Description of the drug VIPIDIA® (VIPIDIA)
The pharmacokinetics of alogliptin is similar in healthy individuals and in patients with type 2 diabetes mellitus.
The absolute bioavailability of alogliptin is approximately 100%. Concomitant administration with a high-fat meal did not affect the AUC of alogliptin, so it can be taken regardless of food intake. In healthy individuals, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed, reaching an average Tmax value in the range of 1 to 2 hours from the moment of administration.
The AUC of alogliptin increases proportionally with a single dose in the therapeutic dose range from 6.25 mg to 100 mg. The intrapatient variability of alogliptin AUC 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 a day for 6 days. This indicates that there is no time dependence in the kinetics of alogliptin after repeated dosing.
Plasma protein binding is approximately 20-30%. After a single intravenous administration of alogliptin at a dose of 12.5 mg in healthy volunteers, Vd in the terminal phase was 417 L, indicating that alogliptin is well distributed in tissues.
Neither healthy volunteers nor patients with type 2 diabetes mellitus experienced clinically significant accumulation of alogliptin after repeated dosing.
Alogliptin is not subject to extensive metabolism; 60 to 70% of alogliptin is excreted unchanged by the kidneys.
After oral administration of 14C-labeled alogliptin, two main metabolites were identified:
- N-demethylated alogliptin, M-I (<1% of the original substance), and N-acetylated alogliptin, M-II (<6% of the original substance). M-I is an active metabolite and highly selective DPP-4 inhibitor, similar in action to alogliptin itself;
- M-II does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.
In vivo studies revealed that CYP2D6 and CYP3A4 are involved in the limited metabolism of alogliptin.
Also, in vitro studies indicate that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 or inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 at concentrations achieved at the recommended dose of 25 mg alogliptin. In vitro, alogliptin may induce CYP3A4 to a small extent, but in vivo, alogliptin does not induce CYP3A4.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and, in vivo, undergoes little or no chiral conversion to the (S)-enantiomer. The (S)-enantiomer is not detected when alogliptin is taken in therapeutic doses.
After oral administration of 14C-labeled alogliptin, 76% of the total radioactivity is excreted by the kidneys and 13% by the intestines. The mean renal clearance of alogliptin (170 ml/min) is greater than the mean GFR (about 120 ml/min), suggesting that alogliptin is partially eliminated through active renal excretion. The average terminal T1/2 is approximately 21 hours.
Vipidia
Use with other hypoglycemic drugs
In order to reduce the risk of hypoglycemia, it is recommended to reduce the dose of sulfonylurea derivatives, insulin or the combination of pioglitazone (thiazolidinedione) with metformin when used simultaneously with the drug.
Unexplored combinations
The efficacy and safety of use in combination with sodium-dependent glucose cotransporter 2 inhibitors or glucagon-like peptide analogues and in triple combination with metformin and sulfonylurea derivatives have not been studied.
Kidney failure
Since patients with moderate renal failure require dosage adjustments, it is recommended that renal function be assessed before and periodically during treatment.
The drug should not be used in patients with severe renal failure, as well as in patients with end-stage chronic renal failure requiring hemodialysis.
Acute pancreatitis
The use of DPP-4 inhibitors is associated with a potential risk of developing acute pancreatitis. In a pooled analysis of 13 clinical trials of alogliptin 25 mg daily, 12.5 mg daily, comparator, and placebo, the incidence of acute pancreatitis was 3, 1, 1, or 0 cases per 1000 patient-years in each group, 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 the drug; If acute pancreatitis is confirmed, the drug should not be resumed. There is no data on whether there is an increased risk of developing pancreatitis while taking the drug in patients with a history of pancreatitis. Therefore, patients with a history of pancreatitis should be careful.
Liver failure
There have been post-marketing reports of liver dysfunction, including liver failure, with alogliptin. Their connection with the use of the drug has not been established. However, patients should be carefully examined for possible abnormalities in liver function. If abnormalities in liver function are detected and an alternative etiology for their occurrence has not been established, the possibility of discontinuing treatment with the drug should be considered.
Influence or ability to drive vehicles and machinery
The drug does not have or has an insignificant effect on the ability to drive vehicles and machines. However, it is necessary to take into account the risk of developing hypoglycemia when using the drug in combination with other hypoglycemic drugs (sulfonylurea derivatives, insulin or combination therapy with pioglitazone and metformin) and use caution when driving vehicles and machinery.
Vipidia, 28 pcs., 12.5 mg, film-coated tablets
The pharmacokinetics of alogliptin are similar in healthy individuals and patients with type 2 diabetes mellitus.
Suction
The absolute bioavailability of alogliptin is approximately 100%. Concomitant administration with a high-fat meal did not affect the AUC of alogliptin, so it can be taken without regard to meals. In healthy individuals, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed with the average Cmax achieved within 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 AUC of alogliptin increases proportionally with a single dose in the therapeutic dose range from 6.25 to 100 mg. The intrapatient variability of alogliptin AUC is small (17%). The AUC0-inf of alogliptin after a single dose was similar to the AUC0-24 after the same dose was administered 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 administration of alogliptin at a dose of 12.5 mg in healthy volunteers, Vd in the terminal phase was 417 L, indicating good distribution 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, M1 (<1% parent material), and N-acetylated alogliptin, M2 (<6% parent material). M1 is an active metabolite and highly selective DPP-4 inhibitor, similar in action to alogliptin itself; M2 does not exhibit inhibitory activity against DPP-4 or other DPP enzymes.
in vitro studies
CYP2D6 and CYP3A4 were found to be involved in the limited metabolism of alogliptin.
Also in vitro
show that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 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.
