Vipdomet 850.12, 5 mg+850 mg 56 pcs.

Pharmacotherapeutic group

Hypoglycemic agent for oral administration combined (dipeptidyl peptidase-4 inhibitor + biguanide).

The ATX code: A10BD13

Pharmacological Action

Pharmacodynamics

The drug Vipdomet® 850 is a combination of two hypoglycemic agents with complementary and different mechanisms of action designed to improve glycemic control in patients with type 2 diabetes mellitus (DM2): alogliptin, an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, and metformin, a member of the biguanide class.

Alogliptin

Alogliptin is a potent and highly selective DPP-4 inhibitor. Its selectivity for DPP-4 is more than 10,000 times greater than its action against other related enzymes, including DPP-8 and DHII1-9. DPP-4 is the major enzyme involved in the rapid degradation of the hormones of the incretin family: glucagon-like peptide-1 (GFP-1) and glucose-dependent insulinotropic polypeptide (GIP). Hormones of the hormone family are secreted in the intestine and their concentrations increase in response to food intake. GFP-1 and GIP increase insulin synthesis and secretion by pancreatic beta cells. GFP-1 also inhibits glucagon secretion and decreases glucose production by the liver. Therefore, by increasing the concentration of incretins, alogliptin increases glucose-dependent insulin secretion and decreases glucagon secretion at elevated blood glucose concentrations. In hyperglycemic DM2 patients, these changes in insulin and glucagon secretion result in decreased glycated hemoglobin (HbAlc) concentration and decreased plasma glucose concentration both on an empty stomach and postprandial basis.

Metformin

Metformin is a biguanide with hypoglycemic action that reduces both basal and postprandial plasma glucose concentrations. It does not stimulate insulin secretion and therefore does not cause hypoglycemia.

It increases the sensitivity of peripheral receptors to insulin and glucose utilization by cells. Reduces glucose production by the liver by inhibiting gluconeogenesis and glycogenolysis. Delays absorption of glucose in the intestine.

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

Metformin has beneficial effects on lipid metabolism: it reduces the concentration of total cholesterol, low-density lipoproteins and triglycerides.

Pharmacokinetics

Alogliptin

The pharmacokinetics of alogliptin are similar in healthy volunteers and in patients with type 2 diabetes.

Intake

The absolute bioavailability of alogliptin is approximately 100%.

In healthy volunteers after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug was observed with time to reach maximum plasma concentration (TSmax) of alogliptin between 1 and 2 h after administration.

No clinically significant cumulation of alogliptin was observed in either healthy volunteers or patients with diabetes mellitus 2 tin after repeated administration.

The area under the concentration-time curve (AUC) of alogliptin increases proportionally with single administration over a therapeutic dose range of 6.25 mg to 100 mg. The coefficient of interindividual variability of AUC of alogliptin in patients is small (17%).

The AUC (0-inf) of alogliptin after a single dose was similar to the AUC (0-24) after the same dose once daily for 6 days. This indicates that there is no time dependence in the kinetics of alogliptin after multiple doses.

Distribution

After a single intravenous dose of 12.5 mg of alogliptin in healthy volunteers, the terminal phase distribution was 417 L, indicating that alogliptin is well distributed in tissues.

The binding to plasma proteins is approximately 20-30%.

Metabolism

Alogliptin is not extensively metabolized; 60 to 70% of alogliptin is excreted unchanged by the kidneys.

After administration of 14C-labeled alogliptin orally, two major metabolites have been identified: N-demethylated alogliptin. M-1 (<1% of the starting substance), and N-acetylated alogliptin, M-11 (<6% of the starting substance). M-1 is an active metabolite and highly selective DPP-4 inhibitor similar in action to alogliptin; M-II shows no inhibitory activity against DPP-4 or other DPP enzymes.

In in vitro studies, CYP2D6 and CYP3A4 were found to be involved in limited metabolism of alogliptin.

Also in vitro studies show that alogliptin does not induce CYP1A2, CYP2B6, CYP2C9 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations achieved at the recommended 25 mg dose of alogliptin. Under in vitro conditions, alogliptin may induce CYP3A4 to a small extent, but under in vivo conditions alogliptin does not induce CYP3A4.

