Instructions for use Aiglimet tablets 50mg/1000mg No. 28
Composition
active ingredients: vildagliptin, metformin hydrochloride;
1 tablet 50 mg/850 mg contains 50 mg of vildagliptin and 850 mg of metformin hydrochloride;
1 tablet 50 mg/1000 mg contains 50 mg of vildagliptin and 1000 mg of metformin hydrochloride;
excipients: microcrystalline cellulose, copovidone K 25, crospovidone (type B), hydroxypropylcellulose, magnesium stearate; film coating – Opadry® Yellow 03F520096 (for 50 mg/850 mg tablets), Opadry® Yellow 03F520097 (for 50 mg/1000 mg tablets): hypromellose, titanium dioxide (E 171), iron oxide yellow (E 172), macrogol, talc.
Dosage form
Film-coated tablets.
Main physicochemical properties:
50 mg/850 mg tablets: oval-shaped tablets, smooth on both sides, with beveled edges, film-coated, yellow in color with a size of approximately 20.7 × 8.8 mm;
50 mg/1000 mg tablets: oval-shaped tablets, smooth on both sides, with beveled edges, film-coated, dark yellow in color with a size of approximately 21.3 × 10.1 mm.
Pharmacotherapeutic group
Antidiabetic drugs. Combination of oral hypoglycemic drugs. ATX code A10B D08.
Pharmacological properties
Pharmacodynamics
Aiglimet® is a combination of two antiglycemic agents with different mechanisms of action that improve glucose control in patients with type 2 diabetes: vildagliptin, a member of the dipeptidyl peptidase-4 (DPP-4) inhibitor family, and metformin hydrochloride, a member of the biguanide class.
Vildagliptin, a member of the islet-enhancing class of agents, is a potent and selective DPP-4 inhibitor. Metformin acts primarily by reducing endogenous hepatic glucose production.
Vildagliptin
Vildagliptin acts primarily by inhibiting DPP-4, an enzyme responsible for the degradation of the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide). Inhibition of DPP-4 activity by vildagliptin results in a rapid and complete increase in endogenous levels of the incretin hormones GLP-1 and GIP after meals and fasting.
By increasing endogenous levels of these incretin hormones, vildagliptin increases beta-cell sensitivity to glucose, resulting in improved glucose-dependent insulin secretion. Treatment of patients with type 2 diabetes mellitus with vildagliptin at doses of 50 to 100 mg per day significantly improved markers of beta-cell function, including HOMA-β (homeostatic model of beta-cell function assessment), proinsulin to insulin ratio, and measures of beta-cell sensitivity in a multiple meal tolerance test. In non-diabetic subjects (with normal glucose levels), vildagliptin did not stimulate insulin secretion or lower glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin increases the sensitivity of pancreatic alpha cells to glucose, resulting in increased glucose-responsive glucagon secretion. The increased insulin/glucagon ratio during hyperglycemia results in increased incretin hormone levels, which in turn leads to decreased hepatic glucose production in the fasting and postprandial periods, leading to decreased glucose levels.
The known effect of elevated GLP-1 levels with gastric acid retention is not observed with vildagliptin treatment.
Metformin hydrochloride
Metformin is an oral antidiabetic agent of the biguanide class, the hypoglycemic effect of which is based mainly on overcoming insulin resistance in the liver and muscle. In the presence of insulin, it reduces both basal and postprandial plasma glucose levels. Metformin does not stimulate insulin secretion, therefore it does not lead to hypoglycemia in monotherapy.
Metformin may cause glucose lowering through three mechanisms:
- Hepatic glucose production is largely responsible for fasting hyperglycemia. Metformin reduces hepatic glucose production, which is activated by insulin resistance, by inhibiting gluconeogenesis and glycogenolysis, thereby simultaneously counteracting the hyperglycemic effect of glucagon. By this mechanism, metformin reduces fasting hyperglycemia.