Alogliptin does not inhibit human renal organic anion transporters ( Organic Anion Transporters)
, OAT1), third (OAT3) types and renal transporters of human organic cations of the second (
Organic Cation Transporters
, OCT2) type.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and in vivo
or undergoes 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% by the intestines. The mean renal clearance of alogliptin (170 ml/min) is greater than the mean GFR (about 120 ml/min), suggesting that alogliptin is partially eliminated through active renal excretion. The average terminal T1/2 of alogliptin is approximately 21 hours.
Selected patient groups
Kidney failure.
A study of alogliptin at a dose of 50 mg/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 (creatinine clearance from 50 to 80 ml/min), moderate (creatinine clearance from 30 to 50 ml/min) and severe degrees of renal failure ( Cl creatinine less than 30 ml/min), as well as patients with 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 is not required in such patients (see "Dosage and Administration"). An approximately two-fold increase in the AUC of alogliptin compared to the control group was observed in patients with moderate renal failure. An approximately fourfold increase in AUC was observed in patients with severe renal failure and end-stage renal failure compared with controls. Patients with end-stage renal disease underwent hemodialysis immediately after taking alogliptin. About 7% of the dose was removed from the body during a 3-hour dialysis session.
Thus, to achieve therapeutic plasma concentrations of alogliptin similar to those in patients with normal renal function, dose adjustment is necessary in patients with moderate renal insufficiency (see "Dosage and Administration"). Alogliptin is not recommended for use in patients with severe renal failure or end-stage renal disease requiring hemodialysis.
Liver failure.
In patients with moderate hepatic impairment, the AUC and Cmax of alogliptin are reduced by approximately 10% and 8%, respectively, compared to patients with normal hepatic function. These values are not clinically significant. Thus, dose adjustment of the drug is not required for mild to moderate liver failure (from 5 to 9 points on the Child-Pugh scale). There are no clinical data on the use of alogliptin in patients with severe liver failure (more than 9 points on the Child-Pugh scale, see “Dosage and Administration”).
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 the drug is required (see “Method of administration and dosage”). Pharmacokinetics in children under 18 years of age have not been studied.
Vipidia is a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus
T.B. MORGUNOVA
, Ph.D.,
V.V.
FADEEV , Doctor of Medical Sciences, Professor,
Department of Endocrinology, Faculty of Medicine, First Moscow State Medical University.
THEM. Sechenov The number of patients with diabetes mellitus (DM) in the world is steadily growing. Over the past 10 years, their number in the world has more than doubled and by 2013 reached 371 million people [1]. In the vast majority of cases, this is type 2 diabetes. The dangerous consequences of diabetes are its micro- and macrovascular complications: nephropathy, retinopathy, damage to large vessels of the heart, brain, and lower extremities. The development of late complications of diabetes is the main cause of disability and mortality in these patients.
Currently, different groups of oral hypoglycemic drugs (OHDs) are used to treat type 2 diabetes. The choice of a hypoglycemic agent depends primarily on the patient’s condition, the level of glycemia at baseline and target glycemic control, as well as the presence of concomitant diseases or complications of diabetes in the patient. When choosing a hypoglycemic drug, factors such as its effectiveness, tolerability, safety and frequency of administration also play an important role. It should be noted that taking a number of PSSPs is associated with the development of hypoglycemia, weight gain, dyspeptic symptoms, etc., which often limit their use in clinical practice. In addition, if monotherapy with one of the oral hypoglycemic drugs is started, then over time, since type 2 diabetes is a progressive disease, in many cases it will be necessary to adjust the therapy by increasing the dose of the drug taken or switching to a combination of drugs.
In recent years, glucose-lowering drugs based on the action of incretins have become quite widely used in clinical practice. The main incretin hormone is glucagon-like peptide-1 (GLP-1) - it stimulates insulin secretion at high glycemic levels and reduces glucagon secretion by α-cells of the pancreas, and also affects the feeling of satiety and the rate of gastric emptying. However, once in the bloodstream, GLP-1 is very quickly destroyed by the enzyme dipeptidyl peptidase-4 (DPP-4). In order to increase the duration of action of endogenous GLP-1 and maintain its physiological level, drugs were created - dipeptidyl peptidase type 4 inhibitors (DPP-4). The use of drugs in this class is associated with a low risk of hypoglycemia, since their effect occurs only in response to an increase in blood glucose levels; they are generally well tolerated and have no effect on body weight. Vipidia (alogliptin benzoate) is a new drug in the DPP-4 class of drugs.
Main characteristics
The drug Vipidia is recommended for use as a hypoglycemic agent in adults with type 2 diabetes in monotherapy, in combination with other glucose-lowering drugs, including insulin. Vipidia is available in dosages of 12.5 and 25 mg: the recommended dose for patients with normal renal function and with a slight decrease in renal function (creatinine clearance > 50 to ≤ 80 ml/min) is 25 mg 1 time per day; with a moderate decrease in renal function (creatinine clearance ≥ 30 to ≤ 50 ml/min), the dose of alogliptin should be reduced by half, i.e. to 12.5 mg 1 time per day.
It is obvious that, despite the same mechanism of action, drugs from the DPP-4 group differ from each other in some characteristics. Vipidia is a highly selective DPP-4 idrien: as shown in in vitro studies, it is characterized by 10,000 times greater selectivity for the DPP-4 enzyme compared to DPP-8 and DPP-9 [2]. Another important characteristic of the drug is the duration of DPP-4 inhibition, up to 81.8-96.7% over 24 hours. In addition, inhibition of the DPP-4 enzyme persists up to 168 hours after taking the drug. It is these properties that provide the long-term hypoglycemic effect of Vipidia and allow it to be taken once a day [3].
In general, Vipidia is characterized by a favorable pharmacokinetic profile: it is rapidly and almost completely absorbed, regardless of food intake; widely distributed in tissues, weakly binds to proteins, thereby demonstrating high bioavailability. In addition, it practically does not interact with other drugs, which is especially important when prescribing hypoglycemic therapy to patients with complications of diabetes or with concomitant diseases, when the patient is already taking a number of medications.