In vitro studies show that alogliptin does not inhibit renal transporters of human organic anions of type 1 (OAT1) and type 3 (OAT3) as well as renal transporters of human organic cations of type 2 (OAT2).

Alogliptin exists predominantly as an (R)-enantiomer (>99%). Under in vivo conditions it either undergoes little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is taken at therapeutic doses.

Elimation

After oral administration of 14C-labeled alogliptin, 76% of total radioactivity was excreted by the kidneys and 13% by the intestine.

The mean renal clearance of alogliptin (170 mL/min) was greater than the mean glomerular filtration rate (approximately 120 mL/min), suggesting that alogliptin was partially excreted by active renal excretion. The average terminal half-life of alogliptin (T1/2) is approximately 21 h.

Pharmacokinetics in selected patient groups

Patients with renal impairment

A study of alogliptin at a dose of 50 mg daily was conducted in patients with varying degrees of severity of chronic renal failure. Patients included into the study were divided into 4 groups according to Cockcroft-Gault formula: patients with mild renal failure (creatinine clearance from 50 to 80 ml/min), moderate renal failure (creatinine clearance from 30 to 50 ml/min) and severe renal failure (creatinine clearance less than 30 ml/min) as well as those in the terminal stage of chronic renal failure who needed hemodialysis.

The AUC of alogliptin was increased approximately 1.7-fold in patients with mild renal failure compared to controls. However, this increase in AUC was within the tolerance range for the control group, therefore no dose adjustment is required in these patients (see section “Dosage and administration”).

A roughly twofold increase in AUC of alogliptin compared to the control group was noted in patients with moderate renal failure, approximately fourfold increase in AUC was noted in patients with severe renal failure, as well as in patients with terminal stage of chronic renal failure compared to the control group. Patients with terminal renal failure underwent hemodialysis immediately after alogliptin administration. About 7% of the dose was removed from the body during the three-hour dialysis session.

Other patient groups

Age (65-81 years), sex, race, and body weight had no clinically significant effect on the pharmacokinetic parameters of alogliptin. No dose adjustment of alogliptin is required (see section “Dosage and administration”).

Pharmacokinetics in children and adolescents under 18 years of age have not been studied (see section “Dosage and administration”).

Metformin

Intake

The TSmax after oral administration of metformin is about 2.5 h. Absolute bioavailability of metformin is 50 to 60% in healthy volunteers. After oral administration 20-30% of the unabsorbed fraction of metformin is excreted through the intestine.

The absorption of metformin is saturable and incomplete. The pharmacokinetics of metformin absorption is not thought to be linear.

When metformin is used at the recommended dose and regimen, equilibrium plasma concentrations (usually <1 µg/mL) are reached within approximately 24-48 hours. According to controlled clinical trials, maximum plasma concentrations of the drug did not exceed the value of 4 µg/ml, even after maximum doses of the drug.

Distribution

Binding to plasma proteins is insignificant. Metformin is distributed in erythrocytes. The mean value of the maximum concentration (Cmax) in blood is lower than Cmax in plasma, and is reached after approximately the same time. The mean volume of distribution (Vd) ranges from 63-276 L.

Metabolism

Metabolites have not been detected in humans.

Excretion

Metformin is excreted unchanged by the kidneys. Renal clearance of metformin is >400 ml/min, indicating that metformin is excreted by glomerular filtration and tubular secretion. After oral administration, the T1/2 is about 6.5 h.

In impaired renal function, metformin clearance decreases in proportion to creatinine clearance and the T1/2 is increased, which may lead to increased plasma concentrations of metformin.

Indications

Type 2 diabetes mellitus in adults aged 18 years and older to improve glycemic control in addition to diet and exercise:

Monotherapy

In patients who have not achieved adequate glycemic control on metformin monotherapy, or as a replacement in those who are already receiving combination treatment with metformin and alogliptin as single agents.

Combination therapy

In combination with pioglitazone (triple combination: metformin + alogliptin + pioglitazone), when therapy with metformin and pioglitazone does not lead to adequate glycemic control. In combination with insulin (triple combination: metformin + alogliptin + insulin), when therapy with insulin and metformin does not lead to adequate glycemic control.

Pharmacological effect

Pharmacotherapeutic group

Combined hypoglycemic agent for oral use (dipeptidyl peptidase-4 inhibitor + biguanide).

