7% and 7.9%, respectively). At 52 weeks, the mean change from baseline HbA1c was statistically significantly greater and more marked in the group using vildagliptin (50 mg) plus metformin than in the group on metformin alone (between-group difference of -1.1%).
In a 24-week trial in patients whose blood glucose was inadequately controlled with metformin, 50 mg vildagliptin twice daily was compared with 30 mg pioglitazone once daily. Mean reductions from baseline HbA1c (8.4%) were 0.9% with vildagliptin added to metformin and 1.0% with pioglitazone added to metformin. For baseline HbA1c >9.0%, the decrease was greater (1.5%) in both treatment groups. Patients receiving pioglitazone in addition to metformin experienced an increase in weight of 1.9 kg. Those receiving vildagliptin in addition to metformin gained 0.3 kg in weight. In a long-term trial lasting up to two years, 50 mg vildagliptin twice daily was compared with up to 6 mg glimepiride once daily in patients treated with metformin. After two years, mean reductions in HbA1c were 0.06% with the vildagliptin/metformin combination and 0.14% with glimepiride/metformin. The change in body weight was -0.2 kg with vildagliptin and +1.2 kg with glimepiride. The incidence of hypoglycaemic episodes was significantly lower in the vildagliptin group (2.3%) than in the glimepiride group (18.2%).
In a 52-week study in patients whose blood glucose was inadequately controlled with metformin, twice-daily 50 mg doses of vildagliptin added to metformin were compared with gliclazide at a dose of up to 320 mg daily added to metformin. After 1 year, mean reductions in HbA1c were 0.81% with the combination of vildagliptin/metformin (baseline HbA1c 8.4%) and 0.85% with gliclazide/metformin (baseline HbA1c 8.5%); statistical non-inferiority was demonstrated. Patients receiving gliclazide in addition to metformin gained 1.4 kg, while those receiving vildagliptin in addition to metformin gained 0.1 kg. Five patients (1.0%) in each group had at least one hypoglycaemic episode.
A 24-week trial evaluated the efficacy of the fixed-dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1000 mg twice daily) as initial therapy in drug-naïve patients. Mean baseline HbA1c (8.6%) decreased by 1.82% on vildagliptin/metformin 50 mg/1000 mg twice daily, by 1.61% on vildagliptin/metformin 50 mg/500 mg twice daily, by 1.36% on metformin 1000 mg twice daily and by 1.09% on vildagliptin 50 mg twice daily. The decrease in HbA1c was greater in patients with a mean baseline ≥10.0%.
A 24-week randomized, double-blind, placebo-controlled trial was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 U) with or without metformin. Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo: In the overall population, the placebo-adjusted reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin the placebo-adjusted mean reduction in HbA1c was -0.63% and -0.84%, respectively. Hypoglycaemia occurred in 8.4% and 7.2% of patients treated with vildagliptin and placebo, respectively. The patients' mean weight showed little overall change (+0.2 kg on vildagliptin and -0.7 kg on placebo).
A 24-week randomized, double-blind, placebo-controlled trial was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo: the placebo-adjusted mean reduction from a mean baseline HbA1c of 8.8% was -0.76%.
Vildagliptin: Two 24-week, double-blind, placebo-controlled trials were carried out in treatment-naïve patients with type 2 diabetes. In these studies, administration of 50 mg vildagliptin once daily resulted in mean changes from baseline in HbA1c ( -0.8% and -0.5%) that were statistically significant compared with placebo.
In addition, vildagliptin monotherapy was compared to metformin, rosiglitazone or pioglitazone in several studies in treatment-naïve patients. The patients had had diabetes for an average of two years. In these studies, vildagliptin showed a clinically relevant reduction in HbA1c as compared with baseline. Non-inferiority was statistically demonstrated as compared with rosiglitazone, but not as compared with metformin and pioglitazone.
In a two-year long-term trial, 50 mg vildagliptin twice daily was compared with daily doses of up to 320 mg gliclazide. After two years, mean reductions in HbA1c were 0.5% with vildagliptin and 0.6% with gliclazide. There was less weight gain with vildagliptin (0.75 kg) and fewer hypoglycaemic episodes (0.7%) than with gliclazide (1.6 kg and 1.7%, respectively).
The studies of combinations with metformin are described above.
A 52-week multi-center, randomized, double-blind trial was conducted in patients with type 2 diabetes and congestive heart failure (NYHA class I - III) to evaluate the effect of vildagliptin 50 mg bid (N=128) compared to placebo (N=126) on left ventricular ejection function (LVEF). Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing CHF. Adjudicated cardiovascular events were overall balanced. There were slightly more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However there were imbalances in baseline CV risk favoring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8%. The incidence of hypoglycemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.