- Impaired peripheral glucose uptake and storage are mainly responsible for postprandial hyperglycemia. Metformin increases the sensitivity of cells to insulin by stimulating the activity of insulin receptor tyrosine kinase, thereby promoting glucose uptake at the cellular level. Metformin increases the permeability of all cell membrane glucose transporters (GLUT). This effect of metformin is particularly pronounced in hyperglycemia. Intracellular glycogen synthesis is increased by stimulating a key enzyme, glycogen synthase. Through this mechanism, metformin reduces postprandial hyperglycemia.
- Metformin reduces the absorption of glucose in the intestinal tract, thereby reducing the impact of glucose after eating.
In addition, metformin has been shown in some studies to increase high-density lipoprotein levels. Metformin also exhibits fibrinolytic properties.
The UKPDS (UK Prospective Diabetes Study) prospective randomized trial established the long-term benefits of intensive blood glucose control in type 2 diabetes. Analysis of the results in overweight patients treated with metformin after insufficient efficacy of diet alone showed:
- a significant reduction in the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1000 patient-years) compared with the diet alone group (43.3 events/1000 patient-years), p = 0.0023, compared with the combined groups receiving sulfonylurea and insulin as monotherapy (40.1 events/1000 patient-years), p = 0.0034;
- significant reduction in the absolute risk of diabetes-related deaths: metformin 7.5 events/1000 patient-years, diet alone 12.7 events/1000 patient-years, p = 0.017;
- significant reduction in the absolute risk of mortality: metformin 13.5 events/1000 patient-years compared to diet alone 20.6 events/1000 patient-years (p = 0.011) and compared to the combined groups receiving sulfonylurea and insulin as monotherapy, 18.9 events/1000 patient-years (p = 0.021);
- significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1000 patient-years, diet alone 18 events/1000 patient-years (p = 0.01).
Pharmacokinetics
Absorption
Vildagliptin with metformin
In a bioequivalence study of vildagliptin with metformin, tablets of different strengths (50 mg/850 mg and 50 mg/1000 mg) were compared with the combination of individual vildagliptin and metformin hydrochloride at the respective doses. Food intake did not affect the extent and extent of absorption of vildagliptin, the active substance of vildagliptin with metformin. The maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) of metformin hydrochloride when vildagliptin with metformin at a dose of 50 mg/1000 mg was taken with food were reduced by 26 and 7%, respectively, and the time to reach (Tmax) was delayed (from 2.0 to 4.0 hours).
The pharmacokinetic properties of the individual active ingredients of the drug are given below. Vildagliptin
Vildagliptin is rapidly absorbed after oral administration in the fasting state. Absolute bioavailability is 85%. Cmax is reached after approximately 1 hour. Food intake does not change the total exposure (AUC).
Metformin hydrochloride
After oral administration of metformin, Cmax is reached after approximately 2.5 hours. Absorption is expected to occur primarily in the upper gastrointestinal tract. The absolute bioavailability of metformin hydrochloride (850 mg tablets) taken in the fasted state is approximately 50 to 60% in healthy volunteers. Single oral doses of 500-2500 mg resulted in a less than proportional increase in Cmax, possibly due to a saturable mechanism. At the usual dosage and regimen of metformin, steady-state plasma concentrations are reached within 24-48 hours and are usually less than 1 μg/ml. In controlled clinical trials, Cmax did not exceed 4 μg/ml even at maximum doses.
Food intake reduces the volume and slightly delays the absorption of metformin hydrochloride, as evidenced by an approximately 40% lower mean Cmax, a 25% lower AUC, and a 35 min delay in Tmax. The clinical significance of this decrease is unknown.
Distribution
Vildagliptin
Vildagliptin is poorly bound to plasma proteins (9.3%), and is distributed equally between plasma and erythrocytes. The mean volume of distribution of vildagliptin at steady state after intravenous administration (Vss) is 71 l, indicating extravascular distribution.