ATX code: A10BD13

Pharmacological action

Pharmacodynamics

Vipdomet® 850 is a combination of two hypoglycemic agents with complementary and different mechanisms of action, designed to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): alogliptin, an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), and metformin, a member of the biguanide class.

Alogliptin

Alogliptin is a potent and highly selective DPP-4 inhibitor. Its selectivity for DPP-4 is more than 10,000 times greater than its selectivity for other related enzymes, including DPP-8 and DGII1-9. DPP-4 is the main enzyme involved in the rapid destruction of the incretin family hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Hormones of the incretin family are secreted in the intestine, their concentration increases in response to food intake. GLP-1 and GIP increase insulin synthesis and secretion by pancreatic beta cells. GLP-1 also inhibits glucagon secretion and reduces hepatic glucose production. Therefore, by increasing the concentration of incretins, alogliptin increases glucose-dependent insulin secretion and reduces glucagon secretion at elevated blood glucose concentrations. In T2DM patients with hyperglycemia, these changes in insulin and glucagon secretion result in decreased glycated hemoglobin (HbAlc) concentrations and decreased plasma glucose concentrations both fasting and postprandially.

Metformin

Metformin is a biguanide with a hypoglycemic effect, reducing both basal and postprandial plasma glucose concentrations. Does not stimulate insulin secretion and therefore does not cause hypoglycemia.

Increases the sensitivity of peripheral receptors to insulin and the utilization of glucose by cells. Reduces liver glucose production by inhibiting gluconeogenesis and glycogenolysis. Delays the absorption of glucose in the intestines.

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

Metformin has a beneficial effect on lipid metabolism: it reduces the concentration of total cholesterol, low-density lipoproteins and triglycerides.

Pharmacokinetics

Alogliptin

The pharmacokinetics of alogliptin are similar in healthy volunteers and in patients with type 2 diabetes mellitus.

Suction

The absolute bioavailability of alogliptin is approximately 100%.

In healthy volunteers, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug was observed with the time to reach the maximum plasma concentration (TCmax) of alogliptin ranging from 1 to 2 hours from the moment of administration.

Neither healthy volunteers nor patients with type 2 diabetes mellitus experienced clinically significant accumulation of alogliptin after repeated dosing.

The area under the concentration-time curve (AUC) of alogliptin increases proportionally with a single dose over the therapeutic dose range of 6.25 mg to 100 mg. The coefficient of interindividual variability of alogliptin AUC in patients is small (17%).

The AUC (0-inf) of alogliptin after a single dose was similar to the AUC (0-24) after taking the same dose once daily for 6 days. This indicates that there is no time dependence in the kinetics of alogliptin after repeated dosing.

Distribution

After a single intravenous dose of 12.5 mg of alogliptin in healthy volunteers, the volume of distribution in the terminal phase was 417 L, indicating that alogliptin is well distributed in tissues.

Plasma protein binding is approximately 20-30%.

Metabolism

Alogliptin is not subject to extensive metabolism; 60 to 70% of alogliptin is excreted unchanged by the kidneys.

Following oral administration of 14C-labeled alogliptin, two major metabolites were identified: N-demethylated alogliptin. M-1 (<1% of the original substance), and N-acetylated alogliptin, M-11 (<6% of the original substance). M-1 is an active metabolite and highly selective DPP-4 inhibitor, similar in action to alogliptin; M-II does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.

In vitro studies have shown that CYP2D6 and CYP3A4 are involved in the limited metabolism of alogliptin.

Also, in vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6, CYP2C9 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations achieved at the recommended 25 mg dose of alogliptin. In vitro, alogliptin may induce CYP3A4 to a small extent, but in vivo, alogliptin does not induce CYP3A4.

In vitro studies show that alogliptin does not inhibit human renal organic anion transporters types 1 (OAT1) and 3 (OAT3), as well as human renal organic cation transporters type 2 (OCT2).

Alogliptin exists predominantly as the (R)-enantiomer (>99%). Under in vivo conditions, it undergoes either little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is taken in therapeutic doses.

Removal

After oral administration of 14C-labeled alogliptin, 76% of the total radioactivity was excreted by the kidneys and 13% through the intestines.

