Evogliptin belongs to the class of DPP-4 inhibitors (DPP-4), or to the class of gliptins. In clinical practice gliptins have proved to be safe and effective oral drugs reducing glucose level in type 2 diabetes patients.
This drug is a prescribed medicine. It can be dispensed on a doctor's prescription only. There are contraindications. Please read the patient information leaflet. Do not use the medicinal agent if it was not prescribed by your treating physician. Always follow the patient information leaflet and your doctor’s recommendations.
Pharmacokinetics
Absorption
Bioavailability of evogliptin after single oral administration is more than 50%. Concomitant administration of evogliptin with food ingestion does not affect the absorption. After single oral administration of evogliptin at dose of 1.25–60 mg, time to reach maximum concentration (t Cmax) among healthy patients was 3–5.5 hours. After single oral administration of evogliptin at dose of 5 mg in healthy volunteers, its maximum plasma concentration (Cmax) was 5.6 ± 1.3 μg/l. Dose increase results in the increase of Cmax and the area under the curve “concentration-time” (AUClast).
After multiple oral administration of evogliptin at dose of 5 mg, 10 mg, and 20 mg once daily, a steady state was reached by the third day of administration. After reaching the steady state, Cmaxof evogliptin was observed in 4-5 hours after the drug administration.
Distribution
Distribution of evogliptin between whole blood and plasma is almost the same, about 46% of evogliptin binds with plasma proteins.
Non-clinical studies established that evogliptin is quickly distributed in body tissues (excluding heart tissue and mesentery). Evogliptin was detected in the blood stream of foetus, and it was excreted in milk of lactating rats.
Metabolism
The most of evogliptin circulating in blood is the intact drug (more than 80%). Biotransformation process results in 5 metabolites which have no DPP-4 inhibiting activity and are detected mostly in plasma and urine. Evogliptin is mostly metabolised with CYP3A4. In vitro studies showed that evogliptin did not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 enzymes and did not induce CYP1A2, 2B6, 3A4 enzymes.
Excretion
After single administration of evogliptin at dose of 1.25–60 mg, the average elimination half-life (t1/2) was from 32.5 to 39.8 hours. After multiple administration, the average elimination half-life was from 32.9 to 38.8 hours.
About 46.1% of the dose taken by healthy adult volunteers is excreted via urine and 42.8% of the dose is excreted via faeces (including metabolites).
Patients with Renal Insufficiency
The increase of AUClastand Cmax after single administration of evogliptin in patients with renal impairment was proportionate to the degree of renal function reduction. Evogliptin exposition, which is determined via AUClast, increased by 1.32 in patients with estimated glomerular filtration rate (e-GFR) from 30 to 59 ml/min and by 1.52 in patients with e-GFR from 15 to 29 ml/min (as compared to the data of healthy volunteers). Cmaxwas 1.80-fold higher in patients with e-GFR from 30 to 59 ml/min and 1.98-fold higher in patients with e-GFR from 15 to 29 ml/min (as compared to the data of healthy volunteers).
The increase of DPP-4 activity inhibition in patients with renal impairment was observed: the duration of period with ≥ 80% of DPP-4 inhibition in plasma positively correlated with the renal function impairment (the lower was the e-GFR, the longer was the period).
Sex Differences
Sex of patients has no clinically significant impact on the evogliptin concentration in plasma.
Commercial Name: Evodin®
International Non-Proprietary Name (INN): evogliptin
Pharmaceutical Form: film-coated tablets
Composition
1 film-coated tablet contains:
active ingredient: evogliptin tartrate 6.869 mg (equal to evogliptin 5.0 mg);
excipients: mannitol, pregelatinised starch, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, colloidal silica, magnesium stearate;
composition of film coat: OPADRY® 03В28796, white (hydroxypropyl methylcellulose, titanium dioxide, macrogol / polyethylene glycol)
Description
White to slightly yellow round film-coated tablets with EVO engraved on one side. Nearly white core in a cross section.
Pharmacotherapeutic Group: Hypoglycemic agent – dipeptidyl peptidase-4 inhibitor.
ATC: А10ВН07
Pharmacological Properties
Pharmacodynamics
Mechanism of action
Evogliptin is an active selective serine protease dipeptidyl peptidase-4 (DPP-4) inhibitor which inactivates incretin hormones (incretins): glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both incretins maintain glucose homeostasis. GLP-1 and GIP are secreted in the intestinal tract, their low basal concentration increases in response to food ingestion.