Metformin hydrochloride
Metformin is poorly bound to plasma proteins. Metformin penetrates into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and are reached at approximately the same time. Erythrocytes are likely to be a secondary distribution site. The mean volume of distribution (Vd) is 63–276 liters.
Metabolism
Vildagliptin
Metabolism is the major route of elimination of vildagliptin in humans (69% of the dose). The major metabolite LAY151 is pharmacologically inactive and is a hydrolysis product of the cyano moiety (57% of the dose), followed by a hydrolysis product of the amide moiety (4% of the dose). Vildagliptin is not metabolised by cytochrome P450 enzymes.
Metformin hydrochloride
Metformin is excreted unchanged in the urine. Metabolites have not been identified in humans.
Breeding
Vildagliptin
85% of the dose is excreted in the urine, 15% in the feces. After oral administration, 23% of the dose is excreted in the urine as unchanged vildagliptin. The half-life after oral administration is approximately 3 hours.
Metformin hydrochloride
Vildagliptin
Linearity/nonlinearity
Vildagliptin Cmax and AUC increased almost dose-proportionally across the therapeutic dose range.
Sex
No differences in the pharmacokinetic parameters of vildagliptin were observed in healthy male and female volunteers.
Age
Plasma concentrations are increased in patients over 70 years of age, but these changes are not considered clinically significant.
Liver failure
Vildagliptin (100 mg) exposure was not increased after a single 100 mg dose in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, exposure was increased by 22% (68% upper limit of CI).
Kidney failure
In a pharmacokinetic study, the AUC of vildagliptin increased on average by 1.4, 1.7 and 2-fold in patients with mild (creatinine clearance [CrCl] 50 - <80 mL/min), moderate (CrCl 30 - <50 mL/min) and severe (CrCl <30 mL/min) renal impairment, respectively, compared to healthy volunteers. The AUC of the metabolite LAY151 increased by 1.6, 3.2 and 7.3-fold, and that of the metabolite BQS867 increased by 1.4, 2.7 and 7.3-fold in patients with mild, moderate and severe renal impairment, respectively. Limited data in patients with end-stage chronic renal failure (ESRD) suggest that the results in this group are similar to those in patients with severe renal impairment. LAY151 AUC in patients with CKD was 6.8-fold higher than in patients with normal renal function. Vildagliptin is removed by hemodialysis only to a limited extent (3% 4 hours after a single dose when the procedure lasts more than 3-4 hours).
Metformin effect: In patients with renal impairment, renal clearance is reduced in proportion to creatinine clearance, with a prolonged half-life and risk of accumulation.
Ethnic groups
Limited data suggest no effect of ethnicity on the pharmacokinetics of vildagliptin.
Indication
Aiglimet® is indicated for the treatment of patients with type 2 diabetes mellitus:
- adult patients in whom adequate glucose control cannot be achieved with oral metformin monotherapy at maximally tolerated doses, or in patients who are already treated with a combination of vildagliptin and metformin as separate drugs;
- in combination with a sulfonylurea (triple combination therapy) as an adjunct to diet and exercise in the treatment of patients whose condition is not adequately controlled with metformin and a sulfonylurea;
- for triple combination therapy with insulin as an adjunct to diet and exercise to improve glucose control in patients who do not achieve adequate glucose control on a stable dose of insulin and metformin as monotherapy.
Contraindication
- Hypersensitivity to vildagliptin or metformin hydrochloride, or to any other components of the drug;
- diabetic ketoacidosis or diabetic precoma;
- renal failure or impaired renal function (creatinine clearance <60 ml/min);
- acute conditions that may alter renal function, such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents;
- acute or chronic diseases that can lead to tissue hypoxia, such as heart or respiratory failure, recent myocardial infarction, shock;
- liver dysfunction;
- acute alcohol intoxication, alcoholism;
- breastfeeding period.