The mean renal clearance of alogliptin (170 ml/min) was greater than the mean glomerular filtration rate (about 120 ml/min), suggesting that alogliptin is partially eliminated by active renal excretion. The average terminal half-life of alogliptin (T1/2) is approximately 21 hours.

Pharmacokinetics in selected patient groups

Patients with renal failure

A study of alogliptin at a dose of 50 mg per day was conducted in patients with varying degrees of severity of chronic renal failure. Patients included in the study were divided into 4 groups according to the Cockcroft-Gault formula: patients with mild renal failure (creatinine clearance from 50 to 80 ml/min), moderate severity (creatinine clearance from 30 to 50 ml/min) and severe renal failure (creatinine clearance less than 30 ml/min), as well as end-stage chronic renal failure requiring hemodialysis.

The AUC of alogliptin in patients with mild renal impairment increased approximately 1.7-fold compared to the control group. However, this increase in AUC was within the acceptable deviation for the control group, so dose adjustment of the drug in such patients is not required (see section “Dosage and Administration”).

An approximately two-fold increase in the AUC of alogliptin compared with the control group was observed in patients with moderate renal failure, and an approximately four-fold increase in the AUC was observed in patients with severe renal failure and in patients with end-stage chronic renal failure compared with the control group. Patients with end-stage renal disease underwent hemodialysis immediately after taking alogliptin. About 7% of the dose was removed from the body during a three-hour dialysis session.

Other patient groups

Age (65-81 years), gender, race, and body weight of patients did not have a clinically significant effect on the pharmacokinetic parameters of alogliptin. No dose adjustment of alogliptin is required (see section “Method of administration and dosage”).

Pharmacokinetics in children and adolescents under 18 years of age have not been studied (see section “Dosage and Administration”).

Metformin

Suction

TCmax after oral administration of metformin is about 2.5 hours. The absolute bioavailability of metformin ranges from 50 to 60% in healthy volunteers. After oral administration, 20-30% of the unabsorbed fraction of metformin is excreted through the intestines.

Absorption of metformin is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is not linear.

When metformin is used in recommended doses and regimen, equilibrium plasma concentrations (usually <1 mcg/ml) are achieved within approximately 24-48 hours. According to controlled clinical studies, maximum plasma concentrations of the drug did not exceed 4 mcg/ml, even after taking the maximum doses of the drug.

Distribution

Communication with plasma proteins is negligible. Metformin is distributed in red blood cells. The average maximum concentration (Cmax) in the blood is lower than the Cmax in plasma, and is reached after approximately the same time. The average volume of distribution (Vd) ranges from 63-276 l.

Metabolism

No metabolites have been detected in humans.

Removal

Metformin is excreted unchanged from the body by the kidneys. The renal clearance of metformin is >400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. After oral administration, T1/2 is about 6.5 hours.

With impaired renal function, the clearance of metformin decreases in proportion to the clearance of creatinine, T1/2 increases, which can lead to an increase in the concentration of metformin in plasma.

Special instructions

Lactic acidosis is a rare but serious (high mortality unless promptly treated) complication that may occur due to accumulation of metformin.

Cases of lactic acidosis when taking metformin occurred mainly in diabetic patients with severe renal failure. Other associated risk factors should be taken into account, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure and any condition associated with severe hypoxia. This may help reduce the incidence of lactic acidosis.

The risk of developing lactic acidosis should be taken into account when nonspecific signs appear, such as muscle cramps accompanied by dyspeptic disorders and/or abdominal pain and/or severe asthenia. Lactic acidosis is characterized by acidotic dyspnea and hypothermia followed by coma. Diagnostic laboratory parameters are a decrease in blood pH (less than 7.35), a lactate concentration in the blood plasma over 5 mmol/l, an increased anion gap and the lactate/pyruvate ratio. If lactic acidosis is suspected, stop taking the drug and consult a doctor immediately (see section “Overdose”).

Kidney function

Alogliptin and metformin are primarily excreted by the kidneys. The risk of lactic acidosis associated with metformin increases with the degree of renal impairment, therefore, before starting treatment and regularly thereafter, it is necessary to determine creatinine clearance: at least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, as well as in patients with creatinine clearance at the lower limit of normal. Particular caution should be exercised in case of possible impairment of renal function in elderly patients with simultaneous use of antihypertensive drugs, diuretics or non-steroidal anti-inflammatory drugs.