Efficiency
Studies examining the effectiveness of Vipidia have shown that a clinically significant improvement in glycemic control (levels of glycated hemoglobin and fasting plasma glucose) in patients with type 2 diabetes is observed with the use of alogliptin, both as monotherapy and in combination with other hypoglycemic drugs: metformin, pioglitazone, sulfonylurea derivatives and insulin. The administration of the drug Vipidia at a dose of 25 mg was accompanied by a decrease in the level of glycated hemoglobin (HbA1c) compared to the baseline by 0.5-0.9% [4-8].
It should be noted that the improvement in glycemic control when prescribing Vipidia occurred quite quickly. Just one week after its addition to metformin or pioglitazone, there was a statistically significant improvement in fasting blood glucose compared with placebo. At the same time, the achieved improvement in the level of fasting glycemia was maintained throughout the study, both in monotherapy and with the addition of alogliptin to other glucose-lowering drugs [4–8].
The effectiveness of the glucose-lowering effect of Vipidia can be confirmed by the results of the ENDURE study (Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus). A multicenter, randomized, double-blind study compared the duration of efficacy and safety of treatment with Vipidia or glipizide in combination with metformin in patients with type 2 diabetes who had not previously achieved adequate glycemic control on a stable dose of metformin. Patients in this study were randomized to Vipidia 12.5 mg once daily + metformin (n = 880) 25 mg once daily + metformin (n = 885) and glipizide 5 mg titrated to a maximum dose of 20 mg , + metformin (n = 874). The duration of treatment was 104 weeks. (2 years). Decrease in HbA1c level by 104th week. was -0.68, -0.72 and -0.59% in the group of patients who were prescribed Vipidia 12.5, 25 mg and glipizide, respectively.
It should be noted that in the treatment group with Vipidia at a dose of 25 mg by the 104th week. treatment, a significantly larger number of patients (48.5%) achieved an HbA1c level ≤ 7% compared to the group of patients taking glipizide (p = 0.004). In addition, therapy with Vipidia at a dose of 12.5 and 25 mg was accompanied by a significantly more pronounced decrease in fasting plasma glucose levels at week 104. compared with glipizide therapy (-0.9, -3.2, 5.4 mg/dL, respectively, p < 0.01).
Based on the results of the study, it was concluded that the addition of Vipidia to metformin monotherapy effectively reduced the level of glycemia and glycated hemoglobin and, importantly, maintained the achieved levels of glycemic control for 2 years [9].
Safety
In general, the tolerability of Vipidia, as shown in studies, is quite good. According to a cumulative analysis of 11 phase 2 and 3 studies, the tolerability of alogliptin, both in monotherapy and in combination with other glucose-lowering drugs, did not differ from the tolerability of comparator drugs (including placebo) [10]. Main side effects: headache, nasopharyngitis, urinary tract infections, upper respiratory tract infections.
The studies conducted assessed the incidence of hypoglycemia. When alogliptin was combined with sulfonylureas, metformin, pioglitazone, or insulin, the incidence of hypoglycemia was similar to placebo. In the 2-year ENDURE study, hypoglycemia occurred much less frequently with alogliptin than with glipizide [4-9].
Separately, the studies assessed the effect of the drug Vipidia on body weight. Weight gain is a common side effect in patients with type 2 diabetes receiving sulfonylureas and can significantly reduce patient adherence to therapy. Therapy with Vipidia did not contribute to weight gain, and, according to a number of studies, in particular the ENDURE study, a slight decrease in body weight was noted, in contrast to glipizide, where weight gain occurred. Thus, the good tolerability, lack of weight gain and low risk of hypoglycemia with the use of alogliptin and other DPP-4 inhibitors determine their significant therapeutic advantage.
Cardiovascular safety
It is well known that patients with type 2 diabetes are at high risk of developing cardiovascular diseases. And one of the most important issues of modern glucose-lowering therapy is cardiovascular safety. Initially, questions of cardiac safety arose in relation to some drugs already approved for use and to drugs still under development for the treatment of type 2 diabetes (rosiglitazone and muraglitazar). In July 2008, the US Food and Drug Administration (FDA) Expert Committee on Endocrinological and Metabolic Drugs issued guidance on assessing the safety of antidiabetic drugs in relation to cardiovascular risks (Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes). This guideline describes the requirements for assessing the cardiovascular safety of new antidiabetic drugs before and after their approval [11]. Subsequently, several studies were launched to evaluate the cardiovascular safety of glucose-lowering drugs.
In 2013, the results of the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) study were published. It assessed the cardiovascular safety of alogliptin compared with placebo in patients with type 2 diabetes who had an acute coronary syndrome 15 to 90 days before randomization. The study included 5,380 patients, and the HbA1c level at study entry was 6.5-11% (or 7.0-11% if the patient was on insulin therapy). Patients were randomized into two groups. One group received alogliptin, the other received placebo. In addition, standard glucose-lowering therapy and secondary prevention of cardiovascular complications were continued. The duration of treatment with alogliptin averaged 533 days (18 months). The primary endpoint was the time from randomization to the first major cardiovascular event: cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Throughout the study, greater reductions in HbA1c levels were achieved in the alogliptin group; by the end of the study, the decrease in glycated hemoglobin levels from baseline was -0.33 vs +0.03% in the alogliptin and placebo groups, respectively. A total of 621 patients experienced some type of major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in the study; with the same frequency - in patients receiving alogliptin and placebo (11.3 and 11.8%, respectively). The results of the study showed that alogliptin therapy does not increase the risk of major cardiovascular events in patients with a very high risk of CVD, i.e., patients with type 2 diabetes who have recently suffered an acute coronary syndrome (risk ratio = 0.962 ; one-sided 97.5% CI: 0; 1.16) [12].