Interaction with other drugs and other types of interactions
Formal drug interaction studies of vildagliptin with metformin have not been conducted. Below is information on the interactions of the active substances, vildagliptin and metformin separately.
Vildagliptin
Since vildagliptin is not a substrate of cytochrome P (CYP) 450 enzymes and does not inhibit or induce CYP 450 enzymes, it is unlikely that vildagliptin will interact with substrates, inhibitors or inducers of these enzymes when co-administered.
Clinical studies have been conducted with oral antidiabetic agents in patients with type 2 diabetes or drugs with a narrow therapeutic window. These studies have not shown clinically significant pharmacokinetic interactions with oral antidiabetic agents (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin.
Metformin hydrochloride
Decreased hypoglycemic efficacy
Glucocorticoids (systemic and topical), beta-2-agonists, diuretics, phenothiazines (e.g., chlorpromazine), thyroid hormones, estrogens, oral contraceptives, hormone replacement products, phenytoin, nicotinic acid, calcium channel blockers, isoniazid, and tetracosactide may increase blood glucose levels.
Potentiation of hypoglycemic efficacy
Furosemide causes an increase in metformin plasma levels (Cmax by 22%, AUC by 15%) and does not change its renal clearance.
Cimetidine increases metformin Cmax by 60% and AUC by 40%. It does not affect the half-life of metformin. 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 to interact with metformin. Accordingly, patients receiving such medicinal products should be closely monitored during treatment with metformin.
ACE inhibitors can lower blood glucose levels.
Blood glucose levels may also be lowered by beta-blockers, although cardioselective (beta-1-selective) beta-blockers exhibit such interactions to a much lesser extent than non-cardioselective agents.
The combined use of MAO inhibitors and oral antidiabetic agents may improve glucose tolerance and increase the hypoglycemic effect.
Concomitant alcohol consumption may potentiate the hypoglycemic effect of metformin and even lead to hypoglycemic coma.
Increase or decrease in the hypoglycemic effect of metformin
H2-antagonists, clonidine and reserpine may increase or decrease the effect of metformin. Impaired blood glucose control (including hyper- or hypoglycemia) has been observed after co-administration of quinolones and metformin.
Interactions that increase the adverse effects of metformin
Diuretics
Renal impairment due to diuretics (especially loop diuretics) may lead to lactic acidosis. Diuretics may increase blood glucose levels.
Iodinated contrast agents
For information on interactions with iodinated contrast agents and the risk of lactic acidosis, see the section "Special warnings and precautions for use".
Alcohol
In acute alcohol intoxication, patients taking metformin are at increased risk of developing lactic acidosis, especially after fasting or in the presence of malnutrition or impaired liver function.
Interactions that affect the effectiveness of other substances
Metformin reduces plasma furosemide levels (Cmax by 33%, AUC by 12%) and shortens the terminal half-life by 32%, without changing the renal clearance of furosemide.
The effect of phenprocoumon may be reduced because its elimination is accelerated by metformin.
Interaction studies with glibenclamide, nifedipine, ibuprofen and propranolol did not reveal a clinically significant effect on the pharmacokinetic parameters of these substances.
Other interactions
Symptoms of hypoglycemia can be reduced with sympatholytics (e.g., beta-blockers, clonidine, guanethidine, reserpine).
Application features
General
Aiglimet® is not a substitute for insulin in insulin-dependent patients. The drug should not be used in patients with type 1 diabetes.
Lactic acidosis
Lactic acidosis is an extremely rare (3 cases per 100,000 person-years) but serious metabolic complication associated with a high fatality rate in the absence of urgent treatment. It may occur as a result of metformin accumulation. Cases of lactic acidosis in patients taking metformin have occurred mainly in diabetic patients with severe renal insufficiency. In patients with impaired liver function, lactate clearance may be limited. The incidence of lactic acidosis can and should be reduced by eliminating other concomitant risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency and any condition associated with hypoxia (see also sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
The preceding signs and symptoms are non-specific and may include muscle spasms accompanied by gastrointestinal disturbances, abdominal pain, increased respiratory rate and severe asthenia. The physician should be aware of these symptoms. The physician should also inform patients about the possible signs of lactic acidosis.