Cardiovascular risk: A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV monotherapy and combination therapy clinical studies of up to more than 2 years in duration was performed. It involved 9,599 patients with type 2 diabetes treated with vildagliptin 50 mg qd or 50 mg bid and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk. The composite endpoint of adjudicated major adverse cardio-vascular events (MACE) including acute myocardial infarction, stroke or CV death was similar for vildagliptin versus combined active and placebo comparators [Mantel-Haenszel risk ratio 0.82 (95% confidence interval 0.61-1.11)] supporting the cardiovascular safety of vildagliptin. A MACE occurred in 83 out of 9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator treated patients. Assessment of each individual MACE components showed no increased risk (similar M-H RR). Confirmed HF events defined as HF requiring hospitalization or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with M-H RR 1.08 (95% CI 0.68-1.70) showing no increased risk of HF in vildagliptin treated patients.
Metformin: The prospective, randomized UKPDS study (UK Prospective Diabetes Study) has established the long-term benefit of intensive glycaemic control in patients with type 2 diabetes. Analysis of the results for overweight patients - treated with metformin after failure of diet alone - showed: a significant reduction in the absolute risk of diabetes-related complications in the metformin group (29.8 events/1000 patient-years) vs. both diet alone (43.3 events/1000 patient-years), p = 0.0023, and the combined sulphonylurea and insulin monotherapy groups (40.1 events/1000 patient-years), p = 0.0034; a significant reduction in the absolute risk of diabetes-related mortality: 7.5 events/1000 patient-years with metformin, 12.7 events/1000 patient-years on diet alone (p = 0.017); a significant reduction in the absolute risk of overall mortality: 13.5 events/1000 patient-years with metformin vs. 20.6 events/1000 patient-years on diet alone (p = 0.011) and 18.9 events/1000 patient-years for the combined sulphonylurea and insulin monotherapy groups (p = 0.021); a significant reduction in the absolute risk of myocardial infarction: 11 events/1000 patient-years with metformin vs. 18 events/1000 patient-years on diet alone (p = 0.01).
Pharmacokinetics: Absorption: Galvus Met: In bioequivalence studies of Galvus Met at three dosage strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1000 mg) vs. free combination of vildagliptin and metformin at the corresponding doses, the bioavailability of both vildagliptin and metformin were shown to be unchanged.
Food does not affect the extent or rate of absorption of vildagliptin. The Cmax and AUC of metformin decreased by 26% and 7%, respectively, when given with food, and the absorption of metformin was delayed (Tmax: 2.0 to 4.0 hours). These changes in Cmax and AUC are consistent, but lower than those observed when metformin alone was given with food. The effects of food on the pharmacokinetics of both the vildagliptin and metformin components of Galvus Met were similar to those when vildagliptin and metformin alone were given with food.
Vildagliptin: Vildagliptin is rapidly absorbed with an oral bioavailability of 85%. Peak plasma concentrations are attained after about 1 hour. Ingestion of food has no relevant effect on absorption. Food does not alter overall exposure (AUC).
Metformin: Following oral administration, Tmax is 2.5 hours, and absorption is complete after 6 hours. Absorption is assumed to take place primarily in the upper gastrointestinal tract. The absolute bioavailability of a 500 mg or 850 mg dose is approximately 50-60% in healthy subjects. Ingestion of a single oral dose of 500-2500 mg was followed by a less than proportional increase in Cmax, possibly due to a saturable mechanism. Using standard metformin dosages, steady-state plasma levels are reached within 24-48 hours. These are generally lower than 1 µg/ml. In controlled clinical studies, Cmax was not found to exceed 4 µg/ml, even at maximum doses.
Food decreases and delays the absorption of metformin. Following ingestion of an 850 mg dose with food, a 40% lower Cmax, 25% decrease in AUC and 35-minute prolongation of Tmax were observed. The clinical relevance of these findings is thus far 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 (Vss) is 71 litres.
Metformin: Plasma protein binding of metformin is negligible. Metformin diffuses to some extent into erythrocytes. Peak blood levels are lower than the peak plasma levels and are achieved at approximately the same time. The red blood cells probably represent a secondary compartment of distribution.
The mean volume of distribution is 63-276 litres.
It is not known whether metformin crosses the placenta or is excreted in breast milk. In rats, small amounts pass into the milk.