Conclusion
Since their introduction, DPP-4 inhibitors have taken a strong place among drugs for the treatment of type 2 diabetes. The low risk of hypoglycemia, the absence of an effect on body weight and the absence of side effects from the gastrointestinal tract distinguish this class from other PSSPs. In general, sufficient glucose-lowering efficacy allows us to recommend DPP-4 inhibitors as first-line therapy in the onset of type 2 diabetes with an initial HbA1c level of 6.5-7.5%. If at the onset of type 2 diabetes the HbA1c level is 7.6-9%, then in this situation it is recommended to start treatment with a combination of two glucose-lowering drugs that act on different mechanisms of disease development. The most rational combinations include combinations of metformin (the basic drug that reduces insulin resistance) and drugs that stimulate insulin secretion: DPP-4 inhibitors, GLP-1 inhibitors, SM or glinides [1].
Vipidia (alogliptin) is a new drug from the DPP-4 class of drugs. Studies have shown a good glucose-lowering effect of the drug both in monotherapy and in combination with other glucose-lowering drugs, as well as maintaining the effect over 2 years of therapy. In addition, important results were obtained in the EXAMINE study, where Vipidia demonstrated its cardiac safety in patients with type 2 diabetes who had recently suffered an acute coronary syndrome, i.e., patients at very high risk of cardiovascular disease.
Literature
1. Algorithms for specialized medical care for patients with diabetes mellitus. 6th ed. Diabetes mellitus, 2013, 1. 2. Capuano A et al. Drug Des Devel Ther., 2013, 7: 989–1001. 3. Covington P et al. Clin Ther., 2008, 30: 499–512. 4. DeFronzo RA et al. Diabetes Care 2008, 31: 2315–2317. 5. Pratley RE et al. Diabetes Obes Metab., 2009, 11: 167–176. 6. Nauck MA et al. Int J Clin Pract., 2009, 63: 46–55. 7. Pratley RE et al. Curr Med Res Opin., 2009, 25: 2361–2371. 8. Rosenstock J et al. Diabetes Obes Metab., 2009, 11: 1145–1152. 9. Del Prato S, Camisasca R, Wilson C, Fleck P. Diabetes Obes Metab., 2014, 16(12): 1239-46. doi: 10.1111/dom.12377. Epub 2014 Sep 25. 10. Hisada M et al. Abstract presented at the 48th Annual Meeting of the EASD 2012. Abstract 839-P. 11. FDA Guidance for Industry. Diabetes mellitus – evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available from: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. 12. White WB, Cannon CP, Heller SR et al. N Engl J Med., 2013, 3, 369(14): 1327-35. doi: 10.1056/NEJMoa1305889. Epub 2013 Sep 2
Source:
Medical Council, No. 2, 2015.
Vipidia 25 mg No. 28 tablet p.p.o.
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINE VIPIDIA™ THIS MEDICINE IS SUBJECT TO ADDITIONAL MONITORING. THIS WILL ALLOW NEW SECURITY INFORMATION TO BE IDENTIFIED QUICKLY. WE URGE HEALTHCARE PROFESSIONALS TO REPORT ANY SUSPECTED ADVERSE REACTIONS. TRADE NAME VIPIDIIA™ INTERNATIONAL NON-PROPENTED NAME ALOGLIPTINA DOSAGE FORM FILM-COATED TABLETS 12.5 MG AND 25 MG COMPOSITION ONE TABLET CONTAINS ACTIVE SUBSTANCE: ALOGLIPTINE BENZOATE 17 MG (EQUIVALENT TO 12.5 MG ALOGLIPTIN) AND 34 MG (EQUIVALENT TO 25 MG ALOGLIPTIN) EXCIDIENTS: CORE: MANNITOL, MICROCRYSTALLINE CELLULOSE, HYDROXYPROPYL CELLULOSE, CROSCARMELLOSE SODIUM, MAGNESIUM STEARATE FILM COVER COMPOSITION: HYPROMELLOSE 2910, TITANIUM DIOXIDE (E 171), IRON OXIDE F YELLOW (E 172), IRON OXIDE RED (E 172), POLYETHYLENE GLYCOL 8000, GRAY INK F1 DESCRIPTION OVAL BICONVEXAL TABLETS, YELLOW FILM COATED, WITH “TAK” AND “ALG-12.5” INCRAPED ON ONE SIDE OF THE TABLET (FOR 12.5 MG DOSAGE); OVAL BICONVEXAL TABLETS, LIGHT RED FILM COATED, WITH “TAK” AND “ALG-25” INCRAPED ON ONE SIDE OF THE TABLET (FOR 25 MG DOSAGE). PHARMACOTHERAPEUTIC GROUP OF DRUGS FOR THE TREATMENT OF DIABETES MELLITUS. ORAL GLOW-LOYING MEDICINES. DIPEPTIDILEPEPTIDASE-4 (DPP-4) INHIBITORS. ALOGLIPTIN ATC CODE A10BH04 PHARMACOLOGICAL PROPERTIES Pharmacokinetics The pharmacokinetics of alogliptin was studied in studies involving both healthy volunteers and patients with type 2 diabetes mellitus. In healthy volunteers, after a single oral dose of up to 800 mg of alogliptin, rapid absorption of the drug is observed, reaching maximum plasma concentrations within one to two hours from the moment of administration (average Tmax). After taking the maximum recommended therapeutic dose of the drug (25 mg), the terminal half-life (T1/2) averaged 21 hours. After repeated dosing up to 400 mg for 14 days in patients with type 2 diabetes, minimal accumulation of alogliptin was observed with an increase in the area under the pharmacokinetic curve (AUC) and maximum plasma concentration (Cmax) by 34% and 9%, respectively. With both single and multiple doses of alogliptin, AUC and Cmax increase in proportion to increasing doses