Diagnosis of lactic acidosis
Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, and may progress to coma. Diagnostic laboratory findings include decreased blood pH, plasma lactate levels above 5 mmol/L, and increased anion gap and lactate/pyruvate ratio. If lactic acidosis is suspected, treatment with this drug should be discontinued and the patient should be hospitalized immediately. The most effective method is to remove lactate and metformin by hemodialysis (see section "Overdose").
Kidney dysfunction
Since metformin is excreted mainly by the kidneys, creatinine clearance should be checked before starting and regularly during treatment:
- at least once a year in patients with normal kidney function;
- at the discretion of the physician in patients with levels at the lower end of the normal range or in elderly patients, as asymptomatic decline in renal function is often observed in elderly patients.
Particular caution should be exercised in situations where renal function may be impaired, for example at the beginning of treatment with antihypertensive or diuretic agents or when using non-steroidal anti-inflammatory drugs.
Vildagliptin should not be used to treat patients with impaired liver function, including patients with baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2.5 times the upper limit of normal (ULN).
Monitoring liver enzyme levels
Rare cases of liver dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, patients were usually asymptomatic and did not experience clinical complications, and liver function tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed to determine baseline values in patients prior to initiation of treatment with Aiglimet®. LFTs should be monitored every 3 months during treatment for the first year of treatment and periodically thereafter. Patients who develop elevated transaminases should have their liver function re-evaluated to confirm that the values have changed, and LFTs should be monitored frequently until the values have returned to normal. If AST and ALT levels exceed 3 times the upper limit of normal, Aiglimet® treatment should be discontinued. Patients who develop jaundice or other signs suggestive of liver function abnormalities should be discontinued.
After discontinuation of treatment with Aiglimet® and normalization of the FPP, re-treatment with this drug should not be initiated.
Heart failure
A clinical study of vildagliptin in patients with New York Heart Association (NYHA) functional class I–III heart failure showed that vildagliptin treatment was not associated with changes in left ventricular ejection fraction or exacerbation of pre-existing congestive heart failure compared to placebo.
There is no experience with the use of vildagliptin in clinical trials in patients with New York Heart Association (NYHA) functional classes III–IV, therefore it should not be used in these patients.
Metformin is contraindicated in patients with heart failure, therefore Aiglimet® is also contraindicated in these patients.
Skin disorders
In nonclinical toxicology studies with vildagliptin, skin lesions, including blistering and ulceration of the extremities of animals, were reported. Although no increased incidence of skin lesions was observed in clinical studies, experience with skin complications in patients with diabetes mellitus was limited. In addition, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, monitoring for skin disorders, such as blistering or ulceration, is recommended in the routine care of patients with diabetes mellitus.
Pancreatitis
During post-marketing surveillance, adverse reactions of acute pancreatitis have occurred. Patients should be informed about the characteristic symptom of acute pancreatitis - persistent, severe abdominal pain.
Pancreatitis resolved after discontinuation of vildagliptin. Vildagliptin and other potentially dangerous drugs should be discontinued if pancreatitis is suspected.
Hypoglycemia
Hypoglycemia does not usually occur in patients receiving therapy with Aiglimet®, but may occur if the caloric content of the diet is insufficient, if physical activity is not compensated by additional caloric content of the diet, or if alcohol is consumed. Elderly people, debilitated or exhausted patients, as well as those with adrenal or pituitary insufficiency or alcohol intoxication are prone to hypoglycemia. Hypoglycemia may be difficult to diagnose in elderly people and patients taking beta-blockers.