Under physiological conditions, incretin activity is limited by DPP-4 (GLP-1 and GIP are quickly hydrolysed by the DPP-4 activity with the formation of inactive products). At low blood glucose levels, the incretins do not affect the insulin and glucagon secretion. In case of normal range or increased blood glucose levels, GLP-1 and GIP raise the synthesis of insulin as well as its pancreatic beta-cells secretion viaintracellular signalling pathways associated with cyclic adenosine monophosphate (AMP). Besides, GLP-1 decreases glucagon secretion by alpha cells of pancreas. Decrease in glucagon concentration with underlying increase of insulin concentration contributes to the reduction of hepatic glucose production resulting in lower blood glucose levels. Evogliptin reversibly binds the DPP-4 preventing the hydrolysis of incretins and steadily increasing concentration of active forms of GLP-1 and GIP. Change in insulin and glucagon secretion in patients with type 2 diabetes mellitus (T2DM) with hyperglycaemia results in the significant decrease of haemoglobin A1c (HbA1c) levels and plasma glucose concentration.
Evogliptin provides the lower risk of hypoglycaemia when comparing to other oral hypoglycaemic drugs. Unlike sulfonylurea and thiazolidinediones (glitazones) which administration is often associated with increase in body weight during therapy, evogliptin does not affect the body weight.
Therapeutic indications
As an adjunct to diet and exercises to improve glycaemic control in type 2 diabetes mellitus in:
- monotherapy;
- combination with metformin.
- Gastrointestinal tract disorders: gastritis.
- Infections and infestations: nasopharyngitis.
- Musculoskeletal and connective tissue disorders: arthralgia.
- Skin and subcutaneous tissue disorders: contact dermatitis.
- General disorders and administration site conditions: toothache.
- Gastrointestinal tract disorders: dyspepsia, diarrhoea, gastritis.
- Infections and infestations: rhinopharingitis, upper respiratory tract infections.
- Skin and subcutaneous tissue disorders: itching.
Contraindications
Hypersensitivity to evogliptin, and/or other DPP-4 inhibitors, and/or any excipient of the drug.
Type 1 diabetes mellitus.
Diabetic ketoacidosis.
Pregnancy and lactation.
Age under 18 years (due to lack of information on efficacy and safety of evogliptin administration in children and young adults under 18 years of age).
Grade II-IV congestive heart failure (CHF) as per the classification of New York Heart Association (NYHA).
Special warnings and precautions for use
- In patients with grade I CHF as per the NYHA classification;
- In patients with moderate and severe renal insufficiency;
- In patients with hepatic insufficiency;
- In patients with a history of acute pancreatitis;
- Elderly patients.
Use during Pregnancy and Lactation
Administration of evogliptin during pregnancy is contraindicated. No controlled randomised studies of evogliptin efficacy and safety in pregnant women were carried out. Results of animal studies showed that evogliptin was detected in the blood stream of fetus across the placenta.
There is no data on evogliptin excretion in human milk. Evogliptin was detected in the blood stream of foetus, and it was excreted in milk of lactating rats.Evogliptin administration during lactation is contraindicated.
Method of Administration and Dosage
Adults
Oral administration regardless of food ingestion. Recommended dose of Evodin® is 5 mg once daily as monotherapy or in combination with metformin; maximum daily dose of Evodin® is 5 mg.
If one or more doses are missed, a patient should take the drug as soon as he/she remembers of it. Further drug administration should be as usual. Double dose should not be taken on the same day.
Elderly Patients
Evogliptin administration in elderly patients is not studied well. Since elderly patients usually experience diminished physiological functions, including hepatic and renal impairment, special care should be taken in case of drug administration and the patient’s condition should be monitored.
Children and Young Adults under 18 Years of Age
Evodin® efficacy and safety in children and young adults under 18 years of age have not been established.
Undesirable effects
Monotherapy
In clinical studies (phase II-III), frequency of adverse events development and their severity were comparable in evogliptin and placebo groups. Also, during clinical trials, no risks associated with long (52 weeks) evogliptin administration were observed.
During evogliptin administration at dosage 5 mg as monotherapy (during 12, 24, and 52 weeks), the following adverse reactions were observed:
Combination with metformin
In two controlled clinical trials of evogliptin 5 mg in case of administration of evogliptin at dose of 5 mg in combination with metformin during 24 and 52 weeks the adverse events reported with a frequency of 3% or higher were:
Hypoglycaemia
All cases of hypoglycaemia registered during the 24-week study of monotherapy and combined therapy were mild and did not require any help of other people.
No clinically significant changes of vital signs were identified in patients taken evogliptin.
Thus, no confirmed safety risks associated with evogliptin administration were observed during the clinical studies.
If any of the adverse reactions specified in the instruction for medical use worsen or any other adverse reactions not mentioned in the instruction emerge, a doctor should be informed thereof.
Overdose
In clinical trials, single dose of up to 60 mg daily was administered in healthy adults. In case of an overdose, perform symptomatic therapy (e.g., remove unabsorbed substance from the gastrointestinal tract, conduct clinical monitoring including electrocardiogram), and perform supportive therapy depending on the patient’s condition.