from 25 mg to 400 mg. The coefficient of variation of alogliptin AUC among patients is small (17%). Absorption The absolute bioavailability of alogliptin is approximately 100%. Since no effect on AUC and Cmax was found when alogliptin was taken with a high-fat meal, the drug can be taken regardless of meals. Distribution Following a single intravenous dose of 12.5 mg 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 20%. Metabolism Alogliptin is not extensively metabolized, resulting in 60% to 71% of the administered dose being excreted unchanged in the urine. Following oral administration of 14C-labeled alogliptin, two minor metabolites were identified: N-demethylated alogliptin MI (less than 1% of the parent substance) and N-acetylated alogliptin M-II (less than 6% of the parent substance). MI is an active metabolite and selective DPP-4 inhibitor, similar in action to alogliptin; M-II does not exhibit inhibitory activity against DPP-4 or other DPP-related enzymes. In vitro studies have shown that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin. Alogliptin exists predominantly as the (R)-enantiomer (>>99%) and undergoes chiral conversion to the (S)-enantiomer in minor amounts in vivo. The (S)-enantiomer is not detected when alogliptin is taken in therapeutic doses (25 mg). Excretion After administration of 14C-labeled alogliptin, 76% of the total radioactivity is excreted by the kidneys and 13% through the intestines, achieving elimination of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/h) indicates renal tubular secretion. System clearance is 14.0 l/h. Pharmacokinetics in Special Populations: Renal Impairment The AUC of alogliptin in patients with mild renal impairment (60≤creatinine clearance (CrCl)<90 mL/min) increased approximately 1.2-fold. An approximately two-fold increase in the AUC of alogliptin was observed in patients with moderate renal impairment (30≤CrCl<60 ml/min). Approximately three- and four-fold increases in the AUC of alogliptin were observed in patients with severe renal impairment (15≤CrCl<30 ml/min) and end-stage chronic renal failure (CrCl<15 ml/min or when dialysis is required), respectively. Hepatic impairment: In patients with moderate hepatic impairment (Child-Pugh class B), the AUC and Cmax of alogliptin are reduced by approximately 10% and 8%, respectively, compared to healthy subjects. These values are not clinically significant. Patients with severe liver dysfunction (Child-Pugh class C) were not studied. Age, gender, race Elderly and senile age (65-81 years), gender and race do not have a clinically significant effect on the pharmacokinetic properties of alogliptin. Pediatric patients The pharmacokinetics of alogliptin in children and adolescents under 18 years of age have not been studied and no data are available. Pharmacodynamics: Administration of a single dose of alogliptin to healthy individuals resulted in maximum inhibition of DPP-4 within two to three hours. The maximum inhibition of DPP-4 exceeded 93% in the dose range from 12.5 mg to 800 mg. DPP-4 inhibition remained above 80% 24 hours after dosing greater than or equal to 25 mg. Peak and total exposure to glucagon-like peptide-1 (GLP-1) over 24 hours was three to four times higher with alogliptin (at doses of 25-200 mg) than with placebo. In a 16-week, double-blind, placebo-controlled study, alogliptin 25 mg demonstrated decreased postprandial glucagon levels and increased postprandial active GLP-1 levels compared with placebo over an eight-hour period following a standardized meal. It is unknown how these results relate to changes in overall glycemic control in patients with type 2 diabetes. In this study, alogliptin 25 mg demonstrated a reduction in 2-hour postprandial glucose levels compared with placebo (-30 mg/dL vs. 17 mg/dL, respectively). A single daily dose (several single doses) of alogliptin in patients with type 2 diabetes for 14 days also resulted in maximum DPP-4 inhibition within one to two hours. Inhibition was greater than 93% for all doses of 25 mg, 100 mg and 400 mg. After 14 days of alogliptin at these doses, DPP-4 inhibition remained above 81% at 24 hours. Effects on cardiac electrophysiological parameters In a randomized, placebo-controlled, four parallel group study, 257 patients received alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg, or placebo once daily for seven days. Any dose of alogliptin was not associated with an increase in the corrected QTc interval. After a dose of 400 mg, the peak plasma concentration of alogliptin was 19 times higher than the peak concentration after the maximum recommended therapeutic dose of 25 mg. INDICATIONS FOR USE VIPIDIA™ IS INDICATED IN ADDITION TO DIET AND EXERCISE TO IMPROVE GLYCEMIC CONTROL