Liver failure

There are no clinical data on the use of Vipdomet® 850 in patients with severe liver failure (more than 9 points on the Child-Pugh scale). The use of the drug in such groups of patients is not recommended. Surgery The use of metformin should be discontinued 48 hours before elective surgery and can be continued no earlier than 48 hours after, provided that during the examination, renal function was found to be normal.

Use with other hypoglycemic drugs

Vipdomet® 850 is not recommended for use in combination with sulfonylurea derivatives, since the safety and effectiveness have not been studied. In order to reduce the risk of hypoglycemia, it is recommended to reduce the dose of insulin and pioglitazone when used simultaneously with Vipdomet® 850 (see section “Dosage and Administration”).

Change in the clinical status of a patient with previously adequately controlled T2DM

If laboratory abnormalities or clinical symptoms of the disease appear in patients with previously adequately controlled T2DM during treatment with Vipdomet® 850, patients should immediately exclude ketoacidosis or lactic acidosis based on the results of a blood test for electrolytes and ketones, plasma glucose concentrations, as well as blood pH, lactate and pyruvate concentrations, as well as plasma concentrations of metformin. If acidosis of any etiology develops, further use of the drug Vipdomet® 850 is stopped and measures are taken to correct the acidosis.

Acute pancreatitis

In a pooled analysis of 13 clinical trials of alogliptin 25 mg/day, 12.5 mg/day, comparator, and placebo, the incidence of acute pancreatitis was 2, 1, 1, or 0 cases per 1000 patient-years in each group, respectively. In the Cardiovascular Outcomes Study, the incidence of acute pancreatitis in patients treated with alogliptin or placebo was 3 and 2 cases per 1000 patient-years, respectively. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain that may radiate to the back. If the development of acute pancreatitis is suspected, stop taking Vipdomet ® 850; If the development of acute pancreatitis is confirmed, the drug should not be resumed. There is no data on whether there is an increased risk of pancreatitis when taking alogliptin in patients with a history of pancreatitis. Therefore, patients with a history of pancreatitis should be careful.

Effect on liver function

During the post-marketing surveillance period, reports of liver dysfunction, including liver failure, were received while taking alogliptin. Their connection with the use of the drug has not been established. However, patients should be carefully monitored for possible liver function test abnormalities. If abnormalities in liver function tests are detected and an alternative etiology is not established, discontinuation of drug treatment should be considered.

Active ingredient

Alogliptin, Metformin

Active components

Alogliptin+Metformin

Composition

1 tablet 12.5 mg + 850 mg contains:

Active ingredients: alogliptin benzoate – 17 mg (in terms of alogliptin – 12.5 mg), metformin hydrochloride – 850 mg.

Excipients:

Core: mannitol – 70 mg, microcrystalline cellulose (PH-101) – 83.2 mg, povidone K30 – 52.6 mg, crospovidone – 56.8 mg, magnesium stearate – 3.4 mg.

Film coating: hypromellose 2910 – 23.07 mg, talc – 3.42 mg, titanium dioxide – 3.21 mg, yellow iron oxide dye – 0.3 mg.

Pregnancy

Pregnancy There are no data on the safety of Vipdomet® 850 in pregnant women. Studies in pregnant rats have shown reproductive toxicity of combination therapy with alogliptin and metformin at doses approximately 5 to 20 times the recommended human dose (for metformin and alogliptin, respectively).

The use of Vipdomet® 850 during pregnancy is contraindicated.

Alogliptin

There are no data on the safety of alogliptin in pregnant women. Animal studies have not shown direct or indirect negative effects of alogliptin on the reproductive system.

Metformin

Limited evidence suggests that taking metformin in pregnant women does not increase the risk of birth defects in their children. Animal studies have not shown direct or indirect negative effects of metformin at clinically significant doses on the reproductive system. Breastfeeding period There is no data on the penetration of alogliptin and metformin into breast milk in animals during combination therapy. When given as monotherapy with alogliptin or metformin, animal studies have shown that alogliptin and metformin are excreted into the milk of lactating rats. There is no data on the penetration of alogliptin into human breast milk. Metformin passes into breast milk in small quantities in humans, so the risk of adverse reactions in a breastfed baby cannot be excluded. In this regard, the use of the drug during breastfeeding is contraindicated.