Metabolism: Vildagliptin: Vildagliptin is largely metabolized (69% of the dose), partly by DPP-4. The major metabolite, LAY151 (57% of the dose), which is formed by hydrolysis, is inactive. There is also an amide hydrolysis product (4% of the dose). Vildagliptin is not metabolized by cytochrome P450 enzymes.
Metformin: Metformin is not metabolized in humans.
Elimination: Vildagliptin: 85% of the dose is excreted in the urine and 15% of the dose is recovered in the faeces. Unchanged vildagliptin accounts for 23% of the dose. The elimination half-life is approximately 3 hours.
Metformin: Metformin is excreted unchanged in the urine. Renal clearance is >400 ml/minute, and hence some 3.5 times greater than creatinine clearance. The drug is thus chiefly eliminated by active tubular secretion. The plasma elimination half-life after oral dosing is about 6.5 hours. When measured in whole blood, the half-life is approximately 17.6 hours.
In subjects with normal renal function, metformin does not accumulate in the body at the standard dosage (1500-2000 mg).
Pharmacokinetics in special patient populations: Sex: Vildagliptin: No differences in the pharmacokinetics of vildagliptin have been observed between men and women.
Elderly patients: Vildagliptin: Plasma concentrations are elevated in patients over 70 years of age. However, the change in exposure to vildagliptin is not clinically relevant.
Hepatic impairment: Vildagliptin: Exposure to vildagliptin (100 mg) was not elevated after a single dose of 100 mg in patients with mild and moderate hepatic impairment. In patients with severe hepatic impairment, exposure was increased by 22% (68% upper CI limit).
Renal impairment: Vildagliptin: Systemic exposure to vildagliptin was elevated in patients with mild, moderate or severe renal impairment and in ESRD patients on haemodialysis; it was elevated by 58% in patients with severe renal impairment (102% upper CI limit).
Metformin: In patients with renal impairment, renal clearance decreases in proportion to creatinine clearance, with the elimination half-life prolonged and a risk of accumulation.
Toxicology: Preclinical data: Animal studies of up to 13 weeks have been conducted with the combined active substances of Galvus Met. No new toxicities associated with the combination were identified. The following data are findings from studies performed with vildagliptin or metformin individually.
Vildagliptin: In a distribution study in rats, concentrations measured in kidney and liver tissue were 10-30 times higher than concentrations in the plasma.
At in vitro concentrations and dog in vivo plasma concentrations that markedly exceeded Cmax-based exposure levels in humans given 50 mg vildagliptin (80-260 times higher for the in vitro findings and 43 times higher for the in vivo findings), an inhibitory action on cardiac sodium channels, a decreased rate of depolarization in Purkinje fibres, slowed conduction in isolated rabbit hearts and a widening of the QRS complex in the ECG of dogs were observed.
A two-year carcinogenicity study was conducted in rats at oral doses up to 900 mg/kg (approximately 370 times human AUC exposure at 50 mg). No increases in tumour incidence attributable to vildagliptin were observed. A two-year carcinogenicity study was conducted in mice at oral doses up to 1000 mg/kg (up to 420 times human AUC exposure at the 50 mg dose). The incidence of mammary tumours was increased in female mice at a dose approximately 260 times higher than the human dose of 50 mg vildagliptin; mammary tumours were not more frequent at approximately 100 times the human exposure. The incidence of haemangiosarcoma was increased in male mice at AUC exposure levels ≥74 times the human dose of 50 mg vildagliptin, and in female mice at around 260 times the human exposure. No significant increase in the incidence of haemangiosarcoma was observed in males at approximately 27 times the human exposure to vildagliptin, and in females at approximately 100 times the human exposure.
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 at up to 2000 mg/kg, or approximately 2000 times the human dose. An in vivo mouse liver comet assay using the same dose was also negative.
In a 13-week toxicity study in cynomolgus monkeys, skin lesions were recorded at doses ≥5 mg/kg/day. These lesions were confined to the extremities (hands, feet, ears and tail).
At 5 mg/kg/day (AUC-based exposure slightly higher than human exposure at the 50 mg dose), only blisters were observed. These were reversible despite continued treatment, and were not associated with histopathological abnormalities.
Flaking skin, peeling skin, scabs and tail sores in connection with histopathological changes were noted at doses above 20 mg/kg/day (approximately 5 times human AUC exposure at the 50 mg dose).
Necrotic lesions of the tail were observed at ≥80 mg/kg/day.
Skin lesions were reversible (up to at least 80 mg/kg) if administration was stopped before necrosis occurred.
Skin lesions have not been observed in humans or in other species given vildagliptin.