IN ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS AS MONOTHERAPY AND IN COMBINATION WITH OTHER THERAPY PARATAMI. METHOD OF APPLICATION AND DOSAGE DOSAGE OF VIPIDIUM™ IS AVAILABLE IN THE FORM OF FILM COATED TABLETS CONTAINING 25MG AND 12.5MG OF THE DRUG, WHICH ALLOWS YOU TO SELECT THE OPTIMAL DOSAGE REGIME. THE RECOMMENDED DOSE IS ONE VIPIDIA™ 25MG TABLET ONCE A DAY. SPECIAL INSTRUCTIONS ON DOSAGE FOR SEPARATE GROUPS OF PATIENTS RENAL IMPAIRMENT - FOR PATIENTS WITH MILD RENAL IMPAIRMENT (60≤CRCL<90ML/MIN), NO DOSAGE CORRECTION OF VIPIDIA™ IS REQUIRED - RECOMMENDED HIGH DOSE OF VIPIDIA™ FOR PATIENTS WITH IMPAIRED RENAL FUNCTION MODERATE SEVERITY 30≤CRCL<60ML/MIN) IS 12.5MG IT IS RECOMMENDED TO DETERMINE RENAL FUNCTION INDICATORS BEFORE STARTING TAKING THIS DRUG, AND ALSO PERIODICALLY DURING THE TREATMENT PROCESS. METHOD OF APPLICATION ORAL USE. VIPIDIA™ SHOULD BE TAKEN ONCE A DAY, REGARDLESS OF FOOD. THE TABLETS SHOULD BE SWALLOWED WHOLE AND WITH WATER. IF THE PATIENT MISSED A TAKE OF VIPIDIA™, THEY SHOULD TAKE IT IMMEDIATELY AFTER REMEMBERING THE MISSED TAKE. DO NOT TAKE A DOUBLE DOSE OF VIPIDIIA™. ADVERSE EFFECTS BECAUSE THE CLINICAL TRIALS WERE CONDUCTED UNDER VERY DIFFERENT CONDITIONS, IT IS NOT POSSIBLE TO DIRECTLY COMPARE THE RATES OF ADVERSE REACTIONS OBSERVED IN THE CLINICAL TRIALS OF THE DRUG WITH THE RATES OBSERVED IN CLINICAL TRIALS OF OTHER DRUGS, AND SUCH FREQUENCIES MAY NOT ALWAYS REFLECT THE SITUATION OF USING THE DRUG ON PRACTICE. IN A POINTED ANALYSIS OF 14 CONTROLLED CLINICAL TRIALS, THE OVERALL RATE OF ADVERSE EVENTS WAS 73% IN PATIENTS RECEIVED ALOGLIPTIN 25 MG, 75% IN THE PLACEBO GROUP, AND 70% IN THE OTHER GROUP COMPARATIVE DRUG. OVERALL, THE RATE OF TREATMENT DISCONTINUATION DUE TO ADVERSE REACTIONS WAS 6.8% IN THE ALOGLIPTINE 25MG GROUP, 8.4% IN THE PLACEBO GROUP, OR 6.2% IN THE OTHER ACTIVE COMPARITOR GROUP. REPORTS OF ADVERSE ADVERSE REACTIONS EXCEEDING 4% HAVE BEEN RECORDED IN PATIENTS WHO RECEIVED ALOGLIPTINE: NASOPHARINGITIS, HEADACHE, UPPER RESPIRATORY TRACT INFECTIONS. THE FOLLOWING ADVERSE REACTIONS ARE DESCRIBED IN THE SPECIAL INSTRUCTIONS SECTION: - PANCREATITIS - HYPERSENSITIVITY REACTIONS - EFFECTS ON THE LIVER - ARTHROALGIA HYPOGLYCEMIA CASES OF HYPOGLYCEMIA WERE RECORDED BASED ON GLU LEVEL VALUES GOAT BLOOD AND/OR CLINICAL SIGNS AND SYMPTOMS OF HYPOGLYCEMIA. IN THE MONOTHERAPY STUDY, THE RATE OF HYPOGLYCEMIA WAS OBSERVED IN 1.5% AND 1.6% OF PATIENTS IN THE ALOGLIPTINE AND PLACEBO GROUPS, RESPECTIVELY. THE USE OF ALOGLIPTIN AS AN ADDITION TO GLYBURIDE OR INSULIN THERAPY DOES NOT INCREASE THE INCIDENCE OF HYPOGLYCEMIA COMPARED WITH PLACEBO. IN A MONOTHERAPY STUDY COMPARING ALOGLIPTIN WITH SULPHONYLUREAS IN ELDERLY PATIENTS, THE RATE OF HYPOGLYCEMIA WAS 5.4% AND 26% IN THE ALOGLIPTIN AND GLIPIZIDE GROUPS. POST-MARKETING EXPERIENCE DURING POST-MARKETING USE OF ALOGLIPTIN, THE FOLLOWING ADVERSE REACTIONS HAVE BEEN IDENTIFIED - HYPERSENSITIVITY (ANAPHYLAXIA, ANIO-EDEMA, RASH, HURTICA), SEVERE SKIN ADVERSE REACTIONS (INCLUDING STEVENS-JOHNSON SYNDROME), INCREASED LIVER ENZYME LEVELS, FULMINANT LIVER FAILURE, SEVERE AND LEADING TO DISABILITIES ARHRALGIA AND ACUTE PANCREATITIS, DIARRHEA, CONSTIPATION, NAUSEA, AND INTESTINAL OBSTRUCTION. SINCE THESE ADVERSE REACTIONS HAVE BEEN REPORTED VOLUNTARILY IN A POPULATION OF UNDETERMINED SIZE, IT IS NOT POSSIBLE TO RELIABLY ESTIMATE THEIR FREQUENCY, THEREFORE THE FREQUENCY IS CLASSIFIED AS UNKNOWN. CONTRAINDICATIONS - HYPERSENSITIVITY TO ALOGLIPTIN OR TO ANY EXCIENTIST - HISTORY OF SEVERE HYPERSENSITIVITY REACTIONS, INCLUDING ANAPHYLACTIC REACTION, ANAPHYLACTIC SHOCK AND ANGIOEDEMA, TO ANY OMU DIPEPTIDYLPEPTIDASE-4 INHIBITOR - TYPE 1 DIABETES MELLITUS - ACUTE OR CHRONIC METABOLIC ACIDOSIS, INCLUDING DIABETIC KETOACIDOSIS ( DIABETIC KETOACIDOSIS MUST BE TREATED WITH INSULIN) - PATIENTS WITH SEVERE LIVER FUNCTION IMPAIRMENTS (CLASS C ON THE CHILD-PUGH SCALE) HAVE NOT BEEN STUDYED, THEREFORE THE PRESCRIPTION OF VIPIDIA™ IS NOT RECOMMENDED FOR SUCH PATIENTS OVANO - SEVERE RENAL FUNCTION DISORDERS (15≤CRCL<30ML/MIN) OR WITH END STAGE CHRONIC RENAL FAILURE (CRCL<15ML/MIN OR WHEN DIALYSIS IS REQUIRED) - AGE UNDER 18 YEARS - PREGNANCY DRUG INTERACTIONS VIPIDIYAM IS MAINLY EXCRETED FROM THE BODY BY THE KIDNEYS AND ONLY IN SIGNIFICANCE THE TELIVE DEGREE IS METABOLIZED BY THE CYTOCHROME ENZYME SYSTEM (CYP) P450. THE STUDIES HAVE NOT REVEALED ANY SIGNIFICANT INTERACTIONS WITH CYTOCHROME SUBSTRATES OR INHIBITORS OR WITH OTHER DRUGS THAT ARE EXCLUDED FROM THE BODY THROUGH THE KIDNEY. IN VITRO DRUG INTERACTION ASSESSMENT IN VITRO STUDIES SUGGEST THAT ALOGLIPTIN DOES NOT INDUCATE CYP1A2, CYP2B6, CYP2C9, CYP2C19 AND CYP3A4, NOR INHIBIT CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 AND CYP2D6 IN THE CLINICAL SKI