Sulfonylureas are known to cause hypoglycemia. Patients receiving Aiglimet® in combination with a sulfonylurea are at risk of hypoglycemia. To reduce the risk of hypoglycemia, it is advisable to use the lowest possible dose of the sulfonylurea.
Surgical interventions
Since Aiglimet® contains metformin, treatment with this drug should be discontinued 48 hours before elective surgery with general, spinal or epidural anesthesia and should not be resumed earlier than 48 hours afterwards (provided that renal function and oral intake are normal).
X-ray examinations
Intravascular administration of iodinated contrast media during X-ray examinations may result in acute renal failure. Therefore, due to the metformin content, Aiglimet® should be discontinued prior to or during such an examination and should not be restarted until 48 hours after the examination and only if renal function is normal.
Hypoxic conditions
Cardiovascular failure (shock), acute heart failure, acute myocardial infarction and other conditions characterized by hypoxia are associated with the occurrence of lactic acidosis, which can lead to prerenal azotemia. If such conditions occur, therapy with Aiglimet® should be discontinued immediately.
The impact of alcohol
Alcohol is known to potentiate the effects of metformin on lactate metabolism. Patients should be cautioned against excessive alcohol consumption.
Metformin, which is part of the drug, reduces the level of vitamin B12 concentration in approximately 7% of patients. The decrease may also be associated with anemia, these manifestations quickly disappear upon discontinuation of treatment. Annual determination of hematological parameters is recommended in patients receiving the drug Aiglimet®.
Changes in clinical status in patients with controlled type 2 diabetes mellitus
Usually, patients' condition is well controlled when using the drug Aiglimet®, but the risk of ketoacidosis or lactic acidosis should be taken into account and at the first deviations from the norm, the drug should be immediately discontinued and appropriate measures taken.
Loss of glucose control
In patients with stabilized glucose levels on any diabetic regimen, loss of glucose control may occur in the event of any stressful situations, such as fever, trauma, infectious diseases, surgery. In such situations, the drug should be discontinued and glycemia should be controlled with insulin, and the drug should be resumed after the patient's condition has normalized.
Use during pregnancy or breastfeeding
Pregnancy
Animal studies have shown reproductive toxicity at high doses of vildagliptin. Animal studies with metformin have not shown reproductive toxicity. Animal studies with vildagliptin and metformin have not shown teratogenicity, but have shown fetotoxic effects at doses toxic to pregnant women. The potential risk to humans is unknown. Aiglimet® should not be used during pregnancy.
Breastfeeding period
Animal studies have shown excretion of metformin and vildagliptin in milk. It is not known whether vildagliptin is excreted in human milk, but metformin is known to be excreted in human milk in small amounts. Given the potential risk of neonatal hypoglycemia associated with metformin and the lack of data on the effects of vildagliptin, Aiglimet® should not be used in women who are breastfeeding.
Fertility
Studies on the effect of Aiglimet® on human fertility have not been conducted.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted on the effect of the drug on the reaction rate when driving or operating other mechanisms. Therefore, patients who may experience dizziness should avoid activities related to driving or operating mechanisms.
Method of administration and doses
The dosage of antihyperglycemic treatment for the control of type 2 diabetes should be selected individually based on the current therapy regimen, efficacy and tolerability. When using the drug Aiglimet®, the maximum daily dose of vildagliptin (100 mg) should not be exceeded.
Method of application
For oral use.
The recommended starting dose of Aiglimet® should be determined based on the current regimen of vildagliptin and/or metformin.
Taking Aiglimet® with or immediately after food may reduce gastrointestinal upset associated with metformin.
Treatment with Aiglimet® can be started by taking 50 mg/850 mg or 50 mg/1000 mg tablets twice a day (one tablet in the morning and one tablet in the evening).
Starting dose for patients inadequately controlled on vildagliptin monotherapy.
Based on the usual starting doses of metformin hydrochloride (daily dose: 500–1000 mg), treatment with Aiglimet® can be initiated with 50 mg/850 mg tablets twice daily, gradually titrating the dose after assessing the adequacy of the treatment response.