Metformin: Preclinical study data have yielded no evidence of special risks for human use, based on studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity and reproductive toxicity.
Reproductive toxicity: Metformin has no effect on fertility, is not teratogenic and does not influence neonatal development.
Mutagenicity: All study results (Ames test, gene mutation test, chromosome aberration test, micronucleus test) have shown that metformin has no mutagenic or clastogenic effects.
Carcinogenicity: Metformin is not carcinogenic in rodents given doses of up to 900 mg/kg/day (rats) and 1500 mg/kg/day (mice).
Patients with type 2 diabetes mellitus (T2DM).
Galvus Met is indicated as an adjunct to diet and exercise in patients whose blood glucose is not adequately controlled on metformin hydrochloride or vildagliptin alone, or in patients already being treated with a free combination of metformin hydrochloride and vildagliptin.
Galvus Met is indicated in combination with a sulphonylurea (i.e. triple combination therapy) as an adjunct to diet and exercise in patients whose blood glucose is not adequately controlled on metformin and a sulphonylurea alone.
Galvus Met is indicated in combination with insulin to improve glycaemic control in patients whose blood glucose cannot be adequately controlled by diet, exercise and treatment with a stable dose of insulin and metformin.
Antidiabetic treatment should be individualized on the basis of effectiveness and tolerability. When using Galvus Met, do not exceed the maximum recommended daily dose of 100 mg vildagliptin.
The recommended starting dose of Galvus Met should be based on the current regimen of vildagliptin and/or metformin.
Starting dose for patients inadequately controlled on vildagliptin monotherapy:
Based on the usual starting dose of metformin (daily dose: 500-1000 mg), Galvus Met should be initiated at the 50 mg/500 mg or 50 mg/850 mg tablet strength twice daily, with the dose of metformin being gradually titrated based on an assessment of the therapeutic response.
Starting dose for patients inadequately controlled on metformin monotherapy:
Based on the current dose of metformin, Galvus Met should be initiated at the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily.
Starting dose for patients switching to Galvus Met from the free combination of metformin and vildagliptin:
Based on the current dose of metformin or vildagliptin, Galvus Met should be initiated at the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength.
Use in combination with insulin or sulphonylurea:
Based on the current dose of metformin, Galvus Met should be taken at the 50 mg/500 mg, 50 mg/850 mg or 50 mg/1000 mg tablet strength twice daily.
When used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia.
Patients with renal impairment:
A GFR should be assessed before initiation of treatment with metformin-containing products (such as Galvus Met) and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3 to 6 months.
The maximum daily dose of metformin should preferably be divided into 2 to 3 daily doses. Factors that may increase the risk of lactic acidosis (see Precautions) should be reviewed before considering initiation of metformin-containing products (such as Galvus Met) in patients with GFR<60 ml/min. Galvus Met is contraindicated in patients with GFR <30 ml/min because of its metformin component (see Contraindications).
The following dosing recommendations apply to metformin and vildagliptin, used separately or in combination, in patients with renal impairment. If no adequate strength of Galvus Met is available, individual components should be used instead of the fixed dose combination. (See table.)
Click on icon to see table/diagram/image
Patients with hepatic impairment:
Galvus Met is not recommended for use in patients with hepatic dysfunction, including patients with pre-treatment AST or ALT >2.5 × ULN (see Precautions).
Metformin is excreted via the kidneys, and elderly patients have a tendency to decreased renal function. Therefore, elderly patients taking metformin-containing products (such as Galvus Met) should have their renal function monitored regularly. Galvus Met should only be used in elderly patients with normal renal function (see Contraindications and Precautions).
Children and adolescents:
The safety and efficacy of Galvus Met have not been established in patients under 18 years of age. Galvus Met is therefore not recommended for use in paediatric patients.
Method of administration:
Galvus Met should be given with meals to reduce the gastrointestinal side effects associated with metformin hydrochloride.
If a dose of Galvus Met is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
Signs and symptoms: Vildagliptin: Oedema and muscle pain were dose-limited in clinical studies. At 600 mg, one subject experienced oedema of the hands and feet, and an excessive increase in creatine phosphokinase (CPK) levels, accompanied by elevated levels of aspartate aminotransferase (AST), C-reactive protein and myoglobin. Three additional subjects in this dosage group presented with oedema of both feet, accompanied by paraesthesia in two cases. All symptoms and laboratory abnormalities resolved after study-drug discontinuation.
In case of overdosage, the medicinal product should be withdrawn and the patient should be given symptomatic and supportive treatment.
Vildagliptin is not dialysable; the major hydrolysis metabolite can be removed by haemodialysis.
