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 adult patients aged 18 years and older to improve glycemic control in addition to diet therapy and exercise:

Monotherapy

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

Combination therapy

In combination with pioglitazone (triple combination: metformin + alogliptin + pioglitazone), when therapy with metformin and pioglitazone does not result in 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.

Active ingredient

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, crosspovidone – 56.8 mg, magnesium stearate – 3.4 mg.

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

How to take, the dosage

The drug is taken orally. Vipdomet® 850 should be taken 1 tablet 2 times a day with meals to reduce adverse reactions of the gastrointestinal tract. The tablets should be swallowed whole, without chewing, with water.

If a patient misses a dose of Vipdomet® 850, the patient should take it as soon as they remember to take it. Do not take a double dose of Vipdomet® 850 at the same time, in this case the dose should be skipped. The dose of the drug Vipdomet® 850 should be adjusted individually.

For patients who have not achieved adequate glycemic control with metformin monotherapy: The recommended dose of Vipdomet® 850 is 1 tablet of 12.5 mg + 850 mg twice daily, depending on the metformin dose already taken, which corresponds to 25 mg of alogliptin and 1,700 mg of metformin daily.

For patients who have not achieved adequate glycemic control when combined therapy with metformin and pioglitazone at the maximum tolerated dose: Vipdomet® 850 is administered in addition to pioglitazone, and the current dose of pioglitazone should be maintained. The recommended dose of Vipdomet® 850 is 1 tablet of 12.5 mg + 850 mg 2 times per day, depending on the metformin dose already taken, which corresponds to 25 mg of alogliptin and 1700 mg of metformin per day.

Caution should be exercised with this therapy due to the risk of hypoglycemia. In case of hypoglycemia, reduction of the administered doses of metformin or pioglitazone may be considered. As a substitution in patients taking alogliptin and metformin as monotherapy (as a combination of alogliptin and metformin or as part of a combination with insulin – alogliptin, metformin and insulin): the daily dose of alogliptin and metformin in Vipdomet® 850 should match the daily doses of alogliptin and metformin taken earlier. Because Vipdomet® 850 is taken twice daily, the daily dose of alogliptin previously taken as alogliptin monotherapy (25 mg) should be divided into 2 doses with the metformin dose unchanged.

For patients who have not achieved adequate glycemic control on therapy with a combination of maximum tolerated dose of metformin and insulin: The dose of Vipdomet® 850 should provide a 12.5 mg dose of alogliptin twice daily (total daily dose of alogliptin 25 mg) and administration of metformin at the previously taken dose. To avoid the risk of hypoglycemia, the insulin dose may be reduced. Maximum recommended daily dose of Vipdomet® 850 is 2 tablets (25 mg of alogliptin). Use of the drug in special clinical groups of patients Elderly patients (aged ≥ 65 years) No dose adjustment of Vipdomet® 850 is required in patients aged ≥ 65 years. Caution should be exercised when selecting doses of alogliptin due to possible impairment of renal function in this group of patients.

Periatric and adolescent use

There are no data on the efficacy and safety of the drug in patients less than 18 years of age.

In patients with impaired renal function

In patients with mild renal impairment (creatinine clearance ≥ 60 ml/min) no dose adjustment of Vipdomet® 850 is required (see section “Pharmacokinetics”). Vipdomet® 850 is not recommended for use in patients with renal insufficiency of moderate severity (creatinine clearance ≥ 30 to 60 ml/min), since these patients require a lower dose of alogliptin than that provided in the fixed combination of Vipdomet® 850. In patients with renal impairment, it is recommended to perform renal function assessment before starting treatment with Vipdomet® 850 and periodically during the treatment (see section “Cautionary Note”). Vipdomet® 850 should not be used in patients with hepatic impairment (see sections “Contraindications” and “Pharmacokinetics”).

Special Instructions

Lactoacidosis is a rare but serious (high mortality if not treated urgently) complication that can occur due to metformin cumulation.

Lactoacidosis with metformin has mainly occurred in patients with diabetes mellitus with severe renal impairment. Other associated risk factors, such as decompensated diabetes mellitus, ketosis, prolonged fasting, alcoholism, liver failure, and any condition associated with severe hypoxia should be considered. This may help reduce the incidence of lactoacidosis.