Contraindications

hypersensitivity to alogliptin or metformin, or to any excipient, or a history of serious hypersensitivity reactions to any DPP-4 inhibitor, including anaphylactic reactions, anaphylactic shock and angioedema;
type 1 diabetes mellitus;
diabetic ketoacidosis, diabetic precoma, coma;
lactic acidosis (including history);
moderate or severe renal failure (creatinine clearance (CC) less than 60 ml/min);
acute conditions with a risk of developing renal dysfunction:
– dehydration (repeated vomiting, diarrhea);
– fever, severe infectious diseases;
– hypoxia conditions (shock, sepsis, kidney infections, bronchopulmonary diseases);
clinically pronounced manifestations of acute and chronic diseases/conditions that can lead to tissue hypoxia (including acute and chronic heart failure with unstable hemodynamic parameters, respiratory failure, acute myocardial infarction);
liver failure, liver dysfunction;
acute alcohol intoxication, chronic alcoholism;
following a hypocaloric diet (less than 1000 kcal/day);
use for less than 48 hours before and within 48 hours after radioisotope or x-ray studies with intravascular administration of an iodine-containing contrast agent (see section “Interaction with other drugs”);
extensive surgical operations and injuries, when insulin therapy is indicated (see section “Special Instructions”);
pregnancy and breastfeeding;
patient age under 18 years due to lack of data on effectiveness and safety;
combined use with sulfonylurea derivatives due to the lack of data on efficacy and safety (see section “Special instructions”).
With caution
in patients over the age of 60 years who perform heavy physical work, which is associated with an increased risk of developing lactic acidosis (see section “Special Instructions”);
use of the drug Vipdomet® 850 in combination with pioglitazone (see section “Special instructions”);
in patients with a history of pancreatitis.

Side Effects

Adverse reactions when using the drug are divided into system-organ classes in accordance with MedDRA, indicating the frequency of their occurrence according to WHO recommendations:

Very common: ≥ 1/10
Common: ≥ 1/100, < 1/10 Uncommon: ≥ 1/1000, < 1/100 Rare: ≥ 1/10,000, < 1/1000 Very rare: <1/10,000 Frequency not established (it is not possible to determine the frequency of occurrence based on the available data).

Table 1: Adverse reactions

Class of organ systems Adverse reaction
Frequency of adverse reactions
Alogliptin
Metformin
Vipdomet
Infectious and parasitic diseases
Upper respiratory tract infections
Often
Often
Nasopharyngitis
Often
Often
Immune system disorders
Hypersensitivity reactions, including anaphylactic reaction
Frequency not set
Metabolic and nutritional disorders
Lactic acidosis
Very rarely
Vitamin B12 deficiency
Very rarely
Hypoglycemia (in case of combined use with the drug, sulfonylurea or insulin)
Often
Often
Nervous system disorders
Headache
Often
Often
Metallic taste in the mouth
Often
Gastrointestinal disorders
Gastroenteritis
Often
Abdominal pain
Often
Very often
Often
Diarrhea
Often
Very often
Often
Vomit
Very often
Often
Gastritis
Often
Gastroesophageal reflux disease
Often
Often
Loss of appetite
Very often
Nausea
Very often
Acute pancreatitis

Frequency not set
Disorders of the liver and biliary tract
Hepatitis
Very rarely
Liver function abnormalities
Very rarely
Liver dysfunction, including liver failure
Frequency not set
Skin and subcutaneous tissue disorders
Itching
Often
Very rarely
Often
Rash
Often
Often
Erythema (redness of the skin)
Very rarely
Exfoliative skin diseases, including Stevens-Johnson syndrome
Frequency not set
Erythema multiforme
Frequency not set
Angioedema
Frequency not set
Hives
Frequency not set
Very rarely

Prescribing

Combined hypoglycemic agent for oral use (dipeptidyl peptidase-4 inhibitor + biguanide)

Complete set of goods

Film-coated tablets, 12.5 mg + 850 mg. 7 film-coated tablets in an Al/Al blister, 2, 4 or 8 blisters along with instructions for use are placed in a cardboard box. The cardboard box can be tamper evident.

Storage conditions

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

Takeda GmbH, Germany