Metformin: Hypoglycaemia has not been seen even after extremely high metformin doses (up to 85 g), but lactic acidosis has occurred under such circumstances. Lactic acidosis is a medical emergency necessitating hospitalization (see Precautions). Both lactate and metformin are removed by haemodialysis.
Hypersensitivity to the active substances or any of the excipients.
Acute or chronic metabolic acidosis, including lactic acidosis or diabetic ketoacidosis, with or without coma.
Severe renal impairment (GFR with creatinine clearance <30 ml/min) (See Dosage & Administration and Precautions).
Acute conditions with the potential to alter renal function, such as: Dehydration; Severe infection; Shock; Intravascular administration of iodinated contrast agents (see Precautions).
Acute or chronic disease which may cause tissue hypoxia, such as: Heart failure; Respiratory failure; Recent myocardial infarction; Shock.
Hepatic impairment (see Dosage & Administration, Precautions and Adverse Reactions).
Acute alcohol intoxication, alcoholism.
Lactation (see Use in Pregnancy & Lactation).
Galvus Met: General considerations: Galvus Met is not a substitute for insulin in patients requiring insulin. Galvus Met should not be used in patients with type 1 diabetes or in patients with ketoacidosis.
Hypoglycaemia: Patients receiving Galvus Met in combination with a sulphonylurea or insulin may be at increased risk of hypoglycaemia. A lower dose of sulphonylurea or insulin should therefore be considered in order to reduce the risk of hypoglycaemia.
Vildagliptin: Hepatic impairment: Vildagliptin is not recommended in patients with hepatic dysfunction, including patients with pre-treatment AST or ALT >2.5 × ULN.
Galvus Met is therefore not recommended in patients with hepatic impairment.
Liver enzyme monitoring: Cases of hepatic dysfunction (including rare cases of hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae, and liver function test (LFT) results returned to normal after discontinuation of treatment. LFTs should be performed prior to the initiation of treatment with Galvus Met to determine the patient's baseline values. Hepatic function should be monitored during Galvus Met treatment at three-month intervals during the first year and periodically thereafter. In patients who develop increased transaminase levels, this test should be repeated. If the results are confirmed, the patient should be monitored at frequent intervals until test results return to normal. Withdrawal of Galvus Met is recommended in patients with elevated AST or ALT levels ≥3 x ULN.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue treatment with Galvus Met.
Following withdrawal of treatment with Galvus Met and normalization of LFT results, treatment with Galvus Met should not be reinitiated.
Pancreatitis: In post-marketing experience there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should therefore be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain.
Resolution of pancreatitis has been observed after discontinuation of vildagliptin. If pancreatitis is suspected, vildagliptin and other potentially suspect medicinal products should be discontinued.
Heart failure: A clinical trial of vildagliptin in patients with New York Heart Association (NYHA) functional class I-III showed that treatment with vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients with NYHA functional class III treated with vildagliptin is still limited and results are inconclusive.There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.
Skin disorders: Skin lesions on the extremities of monkeys, such as blistering and ulceration, have been reported in non-clinical toxicology studies in association with the use of vildagliptin (see Pharmacology: Toxicology: Preclinical data under Actions). Although no increased incidence of skin lesions was observed in clinical trials, there is only limited experience in patients with diabetic skin complications. Therefore, in keeping with routine care of diabetic patients, monitoring for skin disorders, such as blistering or ulceration, is recommended.
Metformin: Heart failure: Metformin is contraindicated in patients with heart failure, therefore Galvus Met is contraindicated in this patient population (see Contraindications).
Lactic acidosis: Lactic acidosis is a very rare (3 cases per 100 000 patient-years), but serious, metabolic complication associated that most often occurs with acute worsening of renal function, or cardiorespiratory illness or sepsis. Metformin accumulation occurs with acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (e.g. due to severe diarrhea or vomiting, fever or reduced fluid intake), the patient should stop taking metformin-containing products (such as Galvus Met) and seek immediate medical attention.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in patients treated with metformin-containing products (such as Galvus Met). Other risk factors for lactic acidosis are excessive alcohol intake, hepatic impairment, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see Contraindications and Interactions).
Cases of lactic acidosis reported thus far in association with metformin have been in patients with marked renal impairment. The incidence of lactic acidosis can and should be reduced by regular monitoring even of risk factors not associated with metformin, such as poorly controlled diabetes, ketoacidosis, prolonged fasting, excessive alcohol consumption, hepatic impairment and any hypoxic conditions.