For patients whose condition is not adequately controlled with metformin hydrochloride monotherapy at the patient's maximum tolerated dose.
The initial dose of Aiglimet® should consist of vildagliptin 50 mg twice daily (total daily dose – 100 mg) and metformin at the dose that the patient is already taking.
For patients switching from concomitant treatment with vildagliptin and metformin as separate drugs.
The initial dose of Aiglimet® should correspond to the doses of vildagliptin and metformin used previously.
Use in combination with insulin or sulfonylurea.
Based on the current metformin dose, Aiglimet® should be taken at a dose of 50 mg/850 mg or 50 mg/1000 mg 2 times a day. When used in combination with a sulfonylurea, a lower dose of the sulfonylurea should be considered to reduce the risk of hypoglycemia.
Special patient groups
Elderly patients (over 65 years of age)
Since metformin is excreted by the kidneys, and elderly patients tend to have decreased renal function, they require regular monitoring of renal function while taking Aiglimet®.
Kidney dysfunction
Aiglimet® should not be used to treat patients with creatinine clearance below 60 ml/min.
Aiglimet® should not be used to treat patients with impaired liver function, including patients whose ALT or AST levels before treatment exceed the ULN by more than 2.5 times.
Children
Aiglimet® is not recommended for use in children and adolescents (under 18 years of age). The safety and efficacy of the drug in children and adolescents have not been established. Data are lacking.
Overdose
No cases of drug overdose have been reported.
Vildagliptin
Three cases of muscle pain and isolated cases of mild and transient paresthesia, fever, edema, and transient elevations in lipase were reported with the 400 mg dose. One patient with the 600 mg dose experienced edema of the feet and hands, and a significant elevation in creatine phosphokinase (CPK) levels, accompanied by elevations in AST, C-reactive protein, and myoglobin. Three other patients in the same dose group experienced edema of both feet, accompanied in two cases by paresthesia. All symptoms and laboratory abnormalities resolved after discontinuation of the study drug.
Treatment
In case of overdose, the drug should be discontinued and the patient should be provided with symptomatic and supportive treatment. Vildagliptin is not dialyzable, but the main hydrolytic metabolite of vildagliptin can be removed by hemodialysis.
Metformin
Metformin overdose has been reported with doses exceeding 50 g. Hypoglycemia has been reported in 10% of cases. However, no causal relationship has been established. A significant overdose of metformin (or an existing risk of lactic acidosis) may lead to lactic acidosis, which requires immediate medical attention and treatment in a medical facility.
Adverse reactions
The data presented relate to the co-administration of vildagliptin and metformin as a free or fixed dose combination.
Rare cases of angioedema have been reported with vildagliptin at a similar frequency to that seen in control groups. A higher percentage of cases were reported when vildagliptin was administered in combination with an ACE inhibitor. Most cases were mild and resolved with continued use of vildagliptin. Rare cases of liver dysfunction (including hepatitis) have been reported with vildagliptin. In these cases, patients were usually asymptomatic and clinically significant, and liver function tests returned to normal after discontinuation of treatment. In controlled monotherapy and add-on therapy studies of up to 24 weeks duration, the incidence of elevations in ALT or AST ≥3 × ULN (defined as present on at least two consecutive measurements or at the final visit) was 0.2% for vildagliptin 50 mg once daily, 0.3% for vildagliptin 50 mg twice daily, and 0.2% for all comparators. These elevations in transaminases were usually asymptomatic, non-progressive in nature, and were not associated with cholestasis or jaundice.
In controlled clinical trials, hypoglycemia was uncommon in patients treated with vildagliptin in combination with metformin and in patients treated with placebo and metformin. There were no cases of severe hypoglycemia in the vildagliptin group.
Gastrointestinal adverse events, including diarrhea and nausea, have been observed during treatment with