SIGNIFICANT CONCENTRATIONS. ASSESSMENT OF DRUG INTERACTIONS IN VIVO INFLUENCE OF ALOGLIPTIN ON OTHER DRUGS IN CLINICAL STUDIES NO INFLUENCE OF ALOGLIPTIN ON THE PHARMACOKINETIC PARAMETERS OF DRUGS WHICH ARE METABOLIZED FROM BY CYP ENZYMES OR ARE EXCLUDED UNCHANGED. NO DOSE ADJUSTMENT OF VIPIDIA™ IS RECOMMENDED BASED ON THE RESULTS OF THE PHARMACOKINETIC STUDIES DESCRIBED. THE EFFECT OF OTHER MEDICINES ON THE PHARMACOKINETICS OF ALOGLIPTIN NO CLINICALLY SIGNIFICANT CHANGES IN PHARMACOKINETICS OBSERVED WHEN USING ALOGLIPTINA CONTAINED WITH METFORMIN, CIMETIDINE GEMFIBROZIL (CYP2C8/9), PIOGLITASE ONOM (CYP2C8), FLUCONAZOLE (CYP2C9), KETOCONAZOLE (CYP3A4), atorvastatin (CYP3A4), CYCLOSPORINE , DIGOXIN. SPECIAL INSTRUCTIONS FOR PANCREATITIS AFTER STARTING TREATMENT WITH VIPIDIIA™, PATIENTS SHOULD BE CAREFULLY MONITORED FOR SYMPTOMS AND SIGNS OF PANCREATITIS. IF PANCREATITIS IS SUSPECTED, VIPIDIA™ SHOULD BE IMMEDIATELY DISCONTINUED AND APPROPRIATE TREATMENT PROVIDED. THERE IS NO KIND OF WHETHER PATIENTS WITH A HISTORY OF PANCREATITIS ARE AT AN INCREASED RISK OF PANCREATITIS WHEN USING VIPIDIUM™. HYPERSENSITIVITY REACTIONS SERIOUS HYPERSENSITIVITY REACTIONS HAVE BEEN REPORTED IN PATIENTS TREATED WITH VIPIDIA™ IN THE POST-MARKETING PERIOD. THESE REACTIONS INCLUDE ANAPHYLACTIC REACTIONS, ANGIOEDEMA, AND EXFOLIATIVE SKIN REACTIONS SUCH AS STEVENS-JOHNSON SYNDROME; If there are suspicions of a serious reaction of high sensitivity, it is necessary to suspend the use of Vipidius ™, to evaluate other potential causes of the complication and prescribe alternative treatment of diabetes. THE DRUG SHOULD BE USED WITH CAUTION IN PATIENTS WITH A HISTORY OF ANGIOEDEMA TO OTHER DPP-4 INHIBITORS, SINCE IT IS UNKNOWN WHETHER SUCH PATIENTS MAY BE PRISPOSITED TO ANgioEDEMA WITH OTHER DPP-4 INHIBITORS USING THE DRUG VIPIDIA™. EFFECTS ON THE LIVER POST-MARKETING REPORTS HAVE REPORTED CASES OF LIVER FAILURE WITH FATAL AND NON-FATAL OUTCOME IN PATIENTS TAKEN VIPIDIA™, ALTHOUGH THEY CONTAIN INSUFFICIENT INFORMATION REQUIRED FOR THE LIVER BECOMING PROBABLE CAUSE. DURING GLYCEMIC CONTROL, PATIENTS EXPERIENCED INCREASES IN SERUM ALANINE AMINOTRANSFERASE (ALT) TO A LEVEL THAT WAS MORE THAN THREE TIMES THE UPPER LIMIT OF NORMAL RANGE (ULR): 1. 3% OF PATIENTS RECEIVING ALOGLIPTIN AND 1.7% OF PATIENTS RECEIVING ALL OTHER COMPARATIVE DRUGS. LIVER FUNCTION TESTS SHOULD BE PERFORMED IN PATIENTS WHO EXPERIENCE SYMPTOMS THAT MAY INDICATE LIVER DAMAGE, INCLUDING FATIGUE, ANOREXIA, DISCOMFORT IN THE UPPER RIGHT ABDOMINAL AREA, DARKENED URINE, OR FUNCTION ELTUKHA. IF THE PATIENT EXPERIENCES CLINICALLY SIGNIFICANT ELEVATIONS OF LIVER ENZYMES, AND IF THE LIVER FUNCTION TEST ABNORMALITY REMAINS PERSISTENT OR WORSES, THE USE OF VIPIDIA™ AND PRO MUST BE CONTINUED CONDUCT AN INVESTIGATION TO ESTABLISH THEIR PROBABLE CAUSE. IN SUCH PATIENTS, VIPIDIIA™ SHOULD NOT BE RECONTINUED WITHOUT OBTAINING ANOTHER EXPLANATION FOR THE ABNORMAL LIVER FUNCTION TEST. COMBINED USE WITH OTHER HYPOGLYCEMIC DRUGS AND THE RISK OF HYPOGLYCEMIA INSULIN AND INSULIN SECRETOGENS, SUCH AS SULPHONYLUREAS, ARE KNOWN TO CAUSE HYPOGLYCEMIA. THEREFORE, A LOWER DOSE OF INSULIN OR INSULIN SECRETOGEN MAY BE REQUIRED TO MINIMIZE THE RISK OF HYPOGLYCEMIA WHEN USED IN COMBINATION WITH VIPIDIA™. ARTHROALGIA POST-MARKETING CASES OF JOINT PAIN HAVE BEEN REPORTED IN PATIENTS TAKEN DIPEPTIDILEPEPTIDASE-4 (DPP-4) INHIBITORS. THE TIME OF ONSTANCE OF ARTHROALGIA SYMPTOMS AFTER THE START OF DRUG THERAPY RANGED FROM ONE DAY TO SEVERAL YEARS. When serious and constant pain in the joints, it is necessary to consider the use of the inhibitor of the diphthydylpeptidase-4 (DPP-4) inhibitor as a possible cause of severe joint pain and stop taking the drug, if necessary. The macro -vascular results in clinical studies did not obtain final and convincing evidence of a decrease in macro -vascular risk when using the drug Vipidius ™ or any other antiabetic drug. A randomized, double blind, placebo-controlled study was carried out by determining cardiovascular outcomes (“Examine”) in 5 380 patients. The test compared the risk of significant cardiovascular complications between alogliptin and placebo when they add to standard diabetes and atherosclerotic vascular disease. The study includes patients who were insufficient glycemic control at the initial level, and who were hospitalized due to complications of acute coronary syndrome (for example, acute myocardial infarction or unstable angina pectoris) within 15 to 90 days before randomization. The average age of patients was 61 years old, and patients were diagnosed with “type 2 diabetes” for approximately 9 years, 87% previously suffered myocardial infarction, and the average HBA1 8.0%. The study showed that aloglintin does not increase the