Prior signs and symptoms are non-specific and may present as muscle cramps accompanied by gastrointestinal disorders, abdominal pain, elevated respiratory rate and pronounced asthenia. The attending physician should take note of these symptoms. The physician should also inform patients of the risk of lactic acidosis.
Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. Signs and symptoms can be recognized by the following laboratory parameters: decreased blood pH (< 7.35), increased plasma lactate levels >5 mmol/litre, an increased anion gap and an elevated lactate/pyruvate ratio.
If lactic acidosis is suspected, treatment with metformin-containing products (such as Galvus Met) should be discontinued and the patient should be hospitalized immediately. It is most effective to eliminate both lactate and metformin by haemodialysis (see Overdosage).
Renal function (see Contraindications): GFR should be assessed before treatment initiation and regularly thereafter (see Dosage & Administration). Metformin-containing products (such as Galvus Met) are contraindicated in patients with GFR < 30 ml/min and should be temporarily discontinued in the presence of conditions that alter renal function (see Contraindications).
Metformin is excreted via the kidneys, and creatinine clearance should therefore be monitored before initiating treatment, and regularly thereafter: once a year in patients with normal renal function; according to the physician's judgment in patients with levels at the lower limit of the normal range, or in elderly patients because asymptomatic reductions in renal function often occur in elderly patients in particular.
Iodinated contrast media: Intravascular administration of iodinated contrast media for radiological tests (i.v. urography, angiography, etc.) may lead to contrast-induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin-containing products (such as Galvus Met) should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see Dosage & Administration and Interactions).
Surgical procedures: Metformin-containing products (such as Galvus Met) must be discontinued at the time of surgery under general, spinal and epidural anaesthesia (except minor procedures not associated with restricted intake of food and fluids) and may be restarted no earlier than 48 hours following surgery until the patients's oral nutrition has resumed and renal function has been re-evaluated and found to be stable.
Alcohol intake: Alcohol potentiates the effect of metformin on lactate metabolism. Patients should therefore be warned against excessive alcohol intake while receiving metformin-containing products (such as Galvus Met).
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Vitamin B12 levels: Metformin has been associated with a decrease in serum vitamin B12 levels, without clinical manifestations, in approximately 7% of patients. Such a decrease is very rarely associated with anaemia and appears to be rapidly reversible by discontinuation of metformin and/or by vitamin B12 supplementation. Measurement of haematological parameters on at least an annual basis is advised for patients receiving metformin-containing products (such as Galvus Met). Any disturbance that occurs should be appropriately investigated and managed.
Change in the clinical status of patients with previously controlled type 2 diabetes: Patients with type 2 diabetes previously well controlled on Galvus Met who develop laboratory abnormalities or clinical illness (especially vague or poorly defined illness) should promptly be evaluated for ketoacidosis and/or lactic acidosis. If acidosis occurs, Galvus Met must be stopped immediately and appropriate measures initiated.
Hypoglycaemia: Hypoglycaemia does not usually occur in patients receiving Galvus Met alone, but it may occur if caloric intake is deficient, if strenuous exercise is not compensated by caloric supplementation or if alcohol is consumed. 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 patients taking beta-blockers.
Sulphonylureas are known to cause hypoglycaemia. Patients taking Galvus Met in combination with a sulphonylurea may be at risk of hypoglycaemia. Therefore, a lower dose of the sulphonylurea may be considered to reduce the risk of hypoglycaemia when used in combination with Galvus Met.
Loss of control of blood glucose: When a patient on antidiabetic therapy is exposed to stress such as fever, trauma, infection, surgery, etc., a temporary loss of glycaemic control may occur. In such situations, it may be necessary to withhold Galvus Met and temporarily administer insulin. Galvus Met may be reinstituted after the acute episode resolves.
Effects on ability to drive and use machines: There have been no studies of the effects of this product on the ability to drive or use machines. Patients who experience dizziness should thus avoid driving vehicles or using machines.
Pregnancy: There are no adequate data on the use of Galvus Met in pregnant women. Animal studies have shown evidence of reproductive toxicity with high doses of vildagliptin, but no evidence of reproductive toxicity with metformin. In animal studies, there was no evidence of teratogenicity with vildagliptin and metformin, but fetotoxic effects were seen at maternally toxic doses (see Pharmacology: Toxicology: Preclinical data under Actions). The potential risk for humans is not known. Galvus Met should not be used during pregnancy.