Interaction with Other Medicinal Preparations
The clinical trials showed that evogliptin is mostly metabolised with CYP3A4 isoenzyme. According to the non-clinical studies, evogliptin neither inhibits CYP1A2, 2B6, 2С8, 2С9, 2С19, 2D6, 3А4 nor induces CYP1A2, 2В6, 3А4. Thus, interaction of evogliptin with other drugs which are a substrate for these enzymes is hardly probable. Although in vitro studies showed that evogliptin is the substrate of p-glycoprotein (P-gp) and the weak substrate of breast cancer resistance protein, it does not inhibit the transfer with these transporters. Besides, evogliptin did not act as OAT1, OAT3, OCT2, OATP181 and OATP183 substrate and did not inhibit them.
Thus, it is hardly probable that evogliptin at therapeutic dose can interact with the drugs acting as the substrate of the aforementioned transporters.
Evogliptin Interaction with Metformin
Concomitant administration of evogliptin 5 mg and metformin 1,000 mg twice daily until steady concentration was reached did not show clinically significant changes in evogliptin and metformin pharmacokinetic parameters. The areas under the curve “concentration-time” determined in steady state did not differ both after concomitant administration of evogliptin and metformin (T) and only evogliptin (R) – AUC(T/R) ratio = 1.02 (90% CI 0.99–1.06) and after concomitant administration of evogliptin and metformin (T) and only metformin (R) (AUC(T/R) ratio = 0.94 (90% CI 0.89–0.98). The maximum drug concentration values determined in steady state did not differ both after concomitant administration of evogliptin and metformin (T) and only evogliptin (R) (Cmax(T/R) ratio = 1.06 (90% CI 1.01–1.12) and after concomitant administration of evogliptin and metformin (T) and only metformin (R) (AUC(T/R) ratio = 0.84 (90% CI 0.79–0.89). The DDP-4 inhibition degree was comparable in case of concomitant administration of evogliptin and metformin and administration of only evogliptin at dose of 5 mg.
However, concomitant administration of evogliptin and metformin showed the tendency towards the increase of active GLP-1 concentration as compared to the administration of only evogliptin or only metformin.
Evogliptin Interaction with Clarithromycin
Multiple administration of potential CYP3A4 inhibitor clarithromycin at daily dose of 1,000 mg until the steady concentration was reached and single administration of evogliptin at dose of 5 mg showed a 2.17-fold increase of evogliptin Cmax and a 2.02-fold increase of evogliptin AUC. Precautions should be taken since evogliptin pharmacokinetic parameters may increase in case of its concomitant administration with CYP3A4 inhibitor.
Evogliptin Interaction with Rifampicin
Multiple administration of potential CYP3A4 inducer rifampicin at daily dose of 600 mg until the steady concentration was reached and single administration of evogliptin at dose 5 mg did not show significant changes of evogliptin Cmaxvalues, however showed the decrease of AUC by 63% as compared to the monotherapy with evogliptin.
Special Precautions
Congestive Heart Failure
When treating patients with grade I CHF as per the NYHA classification, precautions should be taken due to limited practical experience in evogliptin administration in such patients. Administration of evogliptin is contraindicated in patients with grade II-IV CHF as per the NYHA classification due to the absence of clinical experience in administration of the drug in such patients.
Renal Impairment
It is confirmed that about 46.1% of the administered dose in healthy adults was excreted via urine and 42.8% of the dose was excreted via faeces (including metabolites). Due to the risk of keeping the elevated level of intact evogliptin in blood of patients with moderate and severe renal impairment, precautions should be taken during evogliptin administration and the renal function should be controlled. Due to the absence of clinical experience in evogliptin administration in patients with end-stage renal disease who need dialysis, administration of evogliptin in such patients is not recommended.
Hepatic Impairment
No studies in patients with hepatic impairment were conducted. No data on adjusting the evogliptin dose are available. Therefore, when treating such patients precautions should be taken.
Acute Pancreatitis
There is no report of acute pancreatitis in patients administered with evogliptin. However, acute pancreatitis has been reported in patients treated with DPP-4 inhibitors. Thus, characteristic symptoms of acute pancreatitis such as consistent and severe abdominal pain should be informed to patients. If pancreatitis is suspected after administration of evogliptin, the administration of evogliptin should be discontinued and evogliptin should not be re-administered. When treating patients with medical history of pancreatitis, precautions should be taken.
Impact on the Ability to Drive Vehicles
Administration of evogliptin may provoke dizziness which affects the performance of potentially dangerous activities requiring careful attention and quick reactions (motor vehicle driving, working with moving mechanisms).
Nature and contents of container
Film-coated tablets, 5 mg
7 or 14 tablets in a PVC/PCTFE and aluminium foil blister. 4 blisters containing 7 tablets or 2 blisters containing 14 tablets packed in an outer carton together with the instruction for medical use.
Storage Conditions
In a dark place at temperature below 25°C.
Keep out of reach of children!
Shelf Life
2 years.
Do not use after shelf-life expiration date indicated on the package.
Pharmacy Prescription Terms
Available on prescription.
GEROPHARM
Hot-line: 8-800-333-4376 (free call across the Russian Federation)
Please read the patient information leaflet for detailed information on the drug.