risk of significant cardiovascular complications compared to placebo. In the Aloglipna group in 11.3% of patients, there was a risk of significant cardiovascular complications compared with 11.8% of patients in the placebo group. The use in special groups of patients reproductive function limited data on the use of vipidium ™ in pregnant women is insufficient to determine the risk of significant congenital defects or miscarriage associated with the drug. There are risks for the mother and fetus associated with poorly controlled diabetes during pregnancy. As a precaution, it is preferable to avoid the use of aloglinin during pregnancy. Poorly controlled diabetes during pregnancy increases the risk of diabetic ketoacidosis in mothers, preeclampsia, spontaneous miscarriage, premature birth, stillbirth and complications during childbirth. Poorly controlled diabetes increases the risk for the fetus of significant congenital defects, stillbirth and incidence associated with macrosomia. The penetration of alogliptine through the placenta and entering the fetus was observed after oral administration in pregnant rats. The period of lactation in studies, it was shown that alogliptin penetrates into breast milk in rats that carry out breastfeeding in a ratio of 2: 1 to plasma concentration. It is not known about the possibility of penetration of alogliptine into breast milk in humans. The risk cannot be excluded for a baby on breastfeeding. Vipidia ™ must be used with caution in women carrying out breastfeeding. It is necessary to take into account the benefits of breastfeeding for development and health together the clinical need for the mother for Vipidius ™, as well as any potential undesirable effects of Vipidium ™ for babies receiving breastfeeding or the main state of the mother. Patients of childhood safety and the effectiveness of the use of Vipidius ™ in children and adolescents under 18 are not established. There are no data on the use of Vipidia ™ drug in this category of patients. Elderly patients (≥ 65 years old): among all patients (n = 9052) who participated in clinical safety studies and efficiency of alogliptin, 2257 (24.9%) of the patient were 65 years old and older and 386 (4.3%) the patient was Age 75 years and older. In general, there were no differences in safety and efficiency between patients with an age of 65 years and older and more young patients. Although in this clinical experience in the use of the drug, differences in reaction to treatment between elderly patients and patients of a younger age were not revealed, one cannot exclude higher sensitivity in some elderly people. Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms, Vipidius ™ does not have a significant effect on the ability to drive a car and other mechanisms. Nevertheless, it is necessary to warn patients about the risk of developing hypoglycemia, especially when using the drug in combination with a sulfonymic sulfonymic derivative, insulin, or in combination with thiazolidindyn and metformin. An overdose of the maximum doses of alogliptine in clinical studies was 800 mg once in healthy volunteers and 400 mg once a day for 14 days in patients with type 2 diabetes, which is 32 and 16 times, respectively, exceeds the maximum recommended therapeutic dose of 25 mg. When using these doses, no serious undesirable reactions were observed. In the case of an overdose with Vipidius ™, it is advisable to remove a non-aborched substance from the gastrointestinal tract and provide the necessary medical observation, as well as symptomatic therapy. In 3 hours of hemodialysis, it is possible to remove about 7% alogliptine. Thus, the feasibility of hemodialysis during an overdose is unlikely. Data on the excretion of alogliptin by peritoneal dialysis is absent. The output form and packaging of 14 tablets are placed in a contour cell package of aluminum foil. 2 contour packages along with instructions for medical use in the state and Russian languages are invested in a pack of cardboard. Storage conditions are stored at a temperature of not higher than 25 ºС. KEEP OUT OF THE REACH OF CHILDREN! The shelf life of 3 years is not used after the expiration date indicated on the package. Conditions of the vacation from pharmacies according to the recipe manufacturer Takodeda Ayland Limited, Ireland name and country of the owner of the registration certificate of Takeded Farmasyutikals USA, Ink., USA Name and country of the organization of Taededa Ayland Limited, Ireland, the address of the organization that accepts in the territory of the Republic of Kazakhstan Claims of Consumer Quality Products (goods) and responsible for post -passing monitoring of the safety of the drug "Takoded Kazakhstan" in Almaty, ul. Shashkin 44