Lactation: Animal studies have shown that both vildagliptin and metformin are excreted in the milk. It is not known whether vildagliptin passes into human milk, but small amounts of metformin are excreted in human milk. Due to the potential risk of hypoglycaemia in the neonate in connection with metformin, and due to the lack of data in humans as regards vildagliptin, Galvus Met should not be used by women who are breastfeeding (see Contraindications).
The data presented here relate to co-administration of vildagliptin and metformin as a free or fixed-dose combination.
Rare cases of angioedema have been reported with vildagliptin at a rate similar to that in the control group. A greater number of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.
Rare cases of hepatic dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, the patients were generally asymptomatic, without clinical sequelae, and hepatic function returned to normal after discontinuation of treatment. In controlled monotherapy and add-on therapy studies of up to 24 weeks' duration, the incidence of ALT or AST elevations ≥3 x ULN (detected at no fewer than two consecutive measurements or at the final on-treatment visit) was 0.2% for 50 mg vildagliptin once daily, 0.3% for 50 mg vildagliptin twice daily and 0.2% for all comparators. These increases in transaminases were generally asymptomatic, not progressive and not associated with cholestasis or jaundice.
In controlled studies, hypoglycaemia was uncommon in patients receiving vildagliptin in combination with metformin and in patients receiving placebo and metformin. No severe cases of hypoglycaemia occurred in the vildagliptin group.
Gastrointestinal adverse effects, including diarrhoea and nausea, occur very commonly during the introduction of metformin.
Overall, gastrointestinal symptoms were reported in 12.9% of patients treated with the combination of vildagliptin and metformin, compared with 18.1% of patients treated with metformin alone.
In comparative controlled monotherapy studies, hypoglycaemia was uncommon.
Adverse effects reported in patients who received vildagliptin in double-blind studies as monotherapy and add-on therapy are listed below by system organ class and absolute frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to <1/1000), very rare (<1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse effects are ranked in order of decreasing seriousness.
Infections and infestations:
Very rare: Upper respiratory tract infections, nasopharyngitis.
Not known: Pancreatitis.
Nervous system disorders:
Common: Dizziness, tremor.
Uncommon: Peripheral oedema.
Uncommon: Diarrhoea, constipation.
Rare: Elevated transaminase levels.
Uncommon: Hypoglycaemia, weight gain.
None of the adverse effects reported with vildagliptin monotherapy were observed at clinically significantly higher rates when vildagliptin was administered concomitantly with metformin.
The following additional adverse drug reaction has been reported during the post-marketing period: Rare cases of hepatitis that resolved following discontinuation of Galvus Met (see Precautions).
Frequency not known: Urticaria, pancreatitis, bullous and exfoliative skin lesions (including bullous pemphigoid), localized exfoliation and blistering of the skin.
The known adverse effects of metformin are summarized as follows.
Blood and lymphatic system disorders:
Isolated cases of leukopenia, thrombocytopenia and haemolytic anaemia.
Very rare: Reduced vitamin B12
Metabolism and nutrition disorders:
Very rare: Lactic acidosis (incidence: 3 cases per 100 000 patient-years; see Precautions).
Nervous system disorders:
Common: Metallic taste (3%).
Common to very common: Gastrointestinal disorders (5-15%) such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite.
These symptoms usually occur at the start of treatment and resolve spontaneously in most cases.
Isolated cases: Abnormal results in hepatic function tests, e.g. elevated transaminases or hepatitis (reversible after discontinuing metformin).
Skin and subcutaneous tissue disorders:
Very rare: Skin reactions such as erythema, pruritus, urticaria.
Combination of vildagliptin with insulin (with/without metformin):
The incidence of hypoglycaemia in the controlled clinical studies conducted was similar in both treatment groups (14.0% of patients on vildagliptin vs. 16.4% of patients on placebo). Severe hypoglycaemia occurred in n = 2 patients on vildagliptin vs. n = 6 on placebo. The overall effect on mean weight was small in both treatment groups (+0.6 kg on vildagliptin vs. ±0 kg on placebo).
The following adverse effects occurred with vildagliptin in these studies: Metabolism and nutrition disorders:
Common: Decreased blood glucose.
Nervous system disorders:
Common: Headache, chills.
Common: Nausea, gastro-oesophageal reflux disease.
Uncommon: Diarrhoea, flatulence.
Discontinuations due to these adverse effects were rare overall.
Combination with a sulphonylurea:
Hypoglycaemia was common in both treatment groups (5.1% for vildagliptin + metformin + glimepiride vs. 1.9 % for placebo + metformin + glimepiride). One severe hypoglycaemic event was reported in the vildagliptin group. At the end of the study, the effect on mean body weight was small (+0.6 kg in the vildagliptin group and 0.1 kg in the placebo group).