The risk of lactoacidosis should be considered if nonspecific signs occur, such as muscle cramps accompanied by dyspeptic disorders and/or abdominal pain and/or marked asthenia. Lactoacidosis is characterized by acidotic dyspnea and hypothermia followed by coma. Diagnostic laboratory indicators are decreased blood pH (less than 7.35), plasma lactate concentration over 5 mmol/L, elevated anion gap and lactate/pyruvate ratio. If lactoacidosis is suspected, discontinue the drug and immediately consult a physician (see section “Overdose”).

Renal function

Alogliptin and metformin are primarily excreted by the kidneys. The risk of lactoacidosis associated with metformin administration increases with the degree of renal impairment, so creatinine clearance should be determined before treatment and regularly thereafter: at least once a year in patients with normal renal function, and 2-4 times a year in elderly patients, and in patients with creatinine clearance on the lower limit of normal. Particular caution should be exercised with respect to possible renal function impairment in elderly patients when concomitant use of hypotensive drugs, diuretics or nonsteroidal anti-inflammatory drugs.

Hepatic failure

There are no clinical data about use of Vipdomet® 850 in patients with severe hepatic failure (more than 9 points by Child-Pugh score). It is not recommended to use the drug in such groups of patients. Surgical surgeries Metformin administration should be discontinued 48 hours prior to elective surgery and may be continued not earlier than 48 hours after, provided that renal function has been recognized as normal during the examination.

The use with other hypoglycemic drugs

Vipdomet® 850 is not recommended in combination with sulfonylurea derivatives because safety and effectiveness have not been studied. In order to reduce the risk of hypoglycemia it is recommended to decrease the dose of insulin and pioglitazone when used concomitantly with Vipdomet® 850 (see section “Dosage and administration”).

Change in clinical status of a patient with adequately controlled prior DM2

. If there is manifestation of laboratory abnormalities or clinical symptoms of disease in patients with previously adequately controlled DM2 during treatment with Vipdomet® 850, ketoacidosis or lactoacidosis should be immediately excluded in patients based on blood electrolytes and ketones, plasma glucose concentration as well as blood pH, lactate and pyruvate concentration, and plasma metformin concentration. In case of acidosis of any etiology, further use of Vipdomet® 850 should be discontinued and measures for acidosis correction should be taken.

Acute pancreatitis

In a pooled analysis of 13 clinical trials of alogliptin at 25 mg/day, 12.5 mg/day, the reference drug and placebo, the incidence of acute pancreatitis was 2, 1, 1 or 0 cases per 1000 patient-years in each group, respectively. In a study of cardiovascular outcomes, the incidence of acute pancreatitis in patients treated with alogliptin or placebo was 3 and 2 cases per 1,000 patient-years, respectively. Patients should be informed about the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain, which may irradiate to the back. If acute pancreatitis is suspected, the drug Vipdomet® 850 should be discontinued; if acute pancreatitis is confirmed, the drug should not be started again. There are no data on whether there is an increased risk of pancreatitis during administration of alogliptin in patients with a history of pancreatitis. Therefore, caution should be exercised in patients with a history of pancreatitis.

Impacts on liver function

In the post-registration follow-up period, there have been reports of hepatic dysfunction, including hepatic failure, with alogliptin administration. Their association with the use of the drug has not been established. However, patients should be carefully examined for possible liver function test abnormalities. If abnormal liver function tests are found and no alternative etiology has been established, discontinuation of treatment with the drug should be considered.

Synopsis

Contraindications

Side effects

Unwanted reactions with the drug are classified into systemic organ classes according to MedDRA with the frequency of occurrence according to WHO recommendations:

Table 1: Unwanted reactions

Pregnancy use

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 higher than recommended doses in humans (for metformin and alogliptin, respectively).

The use of Vipdomet® 850 during pregnancy is contraindicated.

Alogliptin

There are no data on the safety of using alogliptin in pregnant women. Animal studies have shown no direct or indirect negative effects of alogliptin on the reproductive system.

Metformin

Limited data suggest that metformin administration in pregnant women does not increase the risk of birth defects in children. Animal studies have shown no direct or indirect adverse effects of metformin at clinically relevant doses on the reproductive system. Breastfeeding There are no data on penetration into breast milk in animals of alogliptin and metformin during combination therapy. With alogliptin or metformin monotherapy, animal studies have shown that alogliptin and metformin penetrate into the milk of lactating rats. There are no data on the penetration of alogliptin into human breast milk. Metformin penetrates into breast milk in humans in small amounts, so the risk of adverse reactions in a breastfed child cannot be excluded. In this regard, the use of the drug during breastfeeding is contraindicated.