Adverse effects in patients who received Galvus 50 mg twice daily in combination with metformin and a sulphonylurea (n = 157): Metabolism and nutrition disorders:
Nervous system disorders:
Common: Dizziness, tremor.
Galvus Met: There have been no formal interaction studies for Galvus Met. The following statements reflect the information available on the individual active substances.
Vildagliptin: Since vildagliptin neither inhibits nor induces CYP450 enzymes, it is not likely to interact with co-medications that are metabolized by CYP450 or that act as inhibitors or inducers of these enzymes.
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 were observed with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin.
Metformin: Interactions which influence metformin efficacy: Reduction in hypoglycaemic efficacy: Glucocorticoids (systemic and local), beta-2-agonists, diuretics, phenothiazines (e.g. chlorpromazine), thyroid hormones, oestrogens, oral contraceptives, hormone replacement products, phenytoin, nicotinic acid, calcium channel blockers, isoniazid and tetracosactide may increase blood glucose levels.
Potentiation of hypoglycaemic efficacy: Furosemide increases plasma levels of metformin (Cmax by 22%, AUC by 15%) with no significant change in renal clearance.
Nifedipine increases plasma levels of metformin (Cmax by 20%, AUC by 9-20%) by increasing metformin absorption.
Cimetidine increases metformin Cmax by 60% and AUC by 40%. The elimination half-life of metformin is unaffected. Other active substances (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by active renal tubular secretion have the potential for interaction with metformin. Patients receiving such medicinal products should therefore be closely monitored during treatment with metformin.
ACE inhibitors may lower blood glucose.
Blood glucose may also be lowered by beta-blockers, although cardioselective (beta-1-selective) beta-blockers exhibit such interactions to a much smaller extent than do non-cardioselective agents.
Co-administration of MAO inhibitors and oral antidiabetics may improve glucose tolerance and increase the hypoglycaemic effect.
Concomitant alcohol use may potentiate the hypoglycaemic effect of metformin, and may even cause hypoglycaemic coma.
Increased or reduced hypoglycaemic effect of metformin: H2-antagonists, clonidine and reserpine may increase or reduce the effect of metformin.
Disturbances of blood glucose control (including hyper- or hypoglycaemia) have been observed following co-administration of quinolones and metformin.
Interactions that increase the adverse effects of metformin: Diuretics: Renal dysfunction due to diuretics (especially loop diuretics) may result in lactic acidosis. Diuretics also cause blood glucose levels to rise.
Iodinated contrast media: See Precautions for information on interactions with iodinated radiocontrast agents and the risk of resultant lactic acidosis. Metformin-containing products (such as Galvus Met) must therefore be discontinued prior to, or at the time of, the test and must not be reinstituted until at least 48 hours afterwards, and only after renal function has been checked and found to be normal.
Alcohol: Acute alcohol intoxication in patients taking metformin poses an increased risk of lactic acidosis, particularly after fasting or in the presence of malnutrition or hepatic impairment.
Other - Some drugs can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs [including selective cyclo-oxygenase (COX) II inhibitors], ACE inhibitors, angiotensin II receptor antagonists and diuretics. When starting or using such products in combination with metformin-containing products (such as Galvus Met), close monitoring of renal function is necessary.
Interactions that influence the efficacy of other substances: Metformin lowers plasma levels of furosemide (Cmax by 33%, AUC by 12%), and shortens the terminal half-life by 32%, without altering renal clearance of furosemide.
The effect of phenprocoumon may be reduced since its elimination is accelerated by metformin.
Interaction studies with glibenclamide, nifedipine, ibuprofen and propranolol have shown no clinically relevant effects on the pharmacokinetic parameters of these substances.
Other interactions: The warning signs of hypoglycaemia may be rendered less perceptible by the effects of sympatholytics (e.g. beta-blockers, clonidine, guanethidine, reserpine).
Do not store above 30°C. Protect from moisture.
Keep out of the reach of children.
A10BD08 - metformin and vildagliptin ; Belongs to the class of combinations of oral blood glucose lowering drugs. Used in the treatment of diabetes.
FC tab 50 mg/500 mg (light yellow, ovaloid, bevelled-edged, imprinted with "NVR" on one side and "LLO" on the other) x 60's. 50 mg/850 mg (yellow, ovaloid, bevelled-edged, imprinted with "NVR" on one side and "SEH" on the other side) x 60's. 50 mg/1000 mg (dark yellow, bevelled-edged, imprinted with "NVR" on one side and "FLO" on the other side